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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <title>The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role | Journal of Experimental & Clinical Cancer Research | Full Text</title> <meta name="citation_abstract" content="Streptococcus bovis (S. bovis) bacteria are associated with colorectal cancer and adenoma. S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms."/> <meta name="journal_id" content="13046"/> <meta name="dc.title" content="The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role"/> <meta name="dc.source" content="Journal of Experimental & Clinical Cancer Research 2011 30:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="BioMed Central"/> <meta name="dc.date" content="2011-01-20"/> <meta name="dc.type" content="ReviewPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2011 Abdulamir et al; licensee BioMed Central Ltd."/> <meta name="dc.rights" content="2011 Abdulamir et al; licensee BioMed Central Ltd."/> <meta name="dc.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="dc.description" content="Streptococcus bovis (S. bovis) bacteria are associated with colorectal cancer and adenoma. S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms."/> <meta name="prism.issn" content="1756-9966"/> <meta name="prism.publicationName" content="Journal of Experimental & Clinical Cancer Research"/> <meta name="prism.publicationDate" content="2011-01-20"/> <meta name="prism.volume" content="30"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="ReviewPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="13"/> <meta name="prism.copyright" content="2011 Abdulamir et al; licensee BioMed Central Ltd."/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://jeccr.biomedcentral.com/articles/10.1186/1756-9966-30-11"/> <meta name="prism.doi" content="doi:10.1186/1756-9966-30-11"/> <meta name="citation_pdf_url" content="https://jeccr.biomedcentral.com/counter/pdf/10.1186/1756-9966-30-11"/> <meta name="citation_fulltext_html_url" content="https://jeccr.biomedcentral.com/articles/10.1186/1756-9966-30-11"/> <meta name="citation_journal_title" content="Journal of Experimental & Clinical Cancer Research"/> <meta name="citation_journal_abbrev" content="J Exp Clin Cancer Res"/> <meta name="citation_publisher" content="BioMed Central"/> <meta name="citation_issn" content="1756-9966"/> <meta name="citation_title" content="The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role"/> <meta name="citation_volume" content="30"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2011/12"/> <meta name="citation_online_date" content="2011/01/20"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="13"/> <meta name="citation_article_type" content="Review"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1186/1756-9966-30-11"/> <meta name="DOI" content="10.1186/1756-9966-30-11"/> <meta name="size" content="324625"/> <meta name="citation_doi" content="10.1186/1756-9966-30-11"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1186/1756-9966-30-11&api_key="/> <meta name="description" content="Streptococcus bovis (S. bovis) bacteria are associated with colorectal cancer and adenoma. S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms."/> <meta name="dc.creator" content="Abdulamir, Ahmed S"/> <meta name="dc.creator" content="Hafidh, Rand R"/> <meta name="dc.creator" content="Bakar, Fatimah Abu"/> <meta name="dc.subject" content="Cancer Research"/> <meta name="dc.subject" content="Immunology"/> <meta name="dc.subject" content="Apoptosis"/> <meta name="dc.subject" content="Oncology"/> <meta name="citation_reference" content="citation_journal_title=JAMA, 2; citation_title=Short-term therapy for streptococcal infective endocarditis. 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S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1186%2F1756-9966-30-11/MediaObjects/13046_2010_Article_431_Fig1_HTML.jpg"/> <script type="application/ld+json">{"mainEntity":{"headline":"The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role","description":"Streptococcus bovis (S. bovis) bacteria are associated with colorectal cancer and adenoma. S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms.","datePublished":"2011-01-20T00:00:00Z","dateModified":"2011-01-20T00:00:00Z","pageStart":"1","pageEnd":"13","license":"http://creativecommons.org/licenses/by/2.0","sameAs":"https://doi.org/10.1186/1756-9966-30-11","keywords":["Colorectal Cancer","Adenoma","Endocarditis","Infective Endocarditis","Colorectal Tumor","Cancer Research","Immunology","Apoptosis","Oncology"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2F1756-9966-30-11/MediaObjects/13046_2010_Article_431_Fig1_HTML.jpg"],"isPartOf":{"name":"Journal of Experimental & Clinical Cancer Research","issn":["1756-9966"],"volumeNumber":"30","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"BioMed 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class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Review</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2011-01-20">20 January 2011</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">The association of <i>Streptococcus bovis/gallolyticus</i> with colorectal tumors: The nature and the underlying mechanisms of its etiological role</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ahmed_S-Abdulamir-Aff1" data-author-popup="auth-Ahmed_S-Abdulamir-Aff1" data-author-search="Abdulamir, Ahmed S" data-corresp-id="c1">Ahmed S Abdulamir<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Rand_R-Hafidh-Aff1" data-author-popup="auth-Rand_R-Hafidh-Aff1" data-author-search="Hafidh, Rand R">Rand R Hafidh</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Fatimah_Abu-Bakar-Aff1" data-author-popup="auth-Fatimah_Abu-Bakar-Aff1" data-author-search="Bakar, Fatimah Abu">Fatimah Abu Bakar</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Journal of Experimental & Clinical Cancer Research</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 30</b>, Article number: <span data-test="article-number">11</span> (<span data-test="article-publication-year">2011</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">37k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">28 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/10.1186/1756-9966-30-11/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </div> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p><i>Streptococcus bovis</i> (<i>S. bovis</i>) bacteria are associated with colorectal cancer and adenoma. <i>S. bovis</i> is currently named <i>S. gallolyticus</i>. 25 to 80% of patients with <i>S. bovis/gallolyticus</i> bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of <i>S. bovis/gallolyticus</i>. The presence of <i>S. bovis/gallolyticus</i> bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of <i>S. gallolyticus</i> with colorectal tumors and direct colonization of <i>S. gallolyticus</i> in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of <i>S. bovis/gallolyicus</i> association with colorectal tumors and analyze the possible underlying mechanisms.</p></div></div></section> <section data-title="Introduction & statement of the problem"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction & statement of the problem</h2><div class="c-article-section__content" id="Sec1-content"><p>One of the bacterial agents that has been found to be regularly associated with colorectal cancer is <i>Streptococcus bovis</i> (<i>S. bovis</i>). <i>S. bovis</i> has been shown to have important impact on health since 25 to 80% of patients with <i>S. bovis</i> bacteremia have colorectal tumors and the incidence of association of colonic neoplasia with <i>S. bovis</i> endocarditis has been shown to be 18 to 62% [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Wilson WR, Thompson RL, Wilkowske CJ, Washington JA, Giuliani ER, Geraci JE: Short-term therapy for streptococcal infective endocarditis. Combined intramuscular administration of penicillin and streptomycin. JAMA. 1981, 245: 360-363. 10.1001/jama.245.4.360. 2" href="/articles/10.1186/1756-9966-30-11#ref-CR1" id="ref-link-section-d87701628e394">1</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Gupta A, Madani R, Mukhtar H: Streptococcus bovis endocarditis; a silent sign for colonic tumour. Colorectal Dis. 2010, 12 (3): 164-71. 10.1111/j.1463-1318.2009.01814.x." href="/articles/10.1186/1756-9966-30-11#ref-CR7" id="ref-link-section-d87701628e397">7</a>]. It was shown that 94% of <i>S. bovis</i> bacteremia associated with colorectal cancer was in fact <i>S. bovis</i> biotype I while only 18% was associated with biotype II [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Murray PR, Baron EJ: Manual of clinical microbiology. 2007, Washington, D.C.: ASM Press, 9" href="/articles/10.1186/1756-9966-30-11#ref-CR8" id="ref-link-section-d87701628e406">8</a>]. Later, a new species resembling <i>S. bovis</i> was detected which was named <i>S. gallolyticus</i>[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Osawa R, Fujisawa T, LI S: Streptococcus gallolyticus sp. nov.: gallate degrading organisms formerly assigned to Streptococcus bovis. Syst Appl Microbiol. 1995, 18: 74-78." href="/articles/10.1186/1756-9966-30-11#ref-CR9" id="ref-link-section-d87701628e416">9</a>]. Interestingly, <i>S. bovis</i> biotype I and II/2 isolates were then found to be <i>S. gallolyticus</i>[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Devriese LA, Vandamme P, Pot B, Vanrobaeys M, Kersters K, Haesebrouck F: Differentiation between Streptococcus gallolyticus strains of human clinical and veterinary origins and Streptococcus bovis strains from the intestinal tracts of ruminants. J Clin Microbiol. 1998, 36: 3520-3523." href="/articles/10.1186/1756-9966-30-11#ref-CR10" id="ref-link-section-d87701628e425">10</a>]. Accordingly, <i>S. bovis</i> biotype I was renamed as <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> and biotype II/2 was renamed as <i>S. gallolyticus</i> subspecies <i>pasterianus</i> and <i>S. gallolyticus</i> subspecies <i>macedonicus</i>[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Schlegel L, Grimont F, Ageron E, Grimont PA, Bouvet A: Reappraisal of the taxonomy of the Streptococcus bovis/Streptococcus equinus complex and related species: description of Streptococcus gallolyticus subsp. gallolyticus subsp. nov., S. gallolyticus subsp. macedonicus subsp. nov. and S. gallolyticus subsp. pasteurianus subsp. nov. Int J Syst Evol Microbiol. 2003, 53: 631-645. 10.1099/ijs.0.02361-0." href="/articles/10.1186/1756-9966-30-11#ref-CR11" id="ref-link-section-d87701628e451">11</a>] (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1756-9966-30-11#Tab1">1</a>). <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> bacteria, more than other related taxa, have been found to be constantly associated with underlying colorectal cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Devriese LA, Vandamme P, Pot B, Vanrobaeys M, Kersters K, Haesebrouck F: Differentiation between Streptococcus gallolyticus strains of human clinical and veterinary origins and Streptococcus bovis strains from the intestinal tracts of ruminants. J Clin Microbiol. 1998, 36: 3520-3523." href="/articles/10.1186/1756-9966-30-11#ref-CR10" id="ref-link-section-d87701628e463">10</a>]. Therefore, the term <i>S. bovis/gallolyticus</i> is used in the current review.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 The milestone of the taxonomy of <i>S. bovis/gallolyticus</i> and the closely related members of group D streptococci [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Schlegel L, Grimont F, Ageron E, Grimont PA, Bouvet A: Reappraisal of the taxonomy of the Streptococcus bovis/Streptococcus equinus complex and related species: description of Streptococcus gallolyticus subsp. gallolyticus subsp. nov., S. gallolyticus subsp. macedonicus subsp. nov. and S. gallolyticus subsp. pasteurianus subsp. nov. Int J Syst Evol Microbiol. 2003, 53: 631-645. 10.1099/ijs.0.02361-0." href="/articles/10.1186/1756-9966-30-11#ref-CR11" id="ref-link-section-d87701628e483">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Facklam R: What happened to the streptococci: overview of taxonomic and nomenclature changes. Clin Microbiol Rev. 2002, 15: 613-630. 10.1128/CMR.15.4.613-630.2002." href="/articles/10.1186/1756-9966-30-11#ref-CR127" id="ref-link-section-d87701628e486">127</a>].</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/10.1186/1756-9966-30-11/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Unfortunately, the nature of the association between <i>S. bovis/gallolyticus</i> and colorectal cancer has long been underestimated. It has been controversial whether the association of <i>S. bovis/gallolyticus</i> bacteremia or endocarditis with colorectal tumors is merely a consequence of the gastrointestinal lesion or it could be of etiological nature. Furthermore, there is a growing need to highlight the possible mechanisms that <i>S. bovis/gallolyticus</i> might play in triggering or promoting colorectal cancer, if any. Moreover, the relationship of this bacterium with oncogenic factors, cell growth factors, and pro-inflammatory cytokines has not yet been clarified well. Therefore, the current review was done to scrutinize the nature and the underlying mechanisms of the association of <i>S. bovis/gallolyticus</i> with colorectal cancer.</p></div></div></section><section data-title="Bacterial pathogens and cancer"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Bacterial pathogens and cancer</h2><div class="c-article-section__content" id="Sec2-content"><p>Traditionally, bacterial infections have not been considered a major cause of cancer. However, bacteria have been linked to cancer by two mechanisms: chronic inflammation and production of carcinogenic metabolites [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Parsonnet J: Bacterial infection as a cause of cancer. Environ Health Perspect. 1995, 103 (Suppl 8): 263-268. 10.2307/3432323." href="/articles/10.1186/1756-9966-30-11#ref-CR12" id="ref-link-section-d87701628e662">12</a>]. It was stated that bacteria in general are thought to contribute to carcinogenesis by the formation of potentially toxic by-products of carbohydrates or bile acid metabolism, as well as hydrolysis of other mutagenic precursors [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Parsonnet J: Bacterial infection as a cause of cancer. Environ Health Perspect. 1995, 103 (Suppl 8): 263-268. 10.2307/3432323." href="/articles/10.1186/1756-9966-30-11#ref-CR12" id="ref-link-section-d87701628e665">12</a>].</p><p>The association of <i>Helicobacter pylori</i> (<i>H. pylori</i>) with gastric cancer is the best studied relationship between a bacterial infection and cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK: Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991, 325: 1127-1131. 10.1056/NEJM199110173251603." href="/articles/10.1186/1756-9966-30-11#ref-CR13" id="ref-link-section-d87701628e677">13</a>]. <i>H. pylori</i> has been recognized as a class I human gastric carcinogen by the International Agency for Research on Cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="WHO: monographs on the evaluation of carcinogenic risks to humans: schistosomes, liver flukes, and Helicobacter pylori. IARC. 1994, 61: 177-240." href="/articles/10.1186/1756-9966-30-11#ref-CR14" id="ref-link-section-d87701628e683">14</a>]. The mechanisms by which bacteria contribute to cancer formation are complex and involve the interplay among chronic inflammation, direct microbial effects on host cell physiology, and changes in tissue stem cell homeostasis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Vogelmann R, Amieva MR: The role of bacterial pathogens in cancer. Curr Opin Microbiol. 2007, 10: 76-81. 10.1016/j.mib.2006.12.004." href="/articles/10.1186/1756-9966-30-11#ref-CR15" id="ref-link-section-d87701628e687">15</a>]. In fact, researchers in the field recently started to be sure that some chronic bacterial infections are associated with tumors formation; so, it might be possible to prevent or treat some forms of cancer if the infectious source was addressed [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Malfertheiner P, Sipponen P, Naumann M, Moayyedi P, Megraud F, Xiao SD, Sugano K, Nyren O: Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol. 2005, 100: 2100-2115. 10.1111/j.1572-0241.2005.41688.x." href="/articles/10.1186/1756-9966-30-11#ref-CR16" id="ref-link-section-d87701628e690">16</a>].</p><p>A marked resurgence of interest in the gastrointestinal commensal flora and local host-microbe interactions was observed since it was recognized that intestinal bacteria could be implicated in the pathogenesis of several inflammatory diseases like Crohn's disease or ulcerative colitis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Teitelbaum JE, Triantafyllopoulou M: Inflammatory bowel disease and Streptococcus bovis. Dig Dis Sci. 2006, 51: 1439-1442. 10.1007/s10620-005-9053-5." href="/articles/10.1186/1756-9966-30-11#ref-CR17" id="ref-link-section-d87701628e696">17</a>]. Both diseases are commonly suspected to result from altered host responses to intestinal bacterial flora [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Shanahan F: Probiotics in inflammatory bowel disease--therapeutic rationale and role. Adv Drug Deliv Rev. 2004, 56: 809-818. 10.1016/j.addr.2003.11.003." href="/articles/10.1186/1756-9966-30-11#ref-CR18" id="ref-link-section-d87701628e699">18</a>], and are associated with cancer risk [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Teitelbaum JE, Triantafyllopoulou M: Inflammatory bowel disease and Streptococcus bovis. Dig Dis Sci. 2006, 51: 1439-1442. 10.1007/s10620-005-9053-5." href="/articles/10.1186/1756-9966-30-11#ref-CR17" id="ref-link-section-d87701628e702">17</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Ekbom A, Helmick C, Zack M, Adami HO: Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet. 1990, 336: 357-359. 10.1016/0140-6736(90)91889-I." href="/articles/10.1186/1756-9966-30-11#ref-CR19" id="ref-link-section-d87701628e705">19</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Chao C, Hellmich MR: Gastrin, inflammation, and carcinogenesis. Curr Opin Endocrinol Diabetes Obes. 2010, 17: 33-39." href="/articles/10.1186/1756-9966-30-11#ref-CR21" id="ref-link-section-d87701628e708">21</a>]. Accordingly, World Health Organization considered bacteria as possible causative agents for cancer development.</p></div></div></section><section data-title="Colorectal cancer and infection"><div class="c-article-section" id="Sec3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec3">Colorectal cancer and infection</h2><div class="c-article-section__content" id="Sec3-content"><p>The incidence of colorectal cancer varies widely among countries. In the developed world, colorectal cancer represents a major public health problem. In the UK and the USA, colorectal cancer is the second most common cancer after breast cancer for women, and prostate or lung cancer for men [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Hewitson P, Glasziou P, Watson E, Towler B, Irwig L: Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol. 2008, 103: 1541-1549. 10.1111/j.1572-0241.2008.01875.x." href="/articles/10.1186/1756-9966-30-11#ref-CR22" id="ref-link-section-d87701628e719">22</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55: 74-108. 10.3322/canjclin.55.2.74." href="/articles/10.1186/1756-9966-30-11#ref-CR25" id="ref-link-section-d87701628e722">25</a>].</p><p>The involvement of intestinal microflora in the pathogenesis of colon cancer has been hypothesized. Many cancers arise from sites of infection, chronic irritation, and inflammation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Miki C, Tanaka K, Toiyama Y, Inoue Y, Uchida K, Mohri Y, Kusunoki M: Comparison of the prognostic value of inflammation-based pathologic and biochemical criteria in patients undergoing potentially curative resection for colorectal cancer. Ann Surg. 2010, 251: 389-390. 10.1097/SLA.0b013e3181cb8b31. author reply 390-381" href="/articles/10.1186/1756-9966-30-11#ref-CR26" id="ref-link-section-d87701628e728">26</a>]. The strongest association of chronic inflammation with malignant diseases is found in inflammatory bowel diseases of colon [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther. 2010, 87: 401-406. 10.1038/clpt.2009.312." href="/articles/10.1186/1756-9966-30-11#ref-CR27" id="ref-link-section-d87701628e731">27</a>] with a lifetime incidence of 10% [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Choi PM, Zelig MP: Similarity of colorectal cancer in Crohn's disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut. 1994, 35: 950-954. 10.1136/gut.35.7.950." href="/articles/10.1186/1756-9966-30-11#ref-CR28" id="ref-link-section-d87701628e734">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Wang D, Dubois RN: The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010, 29: 781-788. 10.1038/onc.2009.421." href="/articles/10.1186/1756-9966-30-11#ref-CR29" id="ref-link-section-d87701628e737">29</a>].</p><p>The gut is colonized by many species of bacteria, and it is nearly impossible to narrow carcinogenesis to one organism, but it is possible that a specific bacterium may cause a favorable microclimate for mutagens to inflict their damage [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Parsonnet J: Bacterial infection as a cause of cancer. Environ Health Perspect. 1995, 103 (Suppl 8): 263-268. 10.2307/3432323." href="/articles/10.1186/1756-9966-30-11#ref-CR12" id="ref-link-section-d87701628e743">12</a>]. Some studies provided evidence that some colorectal cancers might be caused by infectious agents. One group of researchers found that bacterial methyltransferases induce mutations in tumor suppressor genes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Mager DL: Bacteria and cancer: cause, coincidence or cure? A review. J Transl Med. 2006, 4: 14-10.1186/1479-5876-4-14." href="/articles/10.1186/1756-9966-30-11#ref-CR30" id="ref-link-section-d87701628e746">30</a>]. Another group found that some microflora might serve as promoters while others might serve as anti-promoters of colorectal carcinogenesis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Killeen SD, Wang JH, Andrews EJ, Redmond HP: Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system. Br J Cancer. 2009, 100: 1589-1602. 10.1038/sj.bjc.6604942." href="/articles/10.1186/1756-9966-30-11#ref-CR31" id="ref-link-section-d87701628e749">31</a>]. A third group concentrated their studies on colicins, which were found to exert antitumor effects [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Hal Nash R: Chronic Diseases With Possible Infectious Etiologies. 1999, http://www.cdcgov/ncidod/EID/vol4no3/relman.htm" href="/articles/10.1186/1756-9966-30-11#ref-CR32" id="ref-link-section-d87701628e752">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Lancaster LE, Wintermeyer W, Rodnina MV: Colicins and their potential in cancer treatment. Blood Cells Mol Dis. 2007, 38: 15-18. 10.1016/j.bcmd.2006.10.006." href="/articles/10.1186/1756-9966-30-11#ref-CR33" id="ref-link-section-d87701628e755">33</a>].</p><p>Later studies showed that cytokine-based sequel of long-standing bacterial inflammation might be the main mechanism of transformational changes in normal colorectal mucosa. In <i>H. pylori</i> infections, the gastric levels of cytokines were found to correlate strongly with inflammation and the degree of gastritis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Chao C, Hellmich MR: Gastrin, inflammation, and carcinogenesis. Curr Opin Endocrinol Diabetes Obes. 2010, 17: 33-39." href="/articles/10.1186/1756-9966-30-11#ref-CR21" id="ref-link-section-d87701628e764">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Taha AS, Kelly RW, Carr G, Stiemer B, Morton R, Park RH, Beattie AD: Altered urinary interleukin-8/creatinine ratio in peptic ulcer disease: pathological and diagnostic implications. Am J Gastroenterol. 1996, 91: 2528-2531." href="/articles/10.1186/1756-9966-30-11#ref-CR34" id="ref-link-section-d87701628e767">34</a>]. It was also reported that colonic cells exposed <i>in vitro</i> to <i>Clostridium difficile</i> toxin A showed induced cytokines production [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Mahida YR, Makh S, Hyde S, Gray T, Borriello SP: Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. Gut. 1996, 38: 337-347. 10.1136/gut.38.3.337." href="/articles/10.1186/1756-9966-30-11#ref-CR35" id="ref-link-section-d87701628e777">35</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Castagnola E, Battaglia T, Bandettini R, Caviglia I, Baldelli I, Nantron M, Moroni C, Garaventa A: Clostridium difficile-associated disease in children with solid tumors. Support Care Cancer. 2009, 17: 321-324. 10.1007/s00520-008-0507-0." href="/articles/10.1186/1756-9966-30-11#ref-CR36" id="ref-link-section-d87701628e780">36</a>]. Alike, <i>S. bovis</i>/<i>gallolyticus</i> bacteria, especially their cell wall antigens, were found to increase remarkably the production of inflammatory cytokines in the colonic mucosa of rats, suggesting direct interaction between <i>S. bovis</i> and colonic mucosal cells which is thought to lead to the development of colorectal cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Ellmerich S, Scholler M, Duranton B, Gosse F, Galluser M, Klein JP, Raul F: Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000, 21: 753-756. 10.1093/carcin/21.4.753." href="/articles/10.1186/1756-9966-30-11#ref-CR37" id="ref-link-section-d87701628e792">37</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e796">40</a>]. Hence, collectively, the bacterial etiology/predisposition of colorectal cancer has become evidently prevailing in the field of research which necessates intensive evaluation of the current trend of research done in this field.</p></div></div></section><section data-title="The association of S. bovis/gallolyticus bacteremia/endocarditis with colorectal cancer"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">The association of <i>S. bovis/gallolyticus</i> bacteremia/endocarditis with colorectal cancer</h2><div class="c-article-section__content" id="Sec4-content"><p><i>S. bovis</i> was traditionally considered as a lower grade pathogen frequently involved in bacteremia and endocarditis. Although McCoy and Mason [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="McCoy W, Mason JM: Enterococcal endocarditis associated with carcinoma of the sigmoid; report of a case. J Med Assoc State Ala. 1951, 21: 162-166." href="/articles/10.1186/1756-9966-30-11#ref-CR41" id="ref-link-section-d87701628e813">41</a>] suggested a relationship between colonic carcinoma and the presence of infectious endocarditis in 1951, it was only in 1974 that the association of <i>S. bovis</i> and colorectal neoplasia was recognized [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Keusch GT: Opportunistic infections in colon carcinoma. Am J Clin Nutr. 1974, 27: 1481-1485." href="/articles/10.1186/1756-9966-30-11#ref-CR42" id="ref-link-section-d87701628e819">42</a>]. Nevertheless, the extent, nature, and basis of this association are still not completely understood. A recent study [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Rusniok C, Couve E, Da Cunha V, El Gana R, Zidane N, Bouchier C, Poyart C, Leclercq R, Trieu-Cuot P, Glaser P: Genome sequence of Streptococcus gallolyticus: insights into its adaptation to the bovine rumen and its ability to cause endocarditis. J Bacteriol. 2010, 192: 2266-2276. 10.1128/JB.01659-09." href="/articles/10.1186/1756-9966-30-11#ref-CR43" id="ref-link-section-d87701628e822">43</a>] sequenced the 2,350 Kb genome of <i>S. gallolyticus</i> and analyzed 2,239 encoded proteins; they found that this bacterium synthesizes many proteins and polysaccharides for the assembly of capsular sheath, collagen-binding proteins, and three types of pili that all render this bacterium highly efficient in causing bacteremia, endocarditis, and colorectal cancer.</p><p>The association of <i>S. bovis/gallolyticus</i> bacteremia/endocarditis with colorectal cancer was assessed by numerous studies. It was found that 25 to 80% of patients with <i>S. bovis/gallolyticus</i> bacteremia and 18 to 62% of patients with <i>S. bovis/gallolyticus</i> endocarditis have underlying colorectal tumors [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Wilson WR, Thompson RL, Wilkowske CJ, Washington JA, Giuliani ER, Geraci JE: Short-term therapy for streptococcal infective endocarditis. Combined intramuscular administration of penicillin and streptomycin. JAMA. 1981, 245: 360-363. 10.1001/jama.245.4.360. 2" href="/articles/10.1186/1756-9966-30-11#ref-CR1" id="ref-link-section-d87701628e840">1</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Gupta A, Madani R, Mukhtar H: Streptococcus bovis endocarditis; a silent sign for colonic tumour. Colorectal Dis. 2010, 12 (3): 164-71. 10.1111/j.1463-1318.2009.01814.x." href="/articles/10.1186/1756-9966-30-11#ref-CR7" id="ref-link-section-d87701628e843">7</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Murray HW, Roberts RB: Streptococcus bovis bacteremia and underlying gastrointestinal disease. Arch Intern Med. 1978, 138: 1097-1099. 10.1001/archinte.138.7.1097." href="/articles/10.1186/1756-9966-30-11#ref-CR44" id="ref-link-section-d87701628e847">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Corredoira J, Alonso MP, Coira A, Casariego E, Arias C, Alonso D, Pita J, Rodriguez A, Lopez MJ, Varela J: Characteristics of Streptococcus bovis endocarditis and its differences with Streptococcus viridans endocarditis. Eur J Clin Microbiol Infect Dis. 2008, 27: 285-291. 10.1007/s10096-007-0441-y." href="/articles/10.1186/1756-9966-30-11#ref-CR45" id="ref-link-section-d87701628e850">45</a>]. The high rate of this association indicates serious clinical impact given that <i>S. bovis/gallolyticus</i> accounts for 14% of the cases of infectious endocarditis, and 13% of all cases of infectious endocarditis are caused by bacteria of gastrointestinal origin [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Bisno A: Streptococcal infection. Harrison's principles of internal medicine. Edited by: Harrison T, Stone R. 1991, New York: McGraw-Hill, 563-569. 12" href="/articles/10.1186/1756-9966-30-11#ref-CR46" id="ref-link-section-d87701628e856">46</a>]. A study conducted for 18 years in Spain showed increased incidence of infective endocarditis cases casued by <i>S. bovis/gallolyticus</i> indicating that <i>S. bovis</i>/gallolyticus bacteremia/endocarditis is an emergent disease [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Corredoira J, Alonso MP, Coira A, Casariego E, Arias C, Alonso D, Pita J, Rodriguez A, Lopez MJ, Varela J: Characteristics of Streptococcus bovis endocarditis and its differences with Streptococcus viridans endocarditis. Eur J Clin Microbiol Infect Dis. 2008, 27: 285-291. 10.1007/s10096-007-0441-y." href="/articles/10.1186/1756-9966-30-11#ref-CR45" id="ref-link-section-d87701628e866">45</a>]. Thorough studies on <i>S. bovis</i> showed that the association between <i>S. bovis</i> bacteraemia and carcinoma of the colon and infective endocarditis is biotype-specific. It was shown that there is 94% association between <i>S. bovis</i> biotype I bacteraemia and infective endocarditis and 71% association between <i>S. bovis</i> biotype I bacteraemia and colonic carcinoma while it is only 18% association between <i>S. bovis</i> biotype II bacteraemia and infective endocarditis and 17% association between <i>S. bovis</i> biotype II bacteraemia and colonic carcinoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Murray PR, Baron EJ: Manual of clinical microbiology. 2007, Washington, D.C.: ASM Press, 9" href="/articles/10.1186/1756-9966-30-11#ref-CR8" id="ref-link-section-d87701628e888">8</a>]. Following the description of <i>S. gallolyticus</i>, Devriese team used whole-cell protein analysis showing that the bacterial isolates studied by his team, which were derived from patients with endocarditis and identified by conventional techniques as <i>S. bovis</i>, were in fact <i>S. gallolyticus</i>. Therefore, they suggested that <i>S. gallolyticus</i> is more likely to be involved in human infections than <i>S. bovis</i>[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Devriese LA, Vandamme P, Pot B, Vanrobaeys M, Kersters K, Haesebrouck F: Differentiation between Streptococcus gallolyticus strains of human clinical and veterinary origins and Streptococcus bovis strains from the intestinal tracts of ruminants. J Clin Microbiol. 1998, 36: 3520-3523." href="/articles/10.1186/1756-9966-30-11#ref-CR10" id="ref-link-section-d87701628e907">10</a>].</p><p>The wide range of the association rates between <i>S. bovis/gallolyticus</i> and colorectal cancer might be attributed to different geographical and ethnic groups studied so far [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Boleij A, Schaeps RM, Tjalsma H: Association between Streptococcus bovis and colon cancer. J Clin Microbiol. 2009, 47: 516-10.1128/JCM.01755-08." href="/articles/10.1186/1756-9966-30-11#ref-CR47" id="ref-link-section-d87701628e916">47</a>]. In a study conducted in Hong Kong, <i>S. bovis</i> biotype II/2 (<i>S. gallolyticus</i> subspecies <i>pasterianus</i>), rather than biotype I (<i>S. gallolyticus</i> subspecies <i>gallolyticus</i>), was found to be dominantly associated with colorectal tumors [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Lee RA, Woo PC, To AP, Lau SK, Wong SS, Yuen KY: Geographical difference of disease association in Streptococcus bovis bacteraemia. J Med Microbiol. 2003, 52: 903-908. 10.1099/jmm.0.05199-0." href="/articles/10.1186/1756-9966-30-11#ref-CR48" id="ref-link-section-d87701628e935">48</a>] while, in Europe and the USA, <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> is dominantly associated with colorectal tumors [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Devriese LA, Vandamme P, Pot B, Vanrobaeys M, Kersters K, Haesebrouck F: Differentiation between Streptococcus gallolyticus strains of human clinical and veterinary origins and Streptococcus bovis strains from the intestinal tracts of ruminants. J Clin Microbiol. 1998, 36: 3520-3523." href="/articles/10.1186/1756-9966-30-11#ref-CR10" id="ref-link-section-d87701628e944">10</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Boleij A, Schaeps RM, Tjalsma H: Association between Streptococcus bovis and colon cancer. J Clin Microbiol. 2009, 47: 516-10.1128/JCM.01755-08." href="/articles/10.1186/1756-9966-30-11#ref-CR47" id="ref-link-section-d87701628e948">47</a>].</p><p>Beside the characteristic adhesive traits of <i>S. bovis/gallolyticus</i> to the intestinal cells, it is also known that, in contrast to most α-haemolytic streptococci, <i>S. bovis/gallolyticus</i> is able to grow in bile [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Luk WK, Liu CL, Yuen KY, Wong SS, Woo PC, Fan ST: Biliary tract infection due to bile-soluble bacteria: an intriguing paradox. Clin Infect Dis. 1998, 26: 1010-1012. 10.1086/517638." href="/articles/10.1186/1756-9966-30-11#ref-CR49" id="ref-link-section-d87701628e960">49</a>] Therefore, unlike other bacteria, <i>S. bovis/gallolyticus</i> can bypass efficiently the hepatic reticulo-endothelial system and access systemic circulation easily which might explain the route responsible for the association between <i>S. bovis/gallolyticus</i> colonic lesions and <i>S. bovis/gallolyticus</i> bacteremia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Vaska VL, Faoagali JL: Streptococcus bovis bacteraemia: identification within organism complex and association with endocarditis and colonic malignancy. Pathology. 2009, 41: 183-186. 10.1080/00313020802436816." href="/articles/10.1186/1756-9966-30-11#ref-CR50" id="ref-link-section-d87701628e973">50</a>]. In this regard, an association was found between <i>S. bovis/gallolyticus</i> bacteraemia/endocarditis and liver disease [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Vaska VL, Faoagali JL: Streptococcus bovis bacteraemia: identification within organism complex and association with endocarditis and colonic malignancy. Pathology. 2009, 41: 183-186. 10.1080/00313020802436816." href="/articles/10.1186/1756-9966-30-11#ref-CR50" id="ref-link-section-d87701628e979">50</a>]. The prevalence of chronic liver disease in patients with <i>S. bovis/gallolyticus</i> endocarditis was significantly higher than in patients with endocarditis caused by another aetiology (60% vs 15.3%) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Tripodi MF, Adinolfi LE, Ragone E, Durante Mangoni E, Fortunato R, Iarussi D, Ruggiero G, Utili R: Streptococcus bovis endocarditis and its association with chronic liver disease: an underestimated risk factor. Clin Infect Dis. 2004, 38: 1394-1400. 10.1086/392503." href="/articles/10.1186/1756-9966-30-11#ref-CR51" id="ref-link-section-d87701628e985">51</a>]. The rate of simultaneous occurrence of liver disease and colon cancer in patients with <i>S. bovis/gallolyticus</i> endocarditis/bacteraemia was found to be 27% [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Zarkin BA, Lillemoe KD, Cameron JL, Effron PN, Magnuson TH, Pitt HA: The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Ann Surg. 1990, 211: 786-791. 10.1097/00000658-199006000-00019. discussion 791-782" href="/articles/10.1186/1756-9966-30-11#ref-CR4" id="ref-link-section-d87701628e992">4</a>]. Therefore, it was inferred that the association of <i>S. bovis/gallolyticus</i> bacteraemia/endocarditis with colorectal neoplasia indicates special pathogenic traits of this bacteria rendering it capable of entering blood circulation selectively through hepatic portal route. Accordingly, it was recommended that the liver as well as the bowel should be fully investigated in patients with <i>S. bovis/gallolyticus</i> endocarditis/bacteraemia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Zarkin BA, Lillemoe KD, Cameron JL, Effron PN, Magnuson TH, Pitt HA: The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Ann Surg. 1990, 211: 786-791. 10.1097/00000658-199006000-00019. discussion 791-782" href="/articles/10.1186/1756-9966-30-11#ref-CR4" id="ref-link-section-d87701628e1001">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Vaska VL, Faoagali JL: Streptococcus bovis bacteraemia: identification within organism complex and association with endocarditis and colonic malignancy. Pathology. 2009, 41: 183-186. 10.1080/00313020802436816." href="/articles/10.1186/1756-9966-30-11#ref-CR50" id="ref-link-section-d87701628e1004">50</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Osawa R, Sasaki E: Novel observations of genotypic and metabolic characteristics of three subspecies of Streptococcus gallolyticus. J Clin Microbiol. 2004, 42: 4912-4913. 10.1128/JCM.42.10.4912-4913.2004." href="/articles/10.1186/1756-9966-30-11#ref-CR52" id="ref-link-section-d87701628e1008">52</a>]. Nevertheless, this does not exclude the possibility that other intestinal bacteria might be associated with colon cancer; a rare report stated that cases of <i>Klepsiella pneumoniae</i> liver abscess were found to be associated with colon cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Hsu WH, Yu FJ, Chuang CH, Chen CF, Lee CT, Lu CY: Occult colon cancer in a patient with diabetes and recurrent Klebsiella pneumoniae liver abscess. Kaohsiung J Med Sci. 2009, 25: 98-103. 10.1016/S1607-551X(09)70048-8." href="/articles/10.1186/1756-9966-30-11#ref-CR53" id="ref-link-section-d87701628e1014">53</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Hiraoka A, Yamashita Y, Uesugi K, Koizumi Y, Yamamoto Y, Doi H, Hasebe A, Ichikawa S, Yano M, Miyamoto Y, et al.: Three cases of liver abscesses complicated with colon cancer without liver metastasis: importance of screening for digestive disease. Intern Med. 2007, 46: 2013-2017. 10.2169/internalmedicine.46.0080." href="/articles/10.1186/1756-9966-30-11#ref-CR54" id="ref-link-section-d87701628e1017">54</a>].</p></div></div></section><section data-title="The extra colonic affection of S. bovis/gallolyticus bacteria"><div class="c-article-section" id="Sec5-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec5">The extra colonic affection of <i>S. bovis/gallolyticus</i> bacteria</h2><div class="c-article-section__content" id="Sec5-content"><p>Beside infective endocarditis, case reports suggested the possibility of infections by <i>S. bovis/gallolyticus</i> in various sites outside colorectum such as osteomyelitis, discitis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Pedrajas Ortiz A, Macias Mir P, Ruiz Serrato A, Garcia Ordonez MA: [Aortic endocarditis and spondylodiscitis due to Streptococcus bovis in a patient in his eighties with colon cancer.]. Rev Esp Geriatr Gerontol. 2010, 45 (4): 243-5. 10.1016/j.regg.2010.02.002." href="/articles/10.1186/1756-9966-30-11#ref-CR55" id="ref-link-section-d87701628e1035">55</a>] and neck abscess [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Vince KG, Kantor SR, Descalzi J: Late infection of a total knee arthroplasty with Streptococcus bovis in association with carcinoma of the large intestine. J Arthroplasty. 2003, 18: 813-815. 10.1016/S0883-5403(03)00268-7." href="/articles/10.1186/1756-9966-30-11#ref-CR56" id="ref-link-section-d87701628e1038">56</a>] which could be linked to colonic malignancy or malignancies in other locations. Although many studies suggested that infective endocarditis is the commonest manifestation of <i>S. bovis/gallolyticus</i> infection in western countries [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Kok H, Jureen R, Soon CY, Tey BH: Colon cancer presenting as Streptococcus gallolyticus infective endocarditis. Singapore Med J. 2007, 48: e43-45." href="/articles/10.1186/1756-9966-30-11#ref-CR5" id="ref-link-section-d87701628e1044">5</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Gupta A, Madani R, Mukhtar H: Streptococcus bovis endocarditis; a silent sign for colonic tumour. Colorectal Dis. 2010, 12 (3): 164-71. 10.1111/j.1463-1318.2009.01814.x." href="/articles/10.1186/1756-9966-30-11#ref-CR7" id="ref-link-section-d87701628e1048">7</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Vaska VL, Faoagali JL: Streptococcus bovis bacteraemia: identification within organism complex and association with endocarditis and colonic malignancy. Pathology. 2009, 41: 183-186. 10.1080/00313020802436816." href="/articles/10.1186/1756-9966-30-11#ref-CR50" id="ref-link-section-d87701628e1051">50</a>], cholecystitis, cholangitis, and biliary tract diseases were reported to be commonest manifestations in other geographical areas, such as Hong Kong [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Lee RA, Woo PC, To AP, Lau SK, Wong SS, Yuen KY: Geographical difference of disease association in Streptococcus bovis bacteraemia. J Med Microbiol. 2003, 52: 903-908. 10.1099/jmm.0.05199-0." href="/articles/10.1186/1756-9966-30-11#ref-CR48" id="ref-link-section-d87701628e1054">48</a>].</p><p>In addition, it was found that <i>S. bovis/gallolyticus</i> bacteremia is associated with malignancy irrespective of site; 29% of patients with positive <i>S. bovis/gallolyticus</i> bacteremia harbored tumor lesions in the colon, duodenum, gallbladder, pancreas, ovary, uterus, lung, or hematopoietic system [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Gold JS, Bayar S, Salem RR: Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. Arch Surg. 2004, 139: 760-765. 10.1001/archsurg.139.7.760." href="/articles/10.1186/1756-9966-30-11#ref-CR57" id="ref-link-section-d87701628e1066">57</a>]. Moreover, other studies observed the occurrence of <i>S. bovis/gallolyticus</i> bacteremia in patients with pancreatic cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Herrington CS, McGee JOD: Diagnostic molecular pathology: a practical approach. 1992, Oxford; New York: IRL Press at Oxford University Press" href="/articles/10.1186/1756-9966-30-11#ref-CR58" id="ref-link-section-d87701628e1072">58</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Corredoira J, Alonso MP, Coira A, Varela J: Association between Streptococcus infantarius (formerly S. bovis II/1) bacteremia and noncolonic cancer. J Clin Microbiol. 2008, 46: 1570-10.1128/JCM.00129-08." href="/articles/10.1186/1756-9966-30-11#ref-CR59" id="ref-link-section-d87701628e1076">59</a>], squamous cell carcinoma of the mouth [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Corredoira J, Alonso MP, Coira A, Varela J: Association between Streptococcus infantarius (formerly S. bovis II/1) bacteremia and noncolonic cancer. J Clin Microbiol. 2008, 46: 1570-10.1128/JCM.00129-08." href="/articles/10.1186/1756-9966-30-11#ref-CR59" id="ref-link-section-d87701628e1079">59</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Gelfand MS, Alford RH: Streptococcus bovis endocarditis and squamous-cell carcinoma of the mouth. N Engl J Med. 1981, 305: 284-285." href="/articles/10.1186/1756-9966-30-11#ref-CR60" id="ref-link-section-d87701628e1082">60</a>], endometrial cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Anaf V, Noel JC, Thys JP, Simon P, Buxant F: A first case of Streptococcus bovis bacteremia and peritonitis from endometrial cancer origin. Acta Chir Belg. 2001, 101: 38-39." href="/articles/10.1186/1756-9966-30-11#ref-CR61" id="ref-link-section-d87701628e1085">61</a>], melanoma metastatic to the gastrointestinal tract [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Brooks R, Ravreby W, G K, Bottone E: More on Streptococcus bovis endocarditis and bowel carcinoma. N Engl J Med. 1978, 298: 572-573. 10.1056/NEJM197805042981804." href="/articles/10.1186/1756-9966-30-11#ref-CR62" id="ref-link-section-d87701628e1088">62</a>], lymphosarcoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Levy B, von Reyn C, Arbeit R, Friedland J, Crumpacker C: More on Streptococcus bovis endocarditis and bowel carcinoma. N Engl J Med. 1978, 298: 572-573. 10.1056/NEJM197803092981014." href="/articles/10.1186/1756-9966-30-11#ref-CR63" id="ref-link-section-d87701628e1091">63</a>], Kaposi sarcoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Glaser JB, Landesman SH: Streptococcus bovis bacteremia and acquired immunodeficiency syndrome. Ann Intern Med. 1983, 99: 878-" href="/articles/10.1186/1756-9966-30-11#ref-CR64" id="ref-link-section-d87701628e1095">64</a>], esophageal carcinoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Pigrau C, Lorente A, Pahissa A, Martinez-Vazquez JM: Streptococcus bovis bacteremia and digestive system neoplasms. Scand J Infect Dis. 1988, 20: 459-460. 10.3109/00365548809032490." href="/articles/10.1186/1756-9966-30-11#ref-CR65" id="ref-link-section-d87701628e1098">65</a>], gastric carcinoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Kupferwasser I, Darius H, Muller AM, Mohr-Kahaly S, Westermeier T, Oelert H, Erbel R, Meyer J: Clinical and morphological characteristics in Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177 cases. Heart. 1998, 80: 276-280." href="/articles/10.1186/1756-9966-30-11#ref-CR66" id="ref-link-section-d87701628e1101">66</a>], gastric lymphoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Klein RS, Catalano MT, Edberg SC, Casey JI, Steigbigel NH: Streptococcus bovis septicemia and carcinoma of the colon. Ann Intern Med. 1979, 91: 560-562." href="/articles/10.1186/1756-9966-30-11#ref-CR67" id="ref-link-section-d87701628e1104">67</a>] and pancreatic carcinoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Gonzlez-Quintela A, Martinez-Rey C, Castroagudin JF, Rajo-Iglesias MC, Dominguez-Santalla MJ: Prevalence of liver disease in patients with Streptococcus bovis bacteraemia. J Infect. 2001, 42: 116-119. 10.1053/jinf.2001.0799." href="/articles/10.1186/1756-9966-30-11#ref-CR68" id="ref-link-section-d87701628e1107">68</a>].</p></div></div></section><section data-title="The association of S. bovis/gallolyticus with colorectal adenoma"><div class="c-article-section" id="Sec6-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec6">The association of <i>S. bovis/gallolyticus</i> with colorectal adenoma</h2><div class="c-article-section__content" id="Sec6-content"><p>High incidence of colorectal cancer in individuals with polyps was observed. Most cases of invasive colorectal adenocarcinomas were found to arise from pre-existing adenomatous polyps [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="CDC: Colorectal cancer: The importance of prevention and early detection. 2001, http://www.cdcgov/cancer/colorctl/colopdf/colaag01.pdf" href="/articles/10.1186/1756-9966-30-11#ref-CR69" id="ref-link-section-d87701628e1123">69</a>]. About 90% of preinvasive neoplastic lesions of the colorectum are polyps or polyp precursors, namely aberrant crypt foci [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Nielsen SD, Christensen JJ, Laerkeborg A, Haunso S, Knudsen JD: [Molecular-biological methods of diagnosing colon-related Streptococcus bovis endocarditis]. Ugeskr Laeger. 2007, 169: 610-611." href="/articles/10.1186/1756-9966-30-11#ref-CR70" id="ref-link-section-d87701628e1126">70</a>]. Neoplastic polyps are often referred to more specifically as adenomas or adenomatous polyps [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Srivastava S, Verma M, Henson DE: Biomarkers for early detection of colon cancer. Clin Cancer Res. 2001, 7: 1118-1126." href="/articles/10.1186/1756-9966-30-11#ref-CR71" id="ref-link-section-d87701628e1129">71</a>]. Adenomatous polyps are considered as good and few surrogate end point markers for colorectal cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Nielsen SD, Christensen JJ, Laerkeborg A, Haunso S, Knudsen JD: [Molecular-biological methods of diagnosing colon-related Streptococcus bovis endocarditis]. Ugeskr Laeger. 2007, 169: 610-611." href="/articles/10.1186/1756-9966-30-11#ref-CR70" id="ref-link-section-d87701628e1132">70</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Kelly C, Evans P, Bergmeier L, Lee SF, Progulske-Fox A, Harris AC, Aitken A, Bleiweis AS, Lehner T: Sequence analysis of the cloned streptococcal cell surface antigen I/II. FEBS Lett. 1989, 258: 127-132. 10.1016/0014-5793(89)81632-1." href="/articles/10.1186/1756-9966-30-11#ref-CR72" id="ref-link-section-d87701628e1135">72</a>].</p><p>It would be of interest to scrutinize any relationship between <i>S. bovis/gallolyticus</i> and colonic polyps taking into account the type of polyp and its malignant potential [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Schlegel L, Grimont F, Ageron E, Grimont PA, Bouvet A: Reappraisal of the taxonomy of the Streptococcus bovis/Streptococcus equinus complex and related species: description of Streptococcus gallolyticus subsp. gallolyticus subsp. nov., S. gallolyticus subsp. macedonicus subsp. nov. and S. gallolyticus subsp. pasteurianus subsp. nov. Int J Syst Evol Microbiol. 2003, 53: 631-645. 10.1099/ijs.0.02361-0." href="/articles/10.1186/1756-9966-30-11#ref-CR11" id="ref-link-section-d87701628e1144">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Boleij A, Schaeps RM, Tjalsma H: Association between Streptococcus bovis and colon cancer. J Clin Microbiol. 2009, 47: 516-10.1128/JCM.01755-08." href="/articles/10.1186/1756-9966-30-11#ref-CR47" id="ref-link-section-d87701628e1147">47</a>]. The relationship between <i>S. bovis/gallolyticus</i> infection and the progressive development of malignant disease in preneoplastic adenomatous polyps was supported by recent reports [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1153">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Kahveci A, Ari E, Arikan H, Koc M, Tuglular S, Ozener C: Streptococcus bovis bacteremia related to colon adenoma in a chronic hemodialysis patient. Hemodial Int. 2010, 14: 91-93. 10.1111/j.1542-4758.2009.00400.x." href="/articles/10.1186/1756-9966-30-11#ref-CR73" id="ref-link-section-d87701628e1157">73</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Murinello A, Mendonca P, Ho C, Traverse P, Peres H, RioTinto R, Morbey A, Campos C, Lazoro A, Milheiro A, et al.: Streptococcus gallolyticus bacteremia assoaiced with colonic adenmatous polyps. GE-J-Port Gastrentrol. 2006, 13: 152-156." href="/articles/10.1186/1756-9966-30-11#ref-CR74" id="ref-link-section-d87701628e1160">74</a>]. Interestingly, <i>S. bovis/gallolyticus</i> was found to be mildly associated with some benign lesions (diverticulosis, inflammatory bowel disease, cecal volvulus, perirectal abscess hemorrhoids, and benign polyps), while it was strongly associated with most malignant diseases (cancer and neoplastic polyps) of the colon [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Reynolds JG, Silva E, McCormack WM: Association of Streptococcus bovis bacteremia with bowel disease. J Clin Microbiol. 1983, 17: 696-697." href="/articles/10.1186/1756-9966-30-11#ref-CR2" id="ref-link-section-d87701628e1166">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1169">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Klein RS, Catalano MT, Edberg SC, Casey JI, Steigbigel NH: Streptococcus bovis septicemia and carcinoma of the colon. Ann Intern Med. 1979, 91: 560-562." href="/articles/10.1186/1756-9966-30-11#ref-CR67" id="ref-link-section-d87701628e1172">67</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Nielsen SD, Christensen JJ, Laerkeborg A, Haunso S, Knudsen JD: [Molecular-biological methods of diagnosing colon-related Streptococcus bovis endocarditis]. Ugeskr Laeger. 2007, 169: 610-611." href="/articles/10.1186/1756-9966-30-11#ref-CR70" id="ref-link-section-d87701628e1176">70</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Burns CA, McCaughey R, Lauter CB: The association of Streptococcus bovis fecal carriage and colon neoplasia: possible relationship with polyps and their premalignant potential. Am J Gastroenterol. 1985, 80: 42-46." href="/articles/10.1186/1756-9966-30-11#ref-CR75" id="ref-link-section-d87701628e1179">75</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="Smaali I, Bachraoui K, Joulek A, Selmi K, Boujnah MR: [Infectious endocarditis secondary to streptococcus bovis revealing adenomatous polyposis coli]. Tunis Med. 2008, 86: 723-724." href="/articles/10.1186/1756-9966-30-11#ref-CR76" id="ref-link-section-d87701628e1182">76</a>]. It was also revealed that <i>S. bovis/gallolyticus</i> in patients with bacteremia and/or endocarditis is selectively related to the presence of the most aggressive type of polyps in the large intestine, villous or tubulovillous adenomas, [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="Smaali I, Bachraoui K, Joulek A, Selmi K, Boujnah MR: [Infectious endocarditis secondary to streptococcus bovis revealing adenomatous polyposis coli]. Tunis Med. 2008, 86: 723-724." href="/articles/10.1186/1756-9966-30-11#ref-CR76" id="ref-link-section-d87701628e1188">76</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Fagundes J, Noujain H, Coy C, Ayrizono M, Góes J, Martinuzzo W: Associação entre endocardite bacteriana e neoplasias - relato de 4 casos. Rev Bras Coloproctol. 2000, 20: 95-99." href="/articles/10.1186/1756-9966-30-11#ref-CR77" id="ref-link-section-d87701628e1191">77</a>] In addition, Hoen team performed a case-control study on subjects underwent colonoscopy comparing between patients with <i>S. bovis/gallolyticus</i> endocarditis and sex- and age- matched unaffected patients. This study showed that colonic adenomatous polyps in the patients' group were twice as many cases as controls (15 of 32 <i>vs</i> 15 of 64), while lesions of colorectal cancer were present approximately 3 times as often as controls (3 of 32 <i>vs</i> 2 of 64) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 78" title="Hoen B, Briancon S, Delahaye F, Terhe V, Etienne J, Bigard MA, Canton P: Tumors of the colon increase the risk of developing Streptococcus bovis endocarditis: case-control study. Clin Infect Dis. 1994, 19: 361-362." href="/articles/10.1186/1756-9966-30-11#ref-CR78" id="ref-link-section-d87701628e1204">78</a>]. On the other hand, another study [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 79" title="Devis A, Dony A, De Boelpaepe F, Verhulst C, Serste JP: [Streptococcus bovis septicemia and colonic cancer]. Acta Chir Belg. 1989, 89: 58-60." href="/articles/10.1186/1756-9966-30-11#ref-CR79" id="ref-link-section-d87701628e1207">79</a>] found that the association between <i>S. bovis/gallolyticus</i> and adenoma is more evident than colorectal cancer; they reported that 36% of positive blood cultures of <i>S. bovis/gallolyticus</i> were found in proliferative lesions, 15% of cancers and 21% of adenomas. A recent study done by our team supported this concept [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1217">39</a>] showing that the level of <i>S. bovis/gallolyticus</i> IgG antibodies in adenoma patients was higher than in colorectal cancer patients or control subjects. However, Burns et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Burns CA, McCaughey R, Lauter CB: The association of Streptococcus bovis fecal carriage and colon neoplasia: possible relationship with polyps and their premalignant potential. Am J Gastroenterol. 1985, 80: 42-46." href="/articles/10.1186/1756-9966-30-11#ref-CR75" id="ref-link-section-d87701628e1223">75</a>] did not get the same findings; they found that the incidence of <i>S. bovis/gallolyticus</i> carriage in all colons with polyps was intermediary between normal colons and colons with carcinoma; however, the difference did not achieve statistical significance.</p><p>Since there is evidence that colon cancer progresses from normal tissue to adenoma and then to carcinoma through an accumulation of genetic alterations [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 80" title="Baron JA, Sandler RS: Nonsteroidal anti-inflammatory drugs and cancer prevention. Annu Rev Med. 2000, 51: 511-523. 10.1146/annurev.med.51.1.511." href="/articles/10.1186/1756-9966-30-11#ref-CR80" id="ref-link-section-d87701628e1232">80</a>], the remarkable association between <i>S. bovis/gallolyticus</i> and adenomatous polyps seems to be of importance. Although ulceration of neoplastic lesions might form a pathway for <i>S. bovis/gallolyticus</i> to enter the bloodstream [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Gupta A, Madani R, Mukhtar H: Streptococcus bovis endocarditis; a silent sign for colonic tumour. Colorectal Dis. 2010, 12 (3): 164-71. 10.1111/j.1463-1318.2009.01814.x." href="/articles/10.1186/1756-9966-30-11#ref-CR7" id="ref-link-section-d87701628e1241">7</a>], the association of <i>S. bovis/gallolyticus</i> bacteremia with non-ulcerated colonic polyps indicates an etiological/promoter role of <i>S. bovis/gallolyticus</i> in polyps progression [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="Cutait R, Mansur A, Habr-Gama A: Endocardite por Streptococcus bovis e pólipos de cólon. Rev Bras Coloproctol. 1988, 8: 109-110." href="/articles/10.1186/1756-9966-30-11#ref-CR81" id="ref-link-section-d87701628e1251">81</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Konda A, Duffy MC: Surveillance of patients at increased risk of colon cancer: inflammatory bowel disease and other conditions. Gastroenterol Clin North Am. 2008, 37: 191-213. 10.1016/j.gtc.2007.12.013. viii" href="/articles/10.1186/1756-9966-30-11#ref-CR82" id="ref-link-section-d87701628e1254">82</a>]. Therefore, the possibility of <i>S. bovis/gallolyticus</i> to act as a promoter for the preneoplastic lesions worths consideration. Ellmerich et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Ellmerich S, Scholler M, Duranton B, Gosse F, Galluser M, Klein JP, Raul F: Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000, 21: 753-756. 10.1093/carcin/21.4.753." href="/articles/10.1186/1756-9966-30-11#ref-CR37" id="ref-link-section-d87701628e1260">37</a>] supported this hypothesis. They treated normal rats with <i>S. bovis</i> wall extracted antigens; rats did not develop hyperplastic colonic crypts; however, 50% of rats, that already received a chemocarcinogen, developed neoplastic lesions upon receiving <i>S. bovis</i> wall extracted antigens. This indicated that <i>S. bovis/gallolyticus</i> might exert their carcinogenic activity in colonic mucosa when preneoplastic lesions are established. Therefore, the role of <i>S. bovis/gallolyticus</i> in the etiology and/or acceleration of the transformation of aberrant crypts to adenoma and to a cancer is being considered.</p><p>Accordingly, the knowledge of <i>S. bovis/gallolyticus</i> association with adenoma of colorectal mucosa has important clinical implications. If colorectal lesions could be discovered at an early stage, curative resection might become possible [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Waisberg J, Matheus Cde O, Pimenta J: Infectious endocarditis from Streptococcus bovis associated with colonic carcinoma: case report and literature review. Arq Gastroenterol. 2002, 39: 177-180. 10.1590/S0004-28032002000300008." href="/articles/10.1186/1756-9966-30-11#ref-CR83" id="ref-link-section-d87701628e1282">83</a>]. Thus, bacteremia due to <i>S. bovis/gallolyticus</i> should prompt rigorous investigation to exclude both endocarditis and tumors of the large bowel [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Konda A, Duffy MC: Surveillance of patients at increased risk of colon cancer: inflammatory bowel disease and other conditions. Gastroenterol Clin North Am. 2008, 37: 191-213. 10.1016/j.gtc.2007.12.013. viii" href="/articles/10.1186/1756-9966-30-11#ref-CR82" id="ref-link-section-d87701628e1288">82</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Beeching NJ, Christmas TI, Ellis-Pegler RB, Nicholson GI: Streptococcus bovis bacteraemia requires rigorous exclusion of colonic neoplasia and endocarditis. Q J Med. 1985, 56: 439-450." href="/articles/10.1186/1756-9966-30-11#ref-CR84" id="ref-link-section-d87701628e1291">84</a>]. Therefore, it was concluded that the discovery of a premalignant proliferative lesion in patients with history of bacteremia/endocarditis justifies the exploration of the colon by barium enema and/or colonoscopy [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Konda A, Duffy MC: Surveillance of patients at increased risk of colon cancer: inflammatory bowel disease and other conditions. Gastroenterol Clin North Am. 2008, 37: 191-213. 10.1016/j.gtc.2007.12.013. viii" href="/articles/10.1186/1756-9966-30-11#ref-CR82" id="ref-link-section-d87701628e1295">82</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Beeching NJ, Christmas TI, Ellis-Pegler RB, Nicholson GI: Streptococcus bovis bacteraemia requires rigorous exclusion of colonic neoplasia and endocarditis. Q J Med. 1985, 56: 439-450." href="/articles/10.1186/1756-9966-30-11#ref-CR84" id="ref-link-section-d87701628e1298">84</a>].</p></div></div></section><section data-title="Etiological versus non-etiological role of S. bovis/gallolyticus in the development of colorectal tumors"><div class="c-article-section" id="Sec7-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec7">Etiological versus non-etiological role of <i>S. bovis/gallolyticus</i> in the development of colorectal tumors</h2><div class="c-article-section__content" id="Sec7-content"><p>The underlying mechanisms for the association of <i>S. bovis/gallolyticus</i> bacteremia/endocarditis with colorectal tumors have long been obscure. The possible reason behind that, maybe, <i>S. bovis/gallolyticus</i> is a member of intestinal flora in 2.5 to 15% of individuals; this usually leads scientists to counteract the malicious role of this bacteria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Murray HW, Roberts RB: Streptococcus bovis bacteremia and underlying gastrointestinal disease. Arch Intern Med. 1978, 138: 1097-1099. 10.1001/archinte.138.7.1097." href="/articles/10.1186/1756-9966-30-11#ref-CR44" id="ref-link-section-d87701628e1319">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Burns CA, McCaughey R, Lauter CB: The association of Streptococcus bovis fecal carriage and colon neoplasia: possible relationship with polyps and their premalignant potential. Am J Gastroenterol. 1985, 80: 42-46." href="/articles/10.1186/1756-9966-30-11#ref-CR75" id="ref-link-section-d87701628e1322">75</a>]. Therefore, a big question is frequently asked whether <i>S. bovis/gallolyticus</i> plays an etiological role in the development of colorectal tumors or it is merely a marker of the disease.</p><p>There are many clues provide strong evidence for the etiological role of <i>S. bovis/gallolyticus</i> in colon cancer development. The striking association between bacteremia caused by <i>S. bovis</i> biotype I and both colonic neoplasia (71%) and bacterial endocarditis (94%), compared with bacteremias caused by the closely related organisms such as <i>S. bovis</i> variant and <i>S. salivarius</i>, suggests the possibility of specific bacterium-host cell interaction involving <i>S. bovis</i> biotype I organisms [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Ruoff KL, Miller SI, Garner CV, Ferraro MJ, Calderwood SB: Bacteremia with Streptococcus bovis and Streptococcus salivarius: clinical correlates of more accurate identification of isolates. J Clin Microbiol. 1989, 27: 305-308." href="/articles/10.1186/1756-9966-30-11#ref-CR85" id="ref-link-section-d87701628e1347">85</a>]. Later, <i>S. gallolyticus</i> subspecies <i>gallolyticus</i>, rather than other closely related taxa, was found to be actively colonizing colorectal tumors and primarily associated with colorectal cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1356">40</a>]. In addition, these bacteria showed special predilection to colonic lesions rather than other members of group D Streptococcus endocarditis. It was found that of 77 infections with group D Streptococcus endocarditis, colonic polyps and colonic carcinoma were significantly more frequent in the <i>S. bovis/gallolyticus</i> group, 67 and 18%, than in the Enterococcus group, 21 and 2%, respectively [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Leport C, Bure A, Leport J, Vilde JL: Incidence of colonic lesions in Streptococcus bovis and enterococcal endocarditis. Lancet. 1987, 1: 748-10.1016/S0140-6736(87)90391-6." href="/articles/10.1186/1756-9966-30-11#ref-CR3" id="ref-link-section-d87701628e1362">3</a>].</p><p>Furthermore, the appearance of new colonic lesions within 2 to 4 years after the incidence of <i>S. bovis/gallolyticus</i> bacteremia/endocarditis provides clearer evidence that <i>S. bovis/gallolyticus</i> is not merely a consequence of the tumor lesion [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Wentling GK, Metzger PP, Dozois EJ, Chua HK, Krishna M: Unusual bacterial infections and colorectal carcinoma--Streptococcus bovis and Clostridium septicum: report of three cases. Dis Colon Rectum. 2006, 49: 1223-1227. 10.1007/s10350-006-0576-4." href="/articles/10.1186/1756-9966-30-11#ref-CR86" id="ref-link-section-d87701628e1374">86</a>]. For this reason, patients with infectious endocarditis and normal colonoscopy may be included in the group that presents risk for developing colonic cancer because of the late appearance of such lesions after the infectious episode of <i>S. bovis/gallolyticus</i>.</p><p>In terms of pathogenesis, as <i>S. bovis/gallolyticus</i> is a transient normal flora in the gut, researchers have postulated that the increased load of <i>S. bovis/gallolyticus</i> in colon might be responsible for its association with colon cancer. Several studies showed increased stool carriage of <i>S. bovis/gallolyticus</i> in patients with inflammatory bowel diseases or malignant/premalignant lesions of the colon; around 56% of patients with <i>S. bovis/gallolyticus</i> bacteremia/endocarditis showed increased faecal carriage, when compared to normal subjects or patients with benign diseases of the colon, such as colonic diverticulosis, inflammatory bowel disease, cecal volvulus, perirectal abscess and hemorrhoids (10-23%) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Reynolds JG, Silva E, McCormack WM: Association of Streptococcus bovis bacteremia with bowel disease. J Clin Microbiol. 1983, 17: 696-697." href="/articles/10.1186/1756-9966-30-11#ref-CR2" id="ref-link-section-d87701628e1395">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Klein RS, Catalano MT, Edberg SC, Casey JI, Steigbigel NH: Streptococcus bovis septicemia and carcinoma of the colon. Ann Intern Med. 1979, 91: 560-562." href="/articles/10.1186/1756-9966-30-11#ref-CR67" id="ref-link-section-d87701628e1399">67</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Burns CA, McCaughey R, Lauter CB: The association of Streptococcus bovis fecal carriage and colon neoplasia: possible relationship with polyps and their premalignant potential. Am J Gastroenterol. 1985, 80: 42-46." href="/articles/10.1186/1756-9966-30-11#ref-CR75" id="ref-link-section-d87701628e1402">75</a>].</p><p>Another clue supporting the etiological role of <i>S. bovis/gallolyticus</i>, patients diagnosed with colon cancer have only 3-6% chance to develop <i>S. bovis/gallolyticus</i> bacteremia/endocarditis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="zur Hausen H: Streptococcus bovis: causal or incidental involvement in cancer of the colon?. Int J Cancer. 2006, 119: xi-xii. 10.1002/ijc.22314." href="/articles/10.1186/1756-9966-30-11#ref-CR87" id="ref-link-section-d87701628e1415">87</a>]; this is far lower than the percentage of the detection of colorectal cancer in patients with <i>S. bovis/gallolyticus</i> bacteremia/endocarditis, >70%.</p><p><i>S. bovis/gallolyticus</i> is shown to have indiscriminate pathogenic factors. It can uniquely colonize the thrombin of platelets and fibrin where colonies become developed with protection from new layers of platelets and fibrin that are formed by stimulation from thromboplastin; hence, <i>S. bovis/gallolyticus</i> can penetrate into the bloodstream through epithelial, oropharyngeal, dermal, respiratory, gastrointestinal, or urogenital lesions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Balkwill F, Charles KA, Mantovani A: Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005, 7: 211-217. 10.1016/j.ccr.2005.02.013." href="/articles/10.1186/1756-9966-30-11#ref-CR88" id="ref-link-section-d87701628e1429">88</a>]. On the other hand, the ulceration of neoplastic lesions are found to be unable to form a consistent pathway for the gut microorganisms to enter the bloodstream [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Gupta A, Madani R, Mukhtar H: Streptococcus bovis endocarditis; a silent sign for colonic tumour. Colorectal Dis. 2010, 12 (3): 164-71. 10.1111/j.1463-1318.2009.01814.x." href="/articles/10.1186/1756-9966-30-11#ref-CR7" id="ref-link-section-d87701628e1432">7</a>]. The access of <i>S. bovis/gallolyticus</i> into blood circulation does not explain the cases of patients with infectious endocarditis and non-ulcerated colonic polyps [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="Cutait R, Mansur A, Habr-Gama A: Endocardite por Streptococcus bovis e pólipos de cólon. Rev Bras Coloproctol. 1988, 8: 109-110." href="/articles/10.1186/1756-9966-30-11#ref-CR81" id="ref-link-section-d87701628e1438">81</a>].</p><p>Above all, <i>S. bovis/gallolyticus</i> bacteria were found to be actively engaged in triggering severe inflammatory reaction in colorectal mucosa, inducing inflammatory and angiogenic cytokines leading to the formation of free radicals that are implicated in the development or propagation of all types of human cancers [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Balkwill F, Mantovani A: Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther. 2010, 87: 401-406. 10.1038/clpt.2009.312." href="/articles/10.1186/1756-9966-30-11#ref-CR27" id="ref-link-section-d87701628e1447">27</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Wang D, Dubois RN: The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010, 29: 781-788. 10.1038/onc.2009.421." href="/articles/10.1186/1756-9966-30-11#ref-CR29" id="ref-link-section-d87701628e1450">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Ellmerich S, Scholler M, Duranton B, Gosse F, Galluser M, Klein JP, Raul F: Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000, 21: 753-756. 10.1093/carcin/21.4.753." href="/articles/10.1186/1756-9966-30-11#ref-CR37" id="ref-link-section-d87701628e1453">37</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1456">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1460">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Ellmerich S, Djouder N, Scholler M, Klein JP: Production of cytokines by monocytes, epithelial and endothelial cells activated by Streptococcus bovis. Cytokine. 2000, 12: 26-31. 10.1006/cyto.1999.0521." href="/articles/10.1186/1756-9966-30-11#ref-CR89" id="ref-link-section-d87701628e1463">89</a>].</p><p>Accordingly, too many clues were found supporting the etiological role of <i>S. bovis/gallolyticus</i> in the development of colorectal tumors; therefore, it is very difficult to assume a non-etiological role of these bacteria. Hence, a more detailed overview is needed to clarify the underlying mechanisms that could be pursued by <i>S. bovis/gallolyticus</i> for the etiology or propagation of colorectal tumors.</p></div></div></section><section data-title="The hypothesized mechanisms of the etiological association of S. bovis/gallolyticus with colorectal tumors"><div class="c-article-section" id="Sec8-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec8">The hypothesized mechanisms of the etiological association of <i>S. bovis/gallolyticus</i> with colorectal tumors</h2><div class="c-article-section__content" id="Sec8-content"><p>The other big question in the current topic, what mechanisms <i>S. bovis/gallolyticus</i> undertakes to induce, promote, or/and progress the development of neoplastic lesions. The most possible mechanisms are as follows:</p><h3 class="c-article__sub-heading" id="Sec9">Carcinogenesis via cytokine-dependent inflammation</h3><p>Chronic inflammation is associated with many malignant changes. Host genetic polymorphisms of the adaptive and innate immune response play an important role in bacteria-induced cancer formation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="El-Omar EM: Role of host genes in sporadic gastric cancer. Best Pract Res Clin Gastroenterol. 2006, 20: 675-686. 10.1016/j.bpg.2006.04.006." href="/articles/10.1186/1756-9966-30-11#ref-CR90" id="ref-link-section-d87701628e1497">90</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005, 5: 749-759. 10.1038/nri1703." href="/articles/10.1186/1756-9966-30-11#ref-CR92" id="ref-link-section-d87701628e1500">92</a>]. Therefore, studying the immunological responses to chronic bacterial infections yields important clues on the carcinogenic mechanisms of bacterial persistent infections and clarifies the relationship between inflammation and cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Ernst PB, Peura DA, Crowe SE: The translation of Helicobacter pylori basic research to patient care. Gastroenterology. 2006, 130: 188-206. 10.1053/j.gastro.2005.06.032. quiz 212-183" href="/articles/10.1186/1756-9966-30-11#ref-CR93" id="ref-link-section-d87701628e1503">93</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Monack DM, Mueller A, Falkow S: Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol. 2004, 2: 747-765. 10.1038/nrmicro955." href="/articles/10.1186/1756-9966-30-11#ref-CR94" id="ref-link-section-d87701628e1506">94</a>]. Clinical studies have shown that the use of non-steroidal anti-inflammatory drugs is associated with reduced risk of gastrointestinal cancers [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Dai Y, Wang WH: Non-steroidal anti-inflammatory drugs in prevention of gastric cancer. World J Gastroenterol. 2006, 12: 2884-2889." href="/articles/10.1186/1756-9966-30-11#ref-CR95" id="ref-link-section-d87701628e1509">95</a>]; hence, these studies provide evidence on the role of inflammation in the development of gastrointestinal cancers.</p><p><i>In vitro</i> experiments showed that the binding of <i>S. bovis</i> wall extracted antigens to various cell lines, including human colonic cancer cells (Caco-2), stimulated the production of inflammatory cytokines by those cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1520">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Nguyen I, Biarc J, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein J, et al.: Streptococcus infantarius and colonic cancer: Identification and purification of cell wall proteins putatively involved in colorectal inflammation and carcinogenesis in rats. International Congress Series. 2006, 257-261. 10.1016/j.ics.2005.11.081." href="/articles/10.1186/1756-9966-30-11#ref-CR96" id="ref-link-section-d87701628e1523">96</a>]. In other studies, the production of inflammatory cytokines in response to <i>S. bovis/gallolyticus</i>, such as TNF-α, IL-1β, IL-6, and IL-8, is found to contribute to the normal defense mechanisms of the host [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Ellmerich S, Djouder N, Scholler M, Klein JP: Production of cytokines by monocytes, epithelial and endothelial cells activated by Streptococcus bovis. Cytokine. 2000, 12: 26-31. 10.1006/cyto.1999.0521." href="/articles/10.1186/1756-9966-30-11#ref-CR89" id="ref-link-section-d87701628e1529">89</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Travers P, Rosen FS: Immuno biology bookshelf the comprehensive resource on CD-ROM. 1997, [London; San Francisco] [New York]: Current Biology; Garland Pub, 1-CD-ROM, 2" href="/articles/10.1186/1756-9966-30-11#ref-CR97" id="ref-link-section-d87701628e1533">97</a>] leading to the formation of nitric oxide and free radicals such as superoxide, peroxynitrites, hydroxyl radicals, and alkylperoxy radicals [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Nguyen I, Biarc J, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein J, et al.: Streptococcus infantarius and colonic cancer: Identification and purification of cell wall proteins putatively involved in colorectal inflammation and carcinogenesis in rats. International Congress Series. 2006, 257-261. 10.1016/j.ics.2005.11.081." href="/articles/10.1186/1756-9966-30-11#ref-CR96" id="ref-link-section-d87701628e1536">96</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Ohshima H, Bartsch H: Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res. 1994, 305: 253-264." href="/articles/10.1186/1756-9966-30-11#ref-CR98" id="ref-link-section-d87701628e1539">98</a>]. Owing to their potent mutagenicity, all these molecular species can contribute to the neoplastic processes by modifying cellular DNA (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). On the other hand, the production of angiogenic factors in colonic mucosa, such as IL-8, which can be triggered by <i>S. bovis/gallolyticus</i> antigens, may also favor the progression of colon carcinogenesis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1548">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1552">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Ellmerich S, Djouder N, Scholler M, Klein JP: Production of cytokines by monocytes, epithelial and endothelial cells activated by Streptococcus bovis. Cytokine. 2000, 12: 26-31. 10.1006/cyto.1999.0521." href="/articles/10.1186/1756-9966-30-11#ref-CR89" id="ref-link-section-d87701628e1555">89</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Norrby K: Interleukin-8 and de novo mammalian angiogenesis. Cell Prolif. 1996, 29: 315-323. 10.1111/j.1365-2184.1996.tb01583.x." href="/articles/10.1186/1756-9966-30-11#ref-CR99" id="ref-link-section-d87701628e1558">99</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Eisma RJ, Spiro JD, Kreutzer DL: Role of angiogenic factors: coexpression of interleukin-8 and vascular endothelial growth factor in patients with head and neck squamous carcinoma. Laryngoscope. 1999, 109: 687-693. 10.1097/00005537-199905000-00002." href="/articles/10.1186/1756-9966-30-11#ref-CR100" id="ref-link-section-d87701628e1561">100</a>] (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). This resembles <i>H. pylori</i> infection for the development of chronic inflammation in the gastric mucosa [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Dixon MF, Genta RM, Yardley JH, Correa P: Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996, 20: 1161-1181. 10.1097/00000478-199610000-00001." href="/articles/10.1186/1756-9966-30-11#ref-CR101" id="ref-link-section-d87701628e1571">101</a>]. Therefore, chronic infection and subsequent chronic inflammation seem responsible for the maintenance and development of pre-existing neoplastic lesions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1574">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1577">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Shacter E, Weitzman SA: Chronic inflammation and cancer. Oncology (Williston Park). 2002, 16: 217-226. 229; discussion 230-212" href="/articles/10.1186/1756-9966-30-11#ref-CR102" id="ref-link-section-d87701628e1580">102</a>].</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Figure 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1756-9966-30-11/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1756-9966-30-11/MediaObjects/13046_2010_Article_431_Fig1_HTML.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1756-9966-30-11/MediaObjects/13046_2010_Article_431_Fig1_HTML.jpg" alt="figure 1" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p><b>Illustration for the discovered and suggested mechanisms underlying the etiological association of</b> <b><i>S. bovis/gallolyticus</i></b> <b>(SBG) bacteria with promoting, propagating, or initiating colorectal tumors, bacteremia, and endocarditis</b>.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1756-9966-30-11/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Moreover, it was found that wall extracted antigens of <i>S. bovis</i> induced <i>in vitro</i> overexpression of cyclooxygenase-2 (COX-2) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1618">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Nguyen I, Biarc J, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein J, et al.: Streptococcus infantarius and colonic cancer: Identification and purification of cell wall proteins putatively involved in colorectal inflammation and carcinogenesis in rats. International Congress Series. 2006, 257-261. 10.1016/j.ics.2005.11.081." href="/articles/10.1186/1756-9966-30-11#ref-CR96" id="ref-link-section-d87701628e1621">96</a>]. COX-2, via prostaglandins, promotes cellular proliferation and angiogenesis and inhibits apoptosis (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>); thus it acts as a promoter in cancer pathway [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Tafte L, Ruoff K: Streptococcus bovis: Answers and Questions. Clin microbial newslett. 2007, 29: 49-55. 10.1016/j.clinmicnews.2007.03.004." href="/articles/10.1186/1756-9966-30-11#ref-CR103" id="ref-link-section-d87701628e1628">103</a>]. It is noteworthy to mention that non-steroidal anti-inflammatory drugs decrease the relative risk of gastrointestinal carcinomas through inhibiting the activity of COX-2 which is over-expressed in up to 85% of colorectal adenocarcinomas [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S: Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res. 1995, 55: 2556-2559." href="/articles/10.1186/1756-9966-30-11#ref-CR104" id="ref-link-section-d87701628e1631">104</a>]. Alike, Haqqani et al., [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Haqqani AS, Sandhu JK, Birnboim HC: Expression of interleukin-8 promotes neutrophil infiltration and genetic instability in mutatect tumors. Neoplasia. 2000, 2: 561-568. 10.1038/sj.neo.7900110." href="/articles/10.1186/1756-9966-30-11#ref-CR105" id="ref-link-section-d87701628e1634">105</a>] revealed that the activation of leukocytes by <i>S. bovis/gallolyticus</i> releases various other inflammatory mediators (NO, free radicals, peroxynitriles, etc.) which could interfere directly or indirectly with the cell proliferation process.</p><p>The recent studies conducted by our team revealed that <i>S. gallolyticus</i> is remarkably associated with colorectal cancer and adenoma when compared to the more dominant intestinal bacteria, <i>B. fragilis</i>. This provided evidence for a possible important role of <i>S. gallolyticus</i> in the carcinogenesis of colorectal cancer from pre-malignant polyps. In addition, we found that NF-κB and IL-8 rather than other transformation factors, p21, p27 and p53 acted as highly important mediators for the <i>S. gallolyticus</i>- associated progression of colorectal adenoma to carcinoma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1655">39</a>]. And NF-κB most probably exerts a promoting carcinogenic effect while IL-8 exerts an angiogenic/propagating effect on colorectal mucosal cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e1659">39</a>]. In addition, a more recent study done by our team showed a direct and active role of <i>S. bovis/gallolyticus</i> in colonizing colorectal cancer tissues leading to the development of colorectal cancer through inflammation-based sequel via, but not limited to, IL-1, COX-2, and IL-8 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1665">40</a>].</p><p>Another aspect of inflammatory cytokines, the local action of cytokines or of chemical mediators is able to promote vasodilatation and the enhancement of capillary permeability, which in turn was found to support the bacterial entry at tumor sites, and increase bacterial adherence to various cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1672">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Ellmerich S, Djouder N, Scholler M, Klein JP: Production of cytokines by monocytes, epithelial and endothelial cells activated by Streptococcus bovis. Cytokine. 2000, 12: 26-31. 10.1006/cyto.1999.0521." href="/articles/10.1186/1756-9966-30-11#ref-CR89" id="ref-link-section-d87701628e1675">89</a>]. It has been suggested that alteration in local conditions and disruption of capillary channels at the site of neoplasm allowed <i>S. bovis/gallolyticus</i> to proliferate and gain entry into blood stream [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Ellmerich S, Scholler M, Duranton B, Gosse F, Galluser M, Klein JP, Raul F: Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000, 21: 753-756. 10.1093/carcin/21.4.753." href="/articles/10.1186/1756-9966-30-11#ref-CR37" id="ref-link-section-d87701628e1681">37</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1684">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1688">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Nguyen I, Biarc J, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein J, et al.: Streptococcus infantarius and colonic cancer: Identification and purification of cell wall proteins putatively involved in colorectal inflammation and carcinogenesis in rats. International Congress Series. 2006, 257-261. 10.1016/j.ics.2005.11.081." href="/articles/10.1186/1756-9966-30-11#ref-CR96" id="ref-link-section-d87701628e1691">96</a>]. Therefore, <i>S. bovis/gallolyticus</i> shows characteristic potential in inducing mucosal inflammation and changing the mucosal microclimate leading most probably to tumor development and increased permeability of blood vessels which facilitates this bacterium to enter blood circulation causing bacteremia and/or endocarditits.</p><h3 class="c-article__sub-heading" id="Sec10">Characteristic adherence potential</h3><p>Members of the <i>S. bovis/gallolyticus</i> group are frequent colonizers of the intestinal tract as well as endocardial tissues. However, their ability to adhere to and colonize host tissues was largely unknown. Sillanpaa et al., [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Sillanpaa J, Nallapareddy SR, Qin X, Singh KV, Muzny DM, Kovar CL, Nazareth LV, Gibbs RA, Ferraro MJ, Steckelberg JM, et al.: A collagen-binding adhesin, Acb, and ten other putative MSCRAMM and pilus family proteins of Streptococcus gallolyticus subsp. gallolyticus (Streptococcus bovis Group, biotype I). J Bacteriol. 2009, 191: 6643-6653. 10.1128/JB.00909-09." href="/articles/10.1186/1756-9966-30-11#ref-CR106" id="ref-link-section-d87701628e1708">106</a>] found recently that <i>S. bovis/gallolyticus</i> bacteria possess collagen-binding proteins and pili responsible for adhesion to colorectal mucosa as well as to endocardium (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). On the other hand, Boleij et al., [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Boleij A, Schaeps RM, de Kleijn S, Hermans PW, Glaser P, Pancholi V, Swinkels DW, Tjalsma H: Surface-exposed histone-like protein a modulates adherence of Streptococcus gallolyticus to colon adenocarcinoma cells. Infect Immun. 2009, 77: 5519-5527. 10.1128/IAI.00384-09." href="/articles/10.1186/1756-9966-30-11#ref-CR107" id="ref-link-section-d87701628e1717">107</a>] found a histone-like protein A on the cell wall of <i>S. gallolyticus</i> able to bind heparan sulfate proteoglycans at the colon tumor cell surface during the first stages of infection. This protein is believed to be largely responsible for the selective adhesive potential of <i>S. bovis/gallolyticus</i>. In addition, Vollmer et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Vollmer T, Hinse D, Kleesiek K, Dreier J: Interactions between endocarditis-derived Streptococcus gallolyticus subsp. gallolyticus isolates and human endothelial cells. BMC Microbiol. 2010, 10: 78-10.1186/1471-2180-10-78." href="/articles/10.1186/1756-9966-30-11#ref-CR108" id="ref-link-section-d87701628e1727">108</a>]found recently that the adherence of <i>S. bovis/gallolyticus</i> to the extracellular matrix proteins, collagen I, II and IV, revealed the highest values, followed by fibrinogen, tenascin and laminin. Moreover, all tested strains showed the capability to adhere to polystyrole surfaces and form biofilms [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Vollmer T, Hinse D, Kleesiek K, Dreier J: Interactions between endocarditis-derived Streptococcus gallolyticus subsp. gallolyticus isolates and human endothelial cells. BMC Microbiol. 2010, 10: 78-10.1186/1471-2180-10-78." href="/articles/10.1186/1756-9966-30-11#ref-CR108" id="ref-link-section-d87701628e1733">108</a>]. Another study which assessed 17 endocarditis-derived human isolates, identified 15 <i>S. gallolyticus</i> subspecies <i>gallolyticus</i>, one <i>S. gallolyticus</i> subspecies <i>pasteurianus</i> (biotype II/2) and <i>one S. infantarius</i> subspecies <i>coli</i> (biotype II/1) for their in vitro adherence to components of the extracellular matrix. They found that <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> has very efficient adherence characteristics to the host extracellular matrix; this bacteria showed powerful adherence to collagen type I and type IV, fibrinogen, collagen type V, and fibronectin [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Sillanpaa J, Nallapareddy SR, Singh KV, Ferraro MJ, Murray BE: Adherence characteristics of endocarditis-derived Streptococcus gallolyticus ssp. gallolyticus (Streptococcus bovis biotype I) isolates to host extracellular matrix proteins. FEMS Microbiol Lett. 2008, 289: 104-109. 10.1111/j.1574-6968.2008.01378.x." href="/articles/10.1186/1756-9966-30-11#ref-CR109" id="ref-link-section-d87701628e1762">109</a>] (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). These adherence criteria make <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> a successful colonizer in both intestinal and cardiac tissues. Therefore, it has been stated that the relationship between <i>S. bovis/gallolyticus</i> endocarditis and <i>S. bovis/gallolyticus</i> colonic tumors suggests the existence of certain adhesins on the cell wall of these bacteria allowing the colonization of both colonic and vascular tissues [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Sillanpaa J, Nallapareddy SR, Qin X, Singh KV, Muzny DM, Kovar CL, Nazareth LV, Gibbs RA, Ferraro MJ, Steckelberg JM, et al.: A collagen-binding adhesin, Acb, and ten other putative MSCRAMM and pilus family proteins of Streptococcus gallolyticus subsp. gallolyticus (Streptococcus bovis Group, biotype I). J Bacteriol. 2009, 191: 6643-6653. 10.1128/JB.00909-09." href="/articles/10.1186/1756-9966-30-11#ref-CR106" id="ref-link-section-d87701628e1781">106</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Boleij A, Schaeps RM, de Kleijn S, Hermans PW, Glaser P, Pancholi V, Swinkels DW, Tjalsma H: Surface-exposed histone-like protein a modulates adherence of Streptococcus gallolyticus to colon adenocarcinoma cells. Infect Immun. 2009, 77: 5519-5527. 10.1128/IAI.00384-09." href="/articles/10.1186/1756-9966-30-11#ref-CR107" id="ref-link-section-d87701628e1784">107</a>].</p><h3 class="c-article__sub-heading" id="Sec11">Altering the profile of bacterial flora</h3><p>The members of gut microflora contribute to several intestinal functions, including the development of mucosal immune system, the absorption of complex macromolecules, the synthesis of amino acids and vitamins, and the protection against pathogenic microorganisms. In order to keep the mutual relationship between the microflora and the intestinal function, it is important that microflora is continuously kept under control to preserve gut homeostasis. When this is not achieved or perturbed, several immune disorders can arise, like allergies, inflammation, and cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Rescigno M: The pathogenic role of intestinal flora in IBD and colon cancer. Curr Drug Targets. 2008, 9: 395-403. 10.2174/138945008784221125." href="/articles/10.1186/1756-9966-30-11#ref-CR110" id="ref-link-section-d87701628e1795">110</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 111" title="Yang FJ, Jiao DA, Li SY: [Intestinal bacterial flora and cancer of the large bowel]. Zhonghua Liu Xing Bing Xue Za Zhi. 1996, 17: 52-53." href="/articles/10.1186/1756-9966-30-11#ref-CR111" id="ref-link-section-d87701628e1798">111</a>]. Increased incidence of hepatic dysfunction was reported among patients with infectious endocarditis caused by <i>S. bovis/gallolyticus</i>[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Fagundes J, Noujain H, Coy C, Ayrizono M, Góes J, Martinuzzo W: Associação entre endocardite bacteriana e neoplasias - relato de 4 casos. Rev Bras Coloproctol. 2000, 20: 95-99." href="/articles/10.1186/1756-9966-30-11#ref-CR77" id="ref-link-section-d87701628e1804">77</a>]. Both colonic pathology and liver dysfunction were determined in 92 patients with <i>S. bovis</i> endocarditis/bacteremia. Colonic pathology was identified in 51%, and liver disease or dysfunction was documented in 56% of patients with <i>S. bovis/gallolyticus</i> endocarditis/bacteremia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Zarkin BA, Lillemoe KD, Cameron JL, Effron PN, Magnuson TH, Pitt HA: The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Ann Surg. 1990, 211: 786-791. 10.1097/00000658-199006000-00019. discussion 791-782" href="/articles/10.1186/1756-9966-30-11#ref-CR4" id="ref-link-section-d87701628e1814">4</a>]. It was conceived that either the underlying colonic disease or the alterations in hepatic secretion of bile salts or immunoglobulins may promote the overgrowth of <i>S. bovis</i> and its translocation from the intestinal lumen into the portal venous system [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Zarkin BA, Lillemoe KD, Cameron JL, Effron PN, Magnuson TH, Pitt HA: The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Ann Surg. 1990, 211: 786-791. 10.1097/00000658-199006000-00019. discussion 791-782" href="/articles/10.1186/1756-9966-30-11#ref-CR4" id="ref-link-section-d87701628e1820">4</a>] (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>).</p><p>Alike, it has been speculated that <i>S. bovis/gallolyticus</i> affects portal circulation through bacterial translocation, thereby determining hepatic alterations. Modifications in the hepatic secretion of bile salts and the production of immunoglobulins contribute towards increasing the participation of <i>S. bovis/gallolyticus</i> in abnormal changes in the bacterial flora of the colonic lumen which might then promote carcinogenesis of the intestinal mucosa [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Gupta A, Madani R, Mukhtar H: Streptococcus bovis endocarditis; a silent sign for colonic tumour. Colorectal Dis. 2010, 12 (3): 164-71. 10.1111/j.1463-1318.2009.01814.x." href="/articles/10.1186/1756-9966-30-11#ref-CR7" id="ref-link-section-d87701628e1835">7</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Beeching NJ, Christmas TI, Ellis-Pegler RB, Nicholson GI: Streptococcus bovis bacteraemia requires rigorous exclusion of colonic neoplasia and endocarditis. Q J Med. 1985, 56: 439-450." href="/articles/10.1186/1756-9966-30-11#ref-CR84" id="ref-link-section-d87701628e1838">84</a>].</p><h3 class="c-article__sub-heading" id="Sec12">Promoter of early preneoplastic lesions</h3><p>A series of interesting experiments was conducted to investigate the role of <i>S. bovis/gallolyticus</i> in the initiation versus the propagation of colorectal cancer. Chemical carcinomas of colon were induced by giving adult rats intraperitonial injections of azoxymethane (15 mg/kg body weight) once per week for 2 weeks. Fifteen days (week 4) after the last injection of the carcinogen, the rats received, by gavage twice per week during 5 weeks, either <i>S. bovis</i> (10<sup>10</sup> bacteria) or its wall-extracted antigens (100 μg). One week after the last gavage (week 10), it was found that administration of either <i>S. bovis</i> or its antigens promoted the progression of preneoplastic lesions, but not normal tissue, into neoplastic lesions through the increased formation of hyperproliferative aberrant colonic crypts, which enhanced the expression of proliferation markers and increased the production of IL-8 in the colonic mucosa [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1861">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Ellmerich S, Djouder N, Scholler M, Klein JP: Production of cytokines by monocytes, epithelial and endothelial cells activated by Streptococcus bovis. Cytokine. 2000, 12: 26-31. 10.1006/cyto.1999.0521." href="/articles/10.1186/1756-9966-30-11#ref-CR89" id="ref-link-section-d87701628e1865">89</a>] (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). Therefore, it was suggested that <i>S. bovis/gallolyticus</i> acts as a potential promoter of early preneoplastic lesions in the colon of rats, and their cell wall proteins are more potent inducers of neoplastic transformation than the intact bacteria. Moreover, the development of colonic adenomas was increased remarkably in 50% of the tested rats together with the proliferation markers, namely the polyamine content and the proliferating cell nuclear antigen PCNA [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Ellmerich S, Scholler M, Duranton B, Gosse F, Galluser M, Klein JP, Raul F: Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000, 21: 753-756. 10.1093/carcin/21.4.753." href="/articles/10.1186/1756-9966-30-11#ref-CR37" id="ref-link-section-d87701628e1874">37</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1877">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Nguyen I, Biarc J, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein J, et al.: Streptococcus infantarius and colonic cancer: Identification and purification of cell wall proteins putatively involved in colorectal inflammation and carcinogenesis in rats. International Congress Series. 2006, 257-261. 10.1016/j.ics.2005.11.081." href="/articles/10.1186/1756-9966-30-11#ref-CR96" id="ref-link-section-d87701628e1880">96</a>]. This provided extra evidence that <i>S. bovis/gallolyticus</i> acts more likely as promoter/propagator of colorectal carcinoma rather than just a consequence of the tumor lesion. However, these studies might suggest that bacteria are not sufficient to induce cancer by their own. Hence, tumor development might require independent mutations in the oncogenic signaling pathways together with chronic inflammatory conditions which are needed to promote, propagate, and spread tumor lesions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Balkwill F, Charles KA, Mantovani A: Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005, 7: 211-217. 10.1016/j.ccr.2005.02.013." href="/articles/10.1186/1756-9966-30-11#ref-CR88" id="ref-link-section-d87701628e1887">88</a>].</p><h3 class="c-article__sub-heading" id="Sec13">Induction of uncontrolled cellular proliferation</h3><p>In the presence of wall extracted proteins of <i>S. bovis/gallolyticus</i>, Caco-2 cells exhibited enhanced phosphorylation of 3 classes of mitogen activated protein kinases (MAPKs) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e1901">38</a>]. Several reports showed that MAPKs activation stimulates cells to undergo DNA synthesis and cellular uncontrolled proliferation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 112" title="Ihler GM: Bartonella bacilliformis: dangerous pathogen slowly emerging from deep background. FEMS Microbiol Lett. 1996, 144: 1-11. 10.1111/j.1574-6968.1996.tb08501.x." href="/articles/10.1186/1756-9966-30-11#ref-CR112" id="ref-link-section-d87701628e1904">112</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 114" title="Smith DG, Lawson GH: Lawsonia intracellularis: getting inside the pathogenesis of proliferative enteropathy. Vet Microbiol. 2001, 82: 331-345. 10.1016/S0378-1135(01)00397-2." href="/articles/10.1186/1756-9966-30-11#ref-CR114" id="ref-link-section-d87701628e1907">114</a>] (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). Therefore <i>S. bovis/gallolyticus</i> proteins could promote cell proliferation by triggering MAPKs which might increase the incidence of cell transformation and the rate of genetic mutations. Furthermore, MAPKs, particularly p38 MAPK, can induce COX-2 which is an important factor in tumorogenesis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Wang D, Dubois RN: The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010, 29: 781-788. 10.1038/onc.2009.421." href="/articles/10.1186/1756-9966-30-11#ref-CR29" id="ref-link-section-d87701628e1917">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Lasa M, Abraham SM, Boucheron C, Saklatvala J, Clark AR: Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol. 2002, 22: 7802-7811. 10.1128/MCB.22.22.7802-7811.2002." href="/articles/10.1186/1756-9966-30-11#ref-CR115" id="ref-link-section-d87701628e1920">115</a>] up-regulating the expression of NFkB which is considered the central link between inflammation and carcinogenesis, namely, inflammation-induced tumor progression [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005, 5: 749-759. 10.1038/nri1703." href="/articles/10.1186/1756-9966-30-11#ref-CR92" id="ref-link-section-d87701628e1923">92</a>].</p><h3 class="c-article__sub-heading" id="Sec14">Colonization of Streptococcus gallolyticus in colorectal mucosa</h3><p>The association of <i>S. bovis/gallolyticus</i> with colorectal cancer has usually been described through the incidence of <i>S. bovis/gallolyticus</i> bacteremia and/or endocarditis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Wilson WR, Thompson RL, Wilkowske CJ, Washington JA, Giuliani ER, Geraci JE: Short-term therapy for streptococcal infective endocarditis. Combined intramuscular administration of penicillin and streptomycin. JAMA. 1981, 245: 360-363. 10.1001/jama.245.4.360. 2" href="/articles/10.1186/1756-9966-30-11#ref-CR1" id="ref-link-section-d87701628e1940">1</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Zarkin BA, Lillemoe KD, Cameron JL, Effron PN, Magnuson TH, Pitt HA: The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Ann Surg. 1990, 211: 786-791. 10.1097/00000658-199006000-00019. discussion 791-782" href="/articles/10.1186/1756-9966-30-11#ref-CR4" id="ref-link-section-d87701628e1943">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Murray HW, Roberts RB: Streptococcus bovis bacteremia and underlying gastrointestinal disease. Arch Intern Med. 1978, 138: 1097-1099. 10.1001/archinte.138.7.1097." href="/articles/10.1186/1756-9966-30-11#ref-CR44" id="ref-link-section-d87701628e1946">44</a>]. On the other hand, little bacteriological research has been done [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Potter MA, Cunliffe NA, Smith M, Miles RS, Flapan AD, Dunlop MG: A prospective controlled study of the association of Streptococcus bovis with colorectal carcinoma. J Clin Pathol. 1998, 51: 473-474. 10.1136/jcp.51.6.473." href="/articles/10.1186/1756-9966-30-11#ref-CR116" id="ref-link-section-d87701628e1950">116</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Norfleet RG, Mitchell PD: Streptococcus bovis does not selectively colonize colorectal cancer and polyps. J Clin Gastroenterol. 1993, 17: 25-28. 10.1097/00004836-199307000-00008." href="/articles/10.1186/1756-9966-30-11#ref-CR117" id="ref-link-section-d87701628e1953">117</a>] on elucidating the colonization of <i>S. bovis/gallolyticus</i> in tumor lesions of colorectal cancer to confirm or refute, on solid bases, the direct link between colorectal cancer and <i>S. bovis/gallolyticus</i>. Previous studies [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Potter MA, Cunliffe NA, Smith M, Miles RS, Flapan AD, Dunlop MG: A prospective controlled study of the association of Streptococcus bovis with colorectal carcinoma. J Clin Pathol. 1998, 51: 473-474. 10.1136/jcp.51.6.473." href="/articles/10.1186/1756-9966-30-11#ref-CR116" id="ref-link-section-d87701628e1962">116</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Norfleet RG, Mitchell PD: Streptococcus bovis does not selectively colonize colorectal cancer and polyps. J Clin Gastroenterol. 1993, 17: 25-28. 10.1097/00004836-199307000-00008." href="/articles/10.1186/1756-9966-30-11#ref-CR117" id="ref-link-section-d87701628e1965">117</a>] did not find clear evidence for the colonization of <i>S. bovis/gallolyticus</i> in colorectal tumors. This might be attributed to the complete reliance on bacteriological methods rather than more sensitive molecular assays for the detection of <i>S. bovis/gallolyticus</i> nucleic acids.</p><p>A recent study done by our team assessed the colonization of <i>S. bovis/gallolyticus</i> in the colon [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e1981">40</a>]. In this study, <i>S. bovis/gallolyticus</i>-specific primers and probes were used in PCR and in situ hybridization (ISH) assays, respectively, along with bacteriological isolation of <i>S. bovis/gallolyticus</i> to detect/isolate <i>S. bovis/gallolyticus</i> DNA/cells from feces, tumor mucosal surfaces, and from inside tumor lesions. <i>S. bovis/gallolyticus</i> was remarkably isolated, via bacteriological assays, from tumor tissues of colorectal cancer patients with history of bacteremia, 20.5%, and without history of bacteremia, 12.8%, while only 2% of normal tissues of age- and sex- matched control subjects revealed colonization of <i>S. bovis/gallolyticus</i>. On the other hand, the positive detection of <i>S. bovis/gallolyticus</i> DNA, via PCR and ISH assays, in tumor tissues of colorectal cancer patients with history of bacteremia, 48.7 and 46.1%, and without history of bacteremia, 32.7 and 28.8%, was remarkably higher than in normal tissues of controls, 4%, and 2%, respectively. In addition, by using absolute quantitative PCR for <i>S. bovis/gallolyticus</i> DNA, the <i>S. bovis/gallolyticus</i> count, in terms of copy number (CN), in tumor tissues of colorectal cancer patients with history of bacteremia, 2.96-4.72 log<sub>10</sub> CN/g, and without history of bacteremia, 2.16-2.92 log<sub>10</sub> CN/g, was higher than the near-zero colonization in normal tissues. Moreover, the level of <i>S.bovis/gallolyticus</i> colonization in colorectal cancer patients with history of bacteremia was found significantly higher than in colorectal cancer patients without history of bacteremia (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1756-9966-30-11#Fig1">1</a>). This study provided several new clues. First, <i>S. bovis/gallolyticus</i> colonizes actively the lesion tissues of colorectal cancer patients rather than normal mucosal tissues. Second, the colonization of <i>S. bovis/gallolyticus</i> is mainly found inside tumor lesions rather than on mucosal surfaces. Third, the titer of the colonizing <i>S. bovis/gallolyticus</i> in colorectal cancer patients with history of bacteremia/endocarditis is much higher than in patients without history of bacteremia/endocarditis; this explains why some colorectal cancer patients develop concomitant bacteremia/<i>endocarditis</i> while others do not. Actually, the newly found selective colonization of <i>S. bovis/gallolyticus</i> explains the conclusions of an earlier report [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Tjalsma H, Scholler-Guinard M, Lasonder E, Ruers TJ, Willems HL, Swinkels DW: Profiling the humoral immune response in colon cancer patients: diagnostic antigens from Streptococcus bovis. Int J Cancer. 2006, 119: 2127-2135. 10.1002/ijc.22116." href="/articles/10.1186/1756-9966-30-11#ref-CR118" id="ref-link-section-d87701628e2036">118</a>] stating that colonic lesions provide a suitable microenvironment for <i>S. bovis/gallolyticus</i> colonization resulting in silent tumor-associated infections that only become apparent when cancer patients become immunocompromised, as in bacteraemia, or have coincidental cardiac valve lesions and develop endocarditis. An earlier study conducted by Swidsinski team [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 119" title="Swidsinski A, Khilkin M, Kerjaschki D, Schreiber S, Ortner M, Weber J, Lochs H: Association between intraepithelial Escherichia coli and colorectal cancer. Gastroenterology. 1998, 115: 281-286. 10.1016/S0016-5085(98)70194-5." href="/articles/10.1186/1756-9966-30-11#ref-CR119" id="ref-link-section-d87701628e2042">119</a>] found similar results to our study [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e2045">40</a>] but on different bacteria. They quantified bacteria in colonic biopsy specimens of normal and cancer patients by polymerase chain reaction and found that the colonic mucosa of patients with colorectal carcinoma but not normal colonic mucosa was colonized by intracellular <i>Escherichia coli</i>.</p></div></div></section><section data-title="Early detection of colorectal cancer by detecting S. bovis/gallolyticus as one of the potential causative agents"><div class="c-article-section" id="Sec15-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec15">Early detection of colorectal cancer by detecting <i>S. bovis/gallolyticus</i> as one of the potential causative agents</h2><div class="c-article-section__content" id="Sec15-content"><p>About 65% of population with age more than 60 years are at high risk for colorectal cancer which indicates the need for a proper screening test for the early detection of colorectal cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Rougier P, Mitry E: Epidemiology, treatment and chemoprevention in colorectal cancer. Ann Oncol. 2003, 14 (Suppl 2): ii3-5." href="/articles/10.1186/1756-9966-30-11#ref-CR120" id="ref-link-section-d87701628e2065">120</a>]. For localized cancers, the five-year survival rate is approximately 90 percent for colon cancer and 80 percent for cancer of the rectum; this actually provides the suitable basis for improving patients' survival by applying reliable and early detection methods [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Mager DL: Bacteria and cancer: cause, coincidence or cure? A review. J Transl Med. 2006, 4: 14-10.1186/1479-5876-4-14." href="/articles/10.1186/1756-9966-30-11#ref-CR30" id="ref-link-section-d87701628e2068">30</a>].</p><p>Very few studies were conducted to investigate the seroprevalence of <i>S. bovis/gallolyticus</i> among colorectal cancer patients. Seroprevalence of <i>S. bovis/gallolyticus</i> is considered as a candidate practical marker for the early prediction of an underlying bowel lesion at high risk population. It has been suggested that the presence of antibodies to <i>S. bovis/gallolyticus</i> antigens or the antigens themselves in the bloodstream may act as markers for the carcinogenesis in the colon [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Beeching NJ, Christmas TI, Ellis-Pegler RB, Nicholson GI: Streptococcus bovis bacteraemia requires rigorous exclusion of colonic neoplasia and endocarditis. Q J Med. 1985, 56: 439-450." href="/articles/10.1186/1756-9966-30-11#ref-CR84" id="ref-link-section-d87701628e2083">84</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="zur Hausen H: Streptococcus bovis: causal or incidental involvement in cancer of the colon?. Int J Cancer. 2006, 119: xi-xii. 10.1002/ijc.22314." href="/articles/10.1186/1756-9966-30-11#ref-CR87" id="ref-link-section-d87701628e2086">87</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Potter MA, Cunliffe NA, Smith M, Miles RS, Flapan AD, Dunlop MG: A prospective controlled study of the association of Streptococcus bovis with colorectal carcinoma. J Clin Pathol. 1998, 51: 473-474. 10.1136/jcp.51.6.473." href="/articles/10.1186/1756-9966-30-11#ref-CR116" id="ref-link-section-d87701628e2090">116</a>]. In a study [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Darjee R, Gibb AP: Serological investigation into the association between Streptococcus bovis and colonic cancer. J Clin Pathol. 1993, 46: 1116-1119. 10.1136/jcp.46.12.1116." href="/articles/10.1186/1756-9966-30-11#ref-CR121" id="ref-link-section-d87701628e2093">121</a>], it was stated that it might be possible to develop a test to screen patients for the presence of colonic cancer by measuring IgG antibody titer of <i>S. bovis/gallolyticus</i>. Moreover, the same report [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Darjee R, Gibb AP: Serological investigation into the association between Streptococcus bovis and colonic cancer. J Clin Pathol. 1993, 46: 1116-1119. 10.1136/jcp.46.12.1116." href="/articles/10.1186/1756-9966-30-11#ref-CR121" id="ref-link-section-d87701628e2099">121</a>] revealed that there is a need for a good screening test for colonic cancer, particularly a test which could detect early lesions. The serology-based detection of colorectal cancer has advantages on other tests such as fecal occult blood which is neither sensitive nor specific or carcinoembryonic antigen which is regularly detectable in only advanced diseases [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Tafte L, Ruoff K: Streptococcus bovis: Answers and Questions. Clin microbial newslett. 2007, 29: 49-55. 10.1016/j.clinmicnews.2007.03.004." href="/articles/10.1186/1756-9966-30-11#ref-CR103" id="ref-link-section-d87701628e2102">103</a>].</p><p>Panwalker [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 122" title="Panwalker AP: Unusual infections associated with colorectal cancer. Rev Infect Dis. 1988, 10: 347-364." href="/articles/10.1186/1756-9966-30-11#ref-CR122" id="ref-link-section-d87701628e2108">122</a>] revealed that the lack of any consistent difference in IgM antibody titer of <i>S. bovis</i> biotype I between colorectal cancer patients and control population suggests that the increased immune stimulation of colorectal cancer patients towards <i>S. bovis</i> occurs over a long period of time. Hence, since the association between slow evolving bacterial inflammation and colorectal cancer takes long time, it is prudent to seek specifically for IgG antibodies. Furthermore, IgG antibodies reflect an image of the past as well as the current presence of <i>S. bovis/gallolyticus</i> antigens in the circulation.</p><p>Some recent studies showed the possibility of constructing a serology test for the detection of colonic cancer based on the detection of antibody to <i>S. bovis/gallolyticus</i> or <i>Enterococcus faecalis</i>[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e2129">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 123" title="Groves C: Case presentation. The Jhon Hokins Microbiology Newsletter. 1997, 16: 42-44." href="/articles/10.1186/1756-9966-30-11#ref-CR123" id="ref-link-section-d87701628e2132">123</a>]. Therefore, a simple ELISA test with no more than 2 ml of patient's blood might be a good candidate for screening high risk individuals for the presence of premalignant neoplastic polyps, adenomas, and cancers. However, some older studies of antibody response to <i>S. bovis/gallolyticus</i> and other streptococci have found that antibody is detectable in endocarditis but not in either clinically insignificant bacteremias [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 124" title="Burnie JP, Holland M, Matthews RC, Lees W: Role of immunoblotting in the diagnosis of culture negative and enterococcal endocarditis. J Clin Pathol. 1987, 40: 1149-1158. 10.1136/jcp.40.10.1149." href="/articles/10.1186/1756-9966-30-11#ref-CR124" id="ref-link-section-d87701628e2139">124</a>], or colonic cancers [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 125" title="Kaplan MH, Chmel H, Stephens A, Hsieh HC, Tenenbaum MJ, Rothenberg IR, Joachim GR: Humoral reactions in human endocarditis due to Streptococcus bovis: evidence for a common S bovis antigen. J Infect Dis. 1983, 148: 266-274." href="/articles/10.1186/1756-9966-30-11#ref-CR125" id="ref-link-section-d87701628e2142">125</a>] by using immunoblotting, immunoflourescence and other techniques.</p><p>In a recent study of our team [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Abdulamir AS, Hafidh RR, Mahdi LK, Al-jeboori T, Abubaker F: Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009, 9: 403-10.1186/1471-2407-9-403." href="/articles/10.1186/1756-9966-30-11#ref-CR39" id="ref-link-section-d87701628e2149">39</a>], the level of IgG antibodies, measured via ELISA, against <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> was found to be significantly higher in colorectal cancer patients than in control subjects. This is in full agreement with the study of Darjee and Gibb [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Darjee R, Gibb AP: Serological investigation into the association between Streptococcus bovis and colonic cancer. J Clin Pathol. 1993, 46: 1116-1119. 10.1136/jcp.46.12.1116." href="/articles/10.1186/1756-9966-30-11#ref-CR121" id="ref-link-section-d87701628e2158">121</a>] who showed that patients with colonic cancer had higher median IgG antibody titers to <i>S. bovis</i> and <i>E. faecalis</i> preparations than did the control samples. Hence, the seroprevalence of IgG antibodies against <i>S. gallolyticus</i> subspecies <i>gallolyticus</i> showed the same behavior to that against <i>S. bovis</i> biotype I NCTC8133 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Darjee R, Gibb AP: Serological investigation into the association between Streptococcus bovis and colonic cancer. J Clin Pathol. 1993, 46: 1116-1119. 10.1136/jcp.46.12.1116." href="/articles/10.1186/1756-9966-30-11#ref-CR121" id="ref-link-section-d87701628e2177">121</a>].</p><p>A question might be asked, is it reliable to consider the seroprevalence of IgG antibodies against <i>S. bovis/gallolyticus</i> as an indicator for the detection of colorectal cancer given that <i>S. bovis/gallolyticus</i> is a member of intestinal microflora in 2.5 to 15% of normal individuals. In fact there are many factors support the concept of using the seroprevalence of <i>S. bovis/gallolyticus</i> as a detection tool. First, it was shown that the fecal carriage of <i>S. bovis/gallolyticus</i> increases in cases of colorectal cancer [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Reynolds JG, Silva E, McCormack WM: Association of Streptococcus bovis bacteremia with bowel disease. J Clin Microbiol. 1983, 17: 696-697." href="/articles/10.1186/1756-9966-30-11#ref-CR2" id="ref-link-section-d87701628e2195">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Klein RS, Catalano MT, Edberg SC, Casey JI, Steigbigel NH: Streptococcus bovis septicemia and carcinoma of the colon. Ann Intern Med. 1979, 91: 560-562." href="/articles/10.1186/1756-9966-30-11#ref-CR67" id="ref-link-section-d87701628e2199">67</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Burns CA, McCaughey R, Lauter CB: The association of Streptococcus bovis fecal carriage and colon neoplasia: possible relationship with polyps and their premalignant potential. Am J Gastroenterol. 1985, 80: 42-46." href="/articles/10.1186/1756-9966-30-11#ref-CR75" id="ref-link-section-d87701628e2202">75</a>]. Second, <i>S. bovis/gallolyticus</i> has showed selective adhesion characteristics to the tumor tissue of colorectum [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Sillanpaa J, Nallapareddy SR, Qin X, Singh KV, Muzny DM, Kovar CL, Nazareth LV, Gibbs RA, Ferraro MJ, Steckelberg JM, et al.: A collagen-binding adhesin, Acb, and ten other putative MSCRAMM and pilus family proteins of Streptococcus gallolyticus subsp. gallolyticus (Streptococcus bovis Group, biotype I). J Bacteriol. 2009, 191: 6643-6653. 10.1128/JB.00909-09." href="/articles/10.1186/1756-9966-30-11#ref-CR106" id="ref-link-section-d87701628e2208">106</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Boleij A, Schaeps RM, de Kleijn S, Hermans PW, Glaser P, Pancholi V, Swinkels DW, Tjalsma H: Surface-exposed histone-like protein a modulates adherence of Streptococcus gallolyticus to colon adenocarcinoma cells. Infect Immun. 2009, 77: 5519-5527. 10.1128/IAI.00384-09." href="/articles/10.1186/1756-9966-30-11#ref-CR107" id="ref-link-section-d87701628e2211">107</a>]. Third, the alteration in local conditions and the disruption of capillary channels at the site of neoplasm allow <i>S. bovis/gallolyticus</i> to proliferate and gain entry into the blood stream, [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, Van Dorsselaer A, Leize-Wagner E, Raul F, Klein JP, et al.: Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). Carcinogenesis. 2004, 25: 1477-1484. 10.1093/carcin/bgh091." href="/articles/10.1186/1756-9966-30-11#ref-CR38" id="ref-link-section-d87701628e2218">38</a>] which ultimately induces immune system to actively produce remarkable specific antibodies towards <i>S. bovis/gallolyticus</i>. Fourth, <i>S. bovis/gallolyticus</i> was shown to colonize tumor lesions selectively at high titers and this colonization is located deeply inside tumor tissues rather than superficially on mucosal surfaces; this feature increases the chances of triggering the systemic, along with mucosal, immune response leading to the development of anti- <i>S. bovis/gallolyticus</i> IgM and IgG antibodies [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Abdulamir AS, Hafidh RR, Abu Bakar F: Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010, 9: 249-10.1186/1476-4598-9-249." href="/articles/10.1186/1756-9966-30-11#ref-CR40" id="ref-link-section-d87701628e2230">40</a>]. Fifth, biochemical tests are not helpful diagnostic tools because of the wide variety of phenotypes seen in the <i>S. bovis/gallolyticus</i> complex; thus, instead, it is necessary to use serological or molecular methods [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 126" title="Herrera P, Kwon YM, Ricke SC: Ecology and pathogenicity of gastrointestinal Streptococcus bovis. Anaerobe. 2009, 15: 44-54. 10.1016/j.anaerobe.2008.11.003." href="/articles/10.1186/1756-9966-30-11#ref-CR126" id="ref-link-section-d87701628e2237">126</a>].</p></div></div></section><section data-title="Conclusions"><div class="c-article-section" id="Sec16-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec16">Conclusions</h2><div class="c-article-section__content" id="Sec16-content"><p>It is concluded from the lump of research done in this field that <i>S. bovis/gallolyticus</i> association with colorectal tumors seems to be of etiological nature. And the pro-inflammatory potential of <i>S. bovis/gallolyticus</i> and their pro-carcinogenic properties including the leucocytic recruitment driven by <i>S. bovis/gallolyticus</i>, the tumor tissue- selective adhesion potential of <i>S. bovis/gallolyticus</i>, the selective colonization of <i>S. bovis/gallolyticus</i> in tumor cells, the suitable microenvironment of tumor tissues for the <i>S. bovis/gallolyticus</i> proliferation, the local disruption of tumor tissues and capillaries which allow the entry of <i>S. bovis/gallolyticus</i> into blood circulation, and the <i>S. bovis/gallolyticus</i>- induced cytokines and transcriptional factors, such as IL-1, IFN-γ, IL-8, and NFkB, all collectively provide evidence that <i>S. bovis/gallolyticus</i> is most probably responsible for a slow progressing carcinogenesis of colorectal mucosal tissues. Moreover, the <i>S. bovis/gallolyticus</i>- based carcinogenesis appears to occur through the transformation process from normal tissue to premalignant lesions, adenomas, to finally malignant cancerous tissues. And the proposed carcinogenic potential of <i>S. bovis/gallolyticus</i> is most likely a propagating factor for premalignant tissues. 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Therefore, sincere thanks for those who supported all prior pilot studies in this field.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Institute of Bioscience, University Putra Malaysia, 43400, Serdang, Selangor, Malaysia</p><p class="c-article-author-affiliation__authors-list">Ahmed S Abdulamir, Rand R Hafidh & Fatimah Abu Bakar</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Ahmed_S-Abdulamir-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Ahmed S Abdulamir</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Ahmed%20S%20Abdulamir" class="c-article-button" data-track="click" data-track-action="author link - 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AS, RR, and FAB drafted the review and prepared the review structure. all authors read and approved the final manuscript.</p></div></div></section><section data-title="Authors’ original submitted files for images"><div class="c-article-section" id="Sec17-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec17">Authors’ original submitted files for images</h2><div class="c-article-section__content" id="Sec17-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><p>Below are the links to the authors’ original submitted files for images.</p><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM1"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 1" href="https://static-content.springer.com/esm/art%3A10.1186%2F1756-9966-30-11/MediaObjects/13046_2010_431_MOESM1_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 1</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"> <p>This article is published under license to BioMed Central Ltd. 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The association of <i>Streptococcus bovis/gallolyticus</i> with colorectal tumors: The nature and the underlying mechanisms of its etiological role. <i>J Exp Clin Cancer Res</i> <b>30</b>, 11 (2011). https://doi.org/10.1186/1756-9966-30-11</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1186/1756-9966-30-11?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span 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