prognostic significance and impact of the CXCR4–CXCR7–CXCL12 axis in primary cutaneous melanoma | British Journal of Dermatology

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McConnell,R. Ellis,B. Pathy,R. Plummer,P.E. Lovat,G. 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Expression of the chemokine receptor CXCR4 is known to regulate melanoma metastasis to distant sites with high expression of the CXCL12 ","pageStart":"1210","pageEnd":"1220","siteName":"OUP Academic","thumbnailURL":"https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/bjd/175/6/10.1111_bjd.14720/2/m_bjd14720-fig-0001.jpeg?Expires=1794581910&Signature=xVkReBMRXqXHJx1eMkPVS2oTA6KadmjteZ86cKp9vWE7Q7Nh5-jJrhwChZjzsy~KKAQ5oPR73ijye892R9mxCjOyJ0xT1oEEh3DGO0CHwUwU~uqBYp5mBDRYiNsFkI-RWm4HvWDR0Ir2g6RVB4llR9-zShjA54BDOIzHLt-T~4unpvKuTr-4nbMXBV4zOatxiKGo739fc~B3imXJepQd3u3goLRmxDGSdrbLhXesl7gD-bh~weVonPFY9bMSSbSA9s3ooFiYP0f2oy77AeUuxOxG0xOEYNXWI92VmfT~BW0Fw9W0ZezepAkzobArwvJUdnyuaLdhj3geZiibRB8fiw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA","headline":"The prognostic significance and impact of the CXCR4–CXCR7–CXCL12 axis in primary cutaneous melanoma","image":"https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/bjd/175/6/10.1111_bjd.14720/2/m_bjd14720-fig-0001.jpeg?Expires=1794581910&Signature=xVkReBMRXqXHJx1eMkPVS2oTA6KadmjteZ86cKp9vWE7Q7Nh5-jJrhwChZjzsy~KKAQ5oPR73ijye892R9mxCjOyJ0xT1oEEh3DGO0CHwUwU~uqBYp5mBDRYiNsFkI-RWm4HvWDR0Ir2g6RVB4llR9-zShjA54BDOIzHLt-T~4unpvKuTr-4nbMXBV4zOatxiKGo739fc~B3imXJepQd3u3goLRmxDGSdrbLhXesl7gD-bh~weVonPFY9bMSSbSA9s3ooFiYP0f2oy77AeUuxOxG0xOEYNXWI92VmfT~BW0Fw9W0ZezepAkzobArwvJUdnyuaLdhj3geZiibRB8fiw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA","image:alt":"CXCR4 expression is a prognostic biomarker in cutaneous melanoma. (a) Representative Western blot of CXCR4 and glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) loading control expression in CHL‐1 (wild‐type), WM‐164 (BRAF V600E mutated) or WM‐1361 (NRAS mutated) human metastatic cutaneous melanoma cell lines or primary melanocytes (n = 4). (b) Densitometric analysis of CXCR4 relative to GADPH expression. Each bar represents the mean of four replicates of CXCR4 band intensity normalized to GAPDH band intensity (CXCR4/GAPDH) for each cell line or primary melanocytes derived from four independent donors, and is expressed relative to the mean of each individual experiment (mean ± SD, n = 4). (c) Representative immunohistochemical expression of CXCR4 in a primary American Joint Committee on Cancer (AJCC) stage III cutaneous melanoma depicting both nuclear and cytoplasmic CXCR4 expression. Images were acquired by light microscopy with magnification ×20, scale bar = 50 μm. (d) Scatter graph representing the mean percentage of positive CXCR4‐staining cells in localized (eventual AJCC stage of disease I/II) and metastatic melanomas (eventual AJCC stage III/IV) after 7 years of follow‐up. Horizontal bars represent the median staining percentage (Mann–Whitney U‐test, P = 0·037). (e) Univariate analysis of mean percentage CXCR4 expression and disease‐free survival (7 years) in all AJCC stage melanomas. Vertical lines represent individual patients developing a metastasis. Log‐rank (Mantel–Cox) test, hazard ratio 1·99 (95% confidence interval 0·81–4·91), P = 0·13. (f) Univariate analysis of percentage CXCR4 expression and disease‐free survival (7 years) in AJCC stage II melanomas. A significantly increased risk of metastasis was detected in AJCC stage II tumours expressing > 50% mean CXCR4 compared with tumours expressing < 50% mean CXCR4. Vertical lines represent individual patients developing a metastasis. Log‐rank (Mantel–Cox) test, hazard ratio 3·24 (95% confidence interval 1·08–9·73), P = 0·036."} </script> <meta property="og:site_name" content="OUP Academic" /> <meta property="og:title" content="The prognostic significance and impact of the CXCR4–CXCR7–CXCL12 axis in primary cutaneous melanoma" /> <meta property="og:description" content="SummaryBackground. Expression of the chemokine receptor CXCR4 is known to regulate melanoma metastasis to distant sites with high expression of the CXCL12 " /> <meta property="og:type" content="article" /> <meta property="og:url" content="https://dx.doi.org/10.1111/bjd.14720" /> <meta property="og:updated_time" content="" /> <meta property="og:image" content="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/bjd/175/6/10.1111_bjd.14720/2/m_bjd14720-fig-0001.jpeg?Expires=1794581910&Signature=xVkReBMRXqXHJx1eMkPVS2oTA6KadmjteZ86cKp9vWE7Q7Nh5-jJrhwChZjzsy~KKAQ5oPR73ijye892R9mxCjOyJ0xT1oEEh3DGO0CHwUwU~uqBYp5mBDRYiNsFkI-RWm4HvWDR0Ir2g6RVB4llR9-zShjA54BDOIzHLt-T~4unpvKuTr-4nbMXBV4zOatxiKGo739fc~B3imXJepQd3u3goLRmxDGSdrbLhXesl7gD-bh~weVonPFY9bMSSbSA9s3ooFiYP0f2oy77AeUuxOxG0xOEYNXWI92VmfT~BW0Fw9W0ZezepAkzobArwvJUdnyuaLdhj3geZiibRB8fiw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" /> <meta property="og:image:url" content="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/bjd/175/6/10.1111_bjd.14720/2/m_bjd14720-fig-0001.jpeg?Expires=1794581910&Signature=xVkReBMRXqXHJx1eMkPVS2oTA6KadmjteZ86cKp9vWE7Q7Nh5-jJrhwChZjzsy~KKAQ5oPR73ijye892R9mxCjOyJ0xT1oEEh3DGO0CHwUwU~uqBYp5mBDRYiNsFkI-RWm4HvWDR0Ir2g6RVB4llR9-zShjA54BDOIzHLt-T~4unpvKuTr-4nbMXBV4zOatxiKGo739fc~B3imXJepQd3u3goLRmxDGSdrbLhXesl7gD-bh~weVonPFY9bMSSbSA9s3ooFiYP0f2oy77AeUuxOxG0xOEYNXWI92VmfT~BW0Fw9W0ZezepAkzobArwvJUdnyuaLdhj3geZiibRB8fiw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" /> <meta property="og:image:secure_url" content="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/bjd/175/6/10.1111_bjd.14720/2/m_bjd14720-fig-0001.jpeg?Expires=1794581910&Signature=xVkReBMRXqXHJx1eMkPVS2oTA6KadmjteZ86cKp9vWE7Q7Nh5-jJrhwChZjzsy~KKAQ5oPR73ijye892R9mxCjOyJ0xT1oEEh3DGO0CHwUwU~uqBYp5mBDRYiNsFkI-RWm4HvWDR0Ir2g6RVB4llR9-zShjA54BDOIzHLt-T~4unpvKuTr-4nbMXBV4zOatxiKGo739fc~B3imXJepQd3u3goLRmxDGSdrbLhXesl7gD-bh~weVonPFY9bMSSbSA9s3ooFiYP0f2oy77AeUuxOxG0xOEYNXWI92VmfT~BW0Fw9W0ZezepAkzobArwvJUdnyuaLdhj3geZiibRB8fiw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" /> <meta property="og:image:alt" content="CXCR4 expression is a prognostic biomarker in cutaneous melanoma. (a) Representative Western blot of CXCR4 and glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) loading control expression in CHL‐1 (wild‐type), WM‐164 (BRAF V600E mutated) or WM‐1361 (NRAS mutated) human metastatic cutaneous melanoma cell lines or primary melanocytes (n = 4). (b) Densitometric analysis of CXCR4 relative to GADPH expression. Each bar represents the mean of four replicates of CXCR4 band intensity normalized to GAPDH band intensity (CXCR4/GAPDH) for each cell line or primary melanocytes derived from four independent donors, and is expressed relative to the mean of each individual experiment (mean ± SD, n = 4). (c) Representative immunohistochemical expression of CXCR4 in a primary American Joint Committee on Cancer (AJCC) stage III cutaneous melanoma depicting both nuclear and cytoplasmic CXCR4 expression. Images were acquired by light microscopy with magnification ×20, scale bar = 50 μm. (d) Scatter graph representing the mean percentage of positive CXCR4‐staining cells in localized (eventual AJCC stage of disease I/II) and metastatic melanomas (eventual AJCC stage III/IV) after 7 years of follow‐up. Horizontal bars represent the median staining percentage (Mann–Whitney U‐test, P = 0·037). (e) Univariate analysis of mean percentage CXCR4 expression and disease‐free survival (7 years) in all AJCC stage melanomas. Vertical lines represent individual patients developing a metastasis. Log‐rank (Mantel–Cox) test, hazard ratio 1·99 (95% confidence interval 0·81–4·91), P = 0·13. (f) Univariate analysis of percentage CXCR4 expression and disease‐free survival (7 years) in AJCC stage II melanomas. A significantly increased risk of metastasis was detected in AJCC stage II tumours expressing > 50% mean CXCR4 compared with tumours expressing < 50% mean CXCR4. Vertical lines represent individual patients developing a metastasis. Log‐rank (Mantel–Cox) test, hazard ratio 3·24 (95% confidence interval 1·08–9·73), P = 0·036." /> <meta name="twitter:card" content="summary_large_image" /> <meta name="citation_author" content="McConnell, A.T." /><meta name="citation_author_institution" content="Dermatological Sciences Institute of Cellular Medicine Newcastle University Newcastle upon Tyne U.K" /><meta name="citation_author" content="Ellis, R." /><meta name="citation_author_institution" content="Dermatological Sciences Institute of Cellular Medicine Newcastle University Newcastle upon Tyne U.K" /><meta name="citation_author_institution" content="James Cook University Hospital Middlesbrough U.K" /><meta name="citation_author" content="Pathy, B." /><meta name="citation_author_institution" content="Dermatological Sciences Institute of Cellular Medicine Newcastle University Newcastle upon Tyne U.K" /><meta name="citation_author" content="Plummer, R." /><meta name="citation_author_institution" content="Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne U.K" /><meta name="citation_author" content="Lovat, P.E." /><meta name="citation_author_institution" content="Dermatological Sciences Institute of Cellular Medicine Newcastle University Newcastle upon Tyne U.K" /><meta name="citation_author" content="O'Boyle, G." /><meta name="citation_author_institution" content="Dermatological Sciences Institute of Cellular Medicine Newcastle University Newcastle upon Tyne U.K" /><meta name="citation_author_institution" content="Faculty of Applied Sciences University of Sunderland SunderlandU.K" /><meta name="citation_title" content="The prognostic significance and impact of the CXCR4–CXCR7–CXCL12 axis in primary cutaneous melanoma" /><meta name="citation_firstpage" content="1210" /><meta name="citation_lastpage" content="1220" /><meta name="citation_doi" content="10.1111/bjd.14720" /><meta name="citation_journal_title" content="British Journal of Dermatology" /><meta name="citation_journal_abbrev" content="Br J Dermatol" /><meta name="citation_volume" content="175" /><meta name="citation_issue" content="6" /><meta name="citation_publication_date" content="2016/12/01" /><meta name="citation_issn" content="0007-0963" /><meta name="citation_publisher" content="Oxford Academic" /><meta name="citation_reference" content="citation_title=Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy; 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<div class="navbar-search-advanced"><a href="/bjd/advanced-search" class="advanced-search js-advanced-search">Advanced Search</a></div> </div> <div class="navbar-search-collapsed"><a href="javascript:;" class="icon-menu_search js_expand-navsearch"><span class="screenreader-text">Search Menu</span></a></div> </div> </div> <input id="routename" name="RouteName" type="hidden" value="bjd" /> </div> </div> </div> </div> <div id="ContentTab" class="content active"> <div class="widget widget-ArticleFulltext widget-instance-OUP_Abstract_Article_FullText_Widget"> <div class="module-widget"> <div class="widget-items" data-widgetname="ArticleFulltext"> <h2 scrollto-destination=386856881 id="386856881" class="abstract-title js-splitscreen-abstract-title" >Summary</h2> <section class="abstract"><div class=" sec"><div class="title">Background</div><p class="chapter-para">Expression of the chemokine receptor CXCR4 is known to regulate melanoma metastasis to distant sites with high expression of the CXCL12 ligand. However, the prognostic impact of CXCR4 expression and potential for autocrine‐mediated activation of prosurvival mitogen‐activated protein kinase signalling remains enigmatic. Furthermore, expression of the decoy receptor CXCR7 within the local cutaneous melanoma microenvironment remains undefined.</p></div><div class=" sec"><div class="title">Objectives</div><p class="chapter-para">To define the contribution and prognostic impact of CXCR4–CXCR7–CXCL12 signalling in primary cutaneous melanomas and the immediate tumour microenvironment.</p></div><div class=" sec"><div class="title">Methods</div><p class="chapter-para">Immunohistochemical/immunofluorescent expression of CXCR4, CXCR7 or CXC12 was analysed in human metastatic melanoma cell lines, primary cutaneous cell types and a retrospective cohort of primary melanomas/benign naevi. CXCL12 secretion by melanoma/cutaneous cells was evaluated by enzyme‐linked immunosorbent assay, and autocrine CXCR4–CXCL12 signalling was investigated by addition of a CXCL12‐neutralizing antibody.</p></div><div class=" sec"><div class="title">Results</div><p class="chapter-para">CXCR4 expression was significantly higher in primary melanomas that subsequently metastasized after 7 years (<em>P</em> = 0·037). Stratification for American Joint Committee on Cancer (AJCC) stage II disease revealed significantly decreased disease‐free survival in patients with > 50% CXCR4 expression (<em>P</em> = 0·036), while comparative analysis of CXCL12 expression in the adjacent epidermis of all AJCC stage melanomas revealed increased CXCL12 correlated with prolonged time to metastasis (<em>P</em> = 0·014). CXCR7 was expressed within the primary melanoma microenvironment but was absent on primary tumours. Addition of anti‐CXCL12 to BRAF‐mutant melanoma cells resulted in downregulation of phospho‐CXCR4 and phospho‐extracellular signal‐related kinase, indicating autocrine CXCR4–CXCL12 signalling.</p></div><div class=" sec"><div class="title">Conclusions</div><p class="chapter-para">CXCR4 expression defines a potential prognostic biomarker for AJCC stage II melanoma. 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prognostic significance and impact of the CXCR4–CXCR7–CXCL12 axis in primary cutaneous melanoma | British Journal of Dermatology | Oxford Academic