Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
James Cook University Hospital, Middlesbrough, U.K.
Br J Dermatol. 2016 Dec;175(6):1210-1220. doi: 10.1111/bjd.14720. Epub 2016 Sep 13.
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.
To define the contribution and prognostic impact of CXCR4-CXCR7-CXCL12 signalling in primary cutaneous melanomas and the immediate tumour microenvironment.
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.
CXCR4 expression was significantly higher in primary melanomas that subsequently metastasized after 7 years (P = 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 (P = 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 (P = 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.
CXCR4 expression defines a potential prognostic biomarker for AJCC stage II melanoma. Moreover, targeting the CXCR4-CXCR7-CXCL12 axis may represent a novel therapeutic strategy to prevent early melanoma progression.
趋化因子受体 CXCR4 的表达被认为可调节黑色素瘤向高表达趋化因子配体 CXCL12 的远处部位转移。然而，CXCR4 表达的预后影响和潜在的自分泌激活生存丝裂原活化蛋白激酶信号仍不清楚。此外，局部皮肤黑色素瘤微环境中诱饵受体 CXCR7 的表达仍未定义。
定义 CXCR4-CXCR7-CXCL12 信号在原发性皮肤黑色素瘤及其周围肿瘤微环境中的作用和预后影响。
分析了人转移性黑色素瘤细胞系、原发性皮肤细胞类型和原发性黑色素瘤/良性痣回顾性队列中 CXCR4、CXCR7 或 CXCL12 的免疫组织化学/免疫荧光表达。通过酶联免疫吸附试验评估黑色素瘤/皮肤细胞分泌的 CXCL12，并通过添加 CXCL12 中和抗体研究自分泌 CXCR4-CXCL12 信号。
在经过 7 年时间后发生转移的原发性黑色素瘤中，CXCR4 表达显著升高（P=0.037）。对于 AJCC 分期 II 期疾病的分层显示，CXCR4 表达>50%的患者无疾病生存率显著降低（P=0.036），而对所有 AJCC 分期黑色素瘤相邻表皮中 CXCL12 表达的比较分析显示，CXCL12 表达增加与转移时间延长相关（P=0.014）。CXCR7 在原发性黑色素瘤微环境中表达，但在原发性肿瘤中不表达。向 BRAF 突变黑色素瘤细胞中添加抗-CXCL12 导致磷酸化 CXCR4 和磷酸化细胞外信号调节激酶下调，表明存在自分泌 CXCR4-CXCL12 信号。
CXCR4 表达定义了 AJCC 分期 II 期黑色素瘤的一个潜在预后生物标志物。此外，靶向 CXCR4-CXCR7-CXCL12 轴可能代表一种预防早期黑色素瘤进展的新治疗策略。
