Department of Oncology, Bichat-Beaujon University Hospital, Paris, France; Department of Internal Medicine, Hematology, and Oncology, University Hospital Brno, Brno, Czechia; School of Medicine, Masaryk University, Brno, Czechia.
Department of Oncology, Bichat-Beaujon University Hospital, Paris, France.
Crit Rev Oncol Hematol. 2017 Mar;111:39-51. doi: 10.1016/j.critrevonc.2017.01.004. Epub 2017 Jan 12.
c-MET is a membrane spanning receptor tyrosine kinase for hepatocyte growth factor (HGF) also termed scatter factor. Transmitting signals from mesenchymal to epithelial cells, the HGF/c-MET axis mediates a range of biological processes that stimulate proliferation, motility, invasiveness, morphogenesis, apoptosis, and angiogenesis. Aberrant c-MET signal transduction favours tumorigenesis with the acquisition of invasive and metastatic phenotypes. Biological functions of c-MET may strongly vary according to microenvironmental changes, which occur at different stages of tumorigenesis and include also HGF/c-MET activation in stromal cells. In this review, we focused on abnormalities in non-nasopharyngeal squamous cell carcinoma of the head & neck. While the prevalence of c-MET mutations and amplifications ranges 0-25%, c-MET upregulation can be found in the majority of squamous head & neck carcinomas. Despite marked heterogeneity in published scoring methods, immunohistochemical overexpression of c-MET has been typically linked to advanced stages and associated with impaired survival and/or resistance to radiotherapy, chemoradiotherapy, and cetuximab. Experimental studies in cell lines and patient-derived xenografts using various c-MET antagonists (both as single-agents and in combination with cytotoxic and epidermal growth factor receptor [EGFR]-directed agents) yielded promising results, albeit benefit in clinical trials remains to be demonstrated. Consequently, selecting more active agents and integrating them effectively in studies, which incorporate predictive biomarkers such as c-MET gene mutations, amplifications, and overexpression, remains challenging. Further investigations should increase emphasis on disentangling the role of tumour-stromal interactions and analyse their potential as modifiers of drug response.
c-MET 是肝细胞生长因子 (HGF) 的跨膜受体酪氨酸激酶，也称为分散因子。HGF/c-MET 轴将信号从间质细胞传递到上皮细胞，介导一系列生物学过程，刺激增殖、迁移、侵袭、形态发生、凋亡和血管生成。异常的 c-MET 信号转导有利于肿瘤发生，获得侵袭性和转移性表型。c-MET 的生物学功能可能根据微环境变化而强烈变化，这些变化发生在肿瘤发生的不同阶段，包括基质细胞中 HGF/c-MET 的激活。在这篇综述中，我们重点讨论了头颈部非鼻咽癌中的异常 c-MET。虽然 c-MET 突变和扩增的发生率为 0-25%，但大多数鳞状头颈部癌中都可以发现 c-MET 的上调。尽管发表的评分方法存在明显的异质性，但 c-MET 的免疫组织化学过表达通常与晚期相关，并与生存不良和/或对放疗、放化疗和西妥昔单抗的耐药性相关。使用各种 c-MET 拮抗剂（单独使用或与细胞毒性药物和表皮生长因子受体 [EGFR] 靶向药物联合使用）在细胞系和患者来源的异种移植模型中的实验研究取得了有希望的结果，尽管临床试验中的获益仍有待证明。因此，选择更有效的药物并有效地将其整合到研究中，纳入 c-MET 基因突变、扩增和过表达等预测性生物标志物，仍然具有挑战性。进一步的研究应更加重视阐明肿瘤-基质相互作用的作用，并分析其作为药物反应修饰剂的潜力。
