Owusu Benjamin Yaw, Galemmo Robert, Janetka James, Klampfer Lidija
Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, USA.
Protexase Therapeutics, St. Louis, MO 63110, USA.
Cancers (Basel). 2017 Apr 17;9(4):35. doi: 10.3390/cancers9040035.
The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte Growth Factor (HGF), the specific ligand for the tyrosine kinase receptor c-MET, is a major component of their secretome. Indeed, cancer-associated fibroblasts have been shown to promote growth, survival and migration of cancer cells in an HGF-dependent manner. Fibroblasts also confer resistance to anti-cancer therapy through HGF-induced epithelial mesenchymal transition (EMT) and activation of pro-survival signaling pathways such as ERK and AKT in tumor cells. Constitutive HGF/MET signaling in cancer cells is associated with increased tumor aggressiveness and predicts poor outcome in cancer patients. Due to its role in tumor progression and therapeutic resistance, both HGF and MET have emerged as valid therapeutic targets. Several inhibitors of MET and HGF are currently being tested in clinical trials. Preclinical data provide a strong indication that inhibitors of HGF/MET signaling overcome both primary and acquired resistance to EGFR, HER2, and BRAF targeting agents. These findings support the notion that co-targeting of cancer cells and stromal cells is required to prevent therapeutic resistance and to increase the overall survival rate of cancer patients. HGF dependence has emerged as a hallmark of therapeutic resistance, suggesting that inhibitors of biological activity of HGF should be included into therapeutic regimens of cancer patients.
肿瘤微环境在肿瘤的发生和发展中起着关键作用。基质细胞分泌生长因子、细胞因子和细胞外基质蛋白，促进癌细胞的生长、存活和转移扩散。成纤维细胞是肿瘤基质的主要成分，肝细胞生长因子（HGF）作为酪氨酸激酶受体c-MET的特异性配体，是其分泌组的主要成分。事实上，癌症相关成纤维细胞已被证明以HGF依赖的方式促进癌细胞的生长、存活和迁移。成纤维细胞还通过HGF诱导的上皮-间质转化（EMT）以及激活肿瘤细胞中的促存活信号通路（如ERK和AKT）赋予癌细胞对抗癌治疗的抗性。癌细胞中持续的HGF/MET信号传导与肿瘤侵袭性增加相关，并预示癌症患者预后不良。由于其在肿瘤进展和治疗抗性中的作用，HGF和MET均已成为有效的治疗靶点。目前有几种MET和HGF抑制剂正在进行临床试验。临床前数据有力地表明，HGF/MET信号传导抑制剂可克服对EGFR、HER2和BRAF靶向药物的原发性和获得性抗性。这些发现支持了这样一种观点，即需要同时靶向癌细胞和基质细胞以防止治疗抗性并提高癌症患者的总生存率。HGF依赖性已成为治疗抗性的一个标志，这表明HGF生物活性抑制剂应纳入癌症患者的治疗方案中。
