肝细胞生长因子，肿瘤微环境中的关键促肿瘤因子,Cancers

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肝细胞生长因子，肿瘤微环境中的关键促肿瘤因子
Cancers ( IF 4.5 ) Pub Date : 2017-04-17 , DOI: 10.3390/cancers9040035
Benjamin Yaw Owusu ₁ , Robert Galemmo ₂ , James Janetka ₃ , Lidija Klampfer ₁

Affiliation

肿瘤微环境在肿瘤的发生发展中起着关键作用。基质细胞分泌促进癌细胞生长、存活和转移扩散的生长因子、细胞因子和细胞外基质蛋白。成纤维细胞是肿瘤基质的主要成分，肝细胞生长因子 (HGF) 是酪氨酸激酶受体 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 依赖性方式促进癌细胞的生长、存活和迁移。成纤维细胞还通过 HGF 诱导的上皮间充质转化 (EMT) 和激活肿瘤细胞中促存活信号通路如 ERK 和 AKT 来赋予抗癌治疗抗性。癌细胞中的组成型 HGF/MET 信号传导与肿瘤侵袭性增加有关，并预测癌症患者的不良预后。由于其在肿瘤进展和治疗抵抗中的作用，HGF 和 MET 已成为有效的治疗靶点。目前正在临床试验中测试几种 MET 和 HGF 抑制剂。临床前数据有力地表明，HGF/MET 信号抑制剂克服了对 EGFR、HER2 和 BRAF 靶向药物的原发性和获得性耐药。这些发现支持这样一种观点，即需要共同靶向癌细胞和基质细胞以防止治疗耐药性并提高癌症患者的总体存活率。HGF 依赖性已成为治疗抵抗的标志，

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Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment

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.

更新日期：2017-04-17

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