Deying Wei, Feng Geng, Shumei Liang, Hui Zhao, Ming Liu, Hongqing Wang
Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China
Biosci Rep. 2017 Apr 10;37(2). doi: 10.1042/BSR20160470. Print 2017 Apr 28.
The tumour microenvironment is a highly heterogeneous entity that plays crucial roles in cancer progression. As the most prominent stromal cell types, cancer-associated fibroblasts (CAFs) produce a variety of factors into the tumour microenvironment. In the present study, we firstly isolated CAFs from tumour tissues of the patients with ovarian cancer and demonstrated that the hepatocyte growth factor (HGF) was highly expressed in the supernatants of CAFs. CAF-derived HGF or human recombinant HGF promoted cell proliferation in human ovarian cell lines SKOV3 and HO-8910 cells. Western blotting analysis also showed that CAF-derived HGF or recombinant HGF activated c-Met/phosphoinositide 3-kinase (PI3K)/Akt and glucose-regulated protein 78 (GRP78) signalling pathways in ovarian cancer cells, and these effects could be abrogated by anti-HGF and c-Met inhibitor INCB28060. Moreover, HGF in CAF matrix attenuated paclitaxel (PAC)-caused inhibition of cell proliferation and increase in cell apoptosis through activating c-Met/PI3K/Akt and GRP78 pathways in SKOV3 and HO-8910 cells. The results were further validated in nude mice. These findings suggest that CAF-derived HGF plays crucial roles in cell proliferation and drug resistance in ovarian cancer cells.
肿瘤微环境是一个高度异质性的实体，在癌症进展中起着关键作用。作为最主要的基质细胞类型，癌症相关成纤维细胞（CAFs）向肿瘤微环境中分泌多种因子。在本研究中，我们首先从卵巢癌患者的肿瘤组织中分离出CAFs，并证明肝细胞生长因子（HGF）在CAFs的上清液中高表达。CAF来源的HGF或人重组HGF促进人卵巢癌细胞系SKOV3和HO-8910细胞的增殖。蛋白质印迹分析还表明，CAF来源的HGF或重组HGF激活卵巢癌细胞中的c-Met/磷脂酰肌醇3-激酶（PI3K）/Akt和葡萄糖调节蛋白78（GRP78）信号通路，而抗HGF和c-Met抑制剂INCB28060可消除这些作用。此外，CAF基质中的HGF通过激活SKOV3和HO-8910细胞中的c-Met/PI3K/Akt和GRP78通路，减弱紫杉醇（PAC）引起的细胞增殖抑制和细胞凋亡增加。这些结果在裸鼠中得到进一步验证。这些发现表明，CAF来源的HGF在卵巢癌细胞的细胞增殖和耐药性中起关键作用。
