Rasola Andrea, Anguissola Sergio, Ferrero Norma, Gramaglia Daniela, Maffe Antonella, Maggiora Piera, Comoglio Paolo M, Di Renzo M Flavia
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
Cancer Res. 2004 Mar 1;64(5):1744-50. doi: 10.1158/0008-5472.can-03-2383.
The hepatocyte growth factor (HGF) receptor, encoded by the MET oncogene, is expressed in approximately 70% of human ovarian carcinomas and overexpressed in 30% of cases. Because HGF is known to protect cells from apoptosis, we investigated whether receptor expression modifies ovarian cancer cell response to chemotherapy. The apoptotic effect of the front-line chemotherapeutic drugs paclitaxel and cisplatin on cells treated with HGF was studied. In ovarian cancer cell lines, pretreatment with HGF surprisingly enhances the apoptotic response to low doses of paclitaxel and cisplatin. HGF empowers specifically the intrinsic apoptotic pathway, whereas it protects cells from extrinsic Fas-induced apoptosis. Chemotherapy sensitization is specific for HGF because another growth factor (e.g., epidermal growth factor) increases ovarian cancer cell survival. In nonovarian cancer cell models, as expected, HGF provides protection from drug-induced apoptosis. These data show that HGF sensitizes ovarian carcinoma cells to low-dose chemotherapeutic agents. This suggests that HGF may be used to improve response to chemotherapy in a set of human ovarian carcinomas molecularly classified based on the MET oncogene expression.
由MET癌基因编码的肝细胞生长因子（HGF）受体在约70%的人类卵巢癌中表达，在30%的病例中过度表达。由于已知HGF可保护细胞免于凋亡，我们研究了受体表达是否会改变卵巢癌细胞对化疗的反应。研究了一线化疗药物紫杉醇和顺铂对经HGF处理的细胞的凋亡作用。在卵巢癌细胞系中，令人惊讶的是，用HGF预处理可增强对低剂量紫杉醇和顺铂的凋亡反应。HGF特异性地增强内源性凋亡途径，而它可保护细胞免于外源性Fas诱导的凋亡。化疗增敏作用对HGF具有特异性，因为另一种生长因子（如表皮生长因子）可提高卵巢癌细胞的存活率。在非卵巢癌细胞模型中，正如预期的那样，HGF可保护细胞免于药物诱导的凋亡。这些数据表明，HGF可使卵巢癌细胞对低剂量化疗药物敏感。这表明，基于MET癌基因表达进行分子分类的一组人类卵巢癌中，HGF可用于改善化疗反应。
