The Therapeutic Potential of Hepatocyte Growth Factor to Sensitize Ovarian Cancer Cells to Cisplatin and Paclitaxel In vivo

Abstract

Purpose: Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance.We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics. Experimental Design: Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses. Results: In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own. Conclusions:These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.

The shadow of death on the MET tyrosine kinase receptor

“…Liver and lung myofibroblasts 60,61 Mouse sarcoma cell lines Sarcoma-180 and Meth A 42,43,45,[62][63][64][65] Transformed rat liver epithelial cell lines 66 Mouse hepatocarcinoma cell lines Hepa 1 and Hepa 1-6 67,68 Human hepatoblastoma cell line HepG2 69,70 Ovarian carcinoma cells 71,72 (HGF and Paclitaxel or Cisplatin) Human breast carcinoma cells lines MCF-7 and MDA-MB-231 70 The HGF/SF induces efficient survival of many cell types against various stress conditions or apoptotic inducer. In contrast, in other cell lines, HGF/SF stimulation induces apoptotic cell death, illustrating opposite properties of HGF/SF-MET according to the cell type…”

“…Interestingly, it has been shown that HGF/SF increased ovarian carcinoma cell sensitivity to apoptosis and tumour regression in mice, induced by paclitaxel and cisplatin, the two front-line anticancer agents used in ovarian cancer therapy. 71,72 HGF/SF was then proposed to be used to improve response to chemotherapy in a set of human ovarian carcinomas expressing MET. Therefore, according to proapoptotic or antiapoptotic responses triggered by ligand-activated MET in targeted tumours, adaptive strategies could be considered: either inhibition of MET signalling when invasive growth and survival are induced, or inversely activation of MET signalling by HGF/SF when apoptotic responses are induced.…”

Growth Factors and the Redox State as New Therapeutic Targets for Colorectal Cancer

“…Similarly, it has been suggested that this factor could induce resistance to cisplatin in lung cancer cells (Chen et al, 2008). Nevertheless, in contrast to expectations, it has also been observed that HGF sensitizes ovary cancer cells to the drugs paclitaxel and cisplatin (Bardella et al, 2007). These findings indicate that HGF effects depend on the targeted tumor type.…”

MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

“…MET has been described to be implicated in determining resistance to chemotherapy in several cancers including MM. [49][50] Several reports are suggesting that MET can be involved in drug resistance to therapy specifically targeting EGFR or angiogenesis; for instance, in EGFR mutant non-small cell lung carcinoma (NSCLC) amplification of MET was observed in 22% of tumors resistant to EGFR inhibitors. [20] The MET pathway is overexpressed in MM cell lines showing drug resistance as well as in primary samples from patients with relapse/refractory MM.…”

“…Like western blotting, this method is used to evaluate the expression mostly in MM cell lines since often the amounts of primary cells are limited. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] Moreover, the use of flow cytometry is already part of diagnostic procedure in some institutions and only minimal arrangements are required to include this analysis into the existing workflow.…”