The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Abstract

Survival rates for ovarian cancer have remained relatively stable for the past two decades, despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Up-regulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11-68% of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of over-expression, or its correlation with prognosis.

CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells

“…Furthermore, HGF increased the levels of c-Met and promoted cell proliferation and drug resistance in ovarian cancer cells, consistent with the previous studies [13,20–23]. The intervention strategies of HGF/c-Met axis include (i) down-regulation of HGF or c-Met expression; (ii) disruption of HGF/c-Met interaction; (iii) inhibition of c-Met kinase activity; (iv) interference with downstream signalling pathway [11,24]. Currently, a variety of therapeutic agents targeting HGF/c-Met have been evaluated in clinical trials.…”

“…Currently, a variety of therapeutic agents targeting HGF/c-Met have been evaluated in clinical trials. These agents fall into two board categories: small molecule inhibitors and the antibodies against HGF or c-Met [11,24]. Our data also revealed that c-Met inhibitor INCB28060 abrogated CAFs-induced cell proliferation and drug resistance in ovarian cancer cells.…”

“…Hepatocyte growth factor (HGF) is one of the growth factors secreted by CAFs, and it stimulates cell proliferation, migration and ECM invasion [10]. c-Met, as a specific receptor of HGF, is highly expressed in a number of tumour types including ovarian cancer [10,11]. The interaction of HGF and c-Met further activates downstream signalling pathways to regulate cancer progression.…”

The Detection of sAMY1α in Ovarian Cancer Ascites During First-Line Chemotherapy Predict the Response of Patients to Treatment

“…Genechip is a highly integrated intelligent gene chip that uses micro-samples for detection. It can perform simultaneous research on the obtained large-scale and high-throughput thousands of genes 16 . Metabolomics technology has the advantage of high throughput which can detect thousands of metabolites and screen for differential metabolites.…”

The Role of microRNAs in Epithelial Ovarian Cancer Metastasis

“…For example, epidermal growth factor (EGF) signals through the ERK1/2 and PI3K/AKT pathways to induce EMT [ 68 ]. Hepatocyte growth factor (HGF) acts through its receptor, c-Met, and enhances EMT by activating multiple signaling pathways, including MAPK, Wnt/β-catenin, and PI3K/AKT [ 69 , 70 , 71 ]. Hedgehog glioma-associated oncogene1 (Shh-Gli1) positively regulates EMT via crosstalk with PI3K-AKT [ 72 ].…”