Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer: Importance of Targeting c-MET and HGF Interaction

Abstract

Binding of hepatocyte growth factor (HGF) to the c-MET receptor has mitogenic, motogenic, and morphogenic effects on cells. The versatile biological effects of HGF and c-MET interactions make them important contributors to the development of malignant tumors. We and others have demonstrated a therapeutic value in targeting the interaction of c-MET and HGF in epithelial ovarian cancer (EOC). However, both HGF and c-MET are expressed in the normal ovary as well. Therefore, it is important to understand the differences in mechanisms that control HGF signaling activation and its functional role in the normal ovary and EOC. In the normal ovary, HGF signaling may be under hormonal regulation. During ovulation, HGF-converting proteases are secreted and the subsequent activation of HGF signaling enhances the proliferation of ovarian surface epithelium in order to replenish the area damaged due to expulsion of the ovum. In contrast, EOC cells that exhibit epithelial characteristics constitutively express both c-MET and HGF-converting proteases such as urokinase-type plasminogen activator. In EOC, mechanisms to control the activation of HGF signaling are absent since HGF is provided locally from the tissue microenvironment as well as remotely throughout the body. Potential incessant HGF signaling in EOC may lead to an increase in proliferation, invasion through the stroma, and migration to other tissues of cancer cells. Therefore, targeting the interaction of c-MET and HGF would be beneficial in treating EOC.

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

“…c-Met is a HGF receptor that is expressed in epithelial cells. In ovarian cancer cells, c-Met is highly expressed and its overexpression is associated with adverse prognosis [ 10 , 19 ]. In the present study, we detected the protein levels of HGF and found CAFs produced high levels of HGF.…”

“…CAFs are known to promote tumour development and progression, as well as stimulate metastasis by secreting a variety of factors [ 9 ]. 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 ].…”

“…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.…”

Human colorectal cancer-derived carcinoma associated fibroblasts promote CD44-mediated adhesion of colorectal cancer cells to endothelial cells by secretion of HGF

“…It implies that CC-CAFs potentially enhance colorectal cancer metastasis by up-regulation of CD44 whose association with metastasis has been observed in our clinical specimen and orthotopic liver metastatic model. We also investigated the underlying mechanism of pro-tumor effect of CC-CAFs, based on report by Benjamin et al [22], HGF is a major component of cancer associated fibroblasts secretion, and have been showed to promote cancer progression [13, 23–25]. However, the mechanism has not decisively investigated in colorectal cancer.…”

“…They promote tumor growth, angiogenesis and the malignant progression of various solid tumor through direct cell–cell contact or by paracrine secretion [8, 9], up-regulation of epidermal growth factor (EGF), interleukin-6 (IL-6), insulin-like growth factor, or hepatocyte growth factor in CAFs has been reported recent years [10–12]. Hepatocyte growth factor (HGF) is an important fibroblast secreted protein [13] which binds to Met, a specific receptor expressed in tumor cells and actives downstream signal that mediates development and progression of cancers [14, 15]. It has been reported that HGF/c-Met activation could subsequently result in up-regulation of CD44 expression [16], this implies that possible correlation exists between CAFs and adhesion process, however it has not been elucidated so far.…”