Abstract
Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression. HGF and c-MET usually mediate heterotypic cell–cell interactions, such as epithelial–mesenchymal, including tumor–stroma interactions. In the skin, dermal fibroblasts are the main source of HGF. The presence of c-MET on keratinocytes is crucial for wound healing in the skin. HGF is not released by normal melanocytes, but as melanocytes express c-MET, they are receptive to HGF, which protects them from apoptosis and stimulates their proliferation and motility. Dissimilar to melanocytes, melanoma cells not only express c-MET, but also release HGF, thus activating c-MET in an autocrine manner. Stimulation of the HGF/c-MET pathways contributes to several processes that are crucial for melanoma development, such as proliferation, survival, motility, and invasiveness, including distant metastatic niche formation. HGF might be a factor in the innate and acquired resistance of melanoma to oncoprotein-targeted drugs. It is not entirely clear whether elevated serum HGF level is associated with low progression-free survival and overall survival after treatment with targeted therapies. This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes.
Highlights
Hepatocyte growth factor (HGF), known as scatter factor and tumor cytotoxic factor, is a large multidomain heterodimeric protein that belongs to the cytokine family [1]
This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes
The authors suggested that HGF/c-MET signaling plays an important role in innate resistance to vemurafenib
Summary
HGF (hepatocyte growth factor), known as scatter factor and tumor cytotoxic factor, is a large multidomain heterodimeric protein that belongs to the cytokine family [1]. It has been demonstrated that HGF/c-MET signaling regulates the motogenic function of keratinocytes during skin wound healing by inducing the expression of small G protein ARF6 (ADP-ribosylation factor 6) in those cells [57]. The role of HGF/c-MET signaling in response of melanoma to targeted therapies, and subsequent development of resistance has been investigated, which has resulted in several publications [103,114,115,116,117,118,119] The results of these studies are not fully consistent, and they largely depend on methodology used, but the main reason for the discrepancies between results may lie in the heterogeneity of melanoma leading to the broad spectrum of activities of different pathways within one tumor. The results showing the role of HGF/c-MET signaling in response to targeted therapies and resistance development are grouped based on methodology, which was applied, namely as the results obtained in preclinical studies and the findings derived from clinical studies
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