HGF and Met signaling in cancer

Molecular oncology. Causes of cancer and targets for treatment. Eds Edward P. Gelmann et al., Cambridge University Press (2014)

Among the many genes up-regulated by HGF are those encoding proteases required for HGF and Met processing, as well as MET, creating the potential for its over-expression through persistent ligand stimulation (5). Indeed, MET over-expression is characteristic of several epithelial-cell-derived cancers, and for some is an independent prognostic factor associated with adverse outcome (25). Other mechanisms of oncogenic pathway activation include aberrant paracrine or autocrine ligand production, constitutive kinase activation in the presence or absence of MET gene amplification, and MET gene mutation (2,25). Missense MET mutations occur in several cancers; the earliest reported mutations were found in the TK domain and were associated with hereditary and sporadic forms of papillary renal cell carcinoma (PRC; 14). Mutations throughout the MET coding sequence were later found in lung cancer and in head and neck cancers (20,26).

The impact of specific MET mutations has been studied at the molecular, cellular, and organism levels. Early cell-based investigations indicated that kinase activity was deregulated in various mutant forms and revealed that these could have distinct biological effects (14,27,28). Although mutations that were reconstituted in HGF-producing cells (such as NIH3T3) could not rigorously address the role of ligand binding in oncogenesis, later studies showed that mutations expressed in epithelial cells required ligand for soft agar colony formation and that colony formation by NIH3T3 bearing Met M1250T could be blocked by ligand-binding antagonists (27–29). PRC-associated MET mutations also have been investigated in mice by engineering changes in the murine MET locus (30). Interestingly, mice harboring mutations corresponding to human D1228N, Y1230C, and both M1250T and L1195V mutations, developed sarcomas with high frequency and some lymphomas, whereas the M1250T mice developed carcinomas and lymphomas; no mice developed PRC (30). Furthermore, analogous to the trisomy of chromosome 7 frequently observed in human PRC tumors, trisomy of chromosome 6 (containing the murine Met locus) and preferential duplication of the mutant MET allele was observed in most tumors (30). More recently, investigations of two PRCassociated Met mutants revealed defects in Met internalization that result in persistent signaling, similar to alterations found in the Met juxtamembrane domain (31). These results independently confirm the oncogenicity of PRC-associated MET mutations in vivo.

Other alterations in the MET sequence have been identified in regions encoding the extra-cellular Sema domain (E168D, L229F, S323G, and N375S) and the intra-cellular JM domain (R970C, T992I, S1040P, and exon 14 deletions) of non-smallcell lung carcinoma (NSCLC)-derived cell lines, in 12.5% of small-cell lung cancer (SCLC) cases, and in 8% of samples of lung adenocarcinoma tissues (32–34). Some of these mutations activate proliferation, motility, and invasiveness in cultured cells (26). In Met JM-domain mutants missing exon 14, the loss of Y1003 results in persistent HGF-stimulated signaling that leads, in turn, to increased transforming activity and tumorigenic potential (32,33). A similar mechanism has been reported for a P991S mutation found in the germline of a patient with gastric carcinoma (35). The oncogenic potential of JM mutations R970C and T992I is debated: found in a variety of malignancies and in individuals without cancer, R970C and T992I may be rare polymorphisms that increase cancer risk (33,35,36). Overall, although MET mutations occur at a lower frequency than most other mechanisms of oncogenic pathway activation, they provide strong direct evidence of the pathway’s oncogenic potential, and may identify patients most likely to benefit from Met-targeted therapeutics.

Consistent with the role of this pathway in organogenesis, oncogenic Met signaling resembles developmental transitions between epithelial and mesenchymal cell types normally regulated by HGF: increased protease production coupled with cell dissociation and motility promotes cellular invasion through extra-cellular matrices, enabling tumor invasiveness and metastasis (1–6). Conversely, silencing the endogenous, over-expressed MET gene in tumor cells suppresses tumor growth and metastasis, and induces the regression of established metastases in mouse models (37). In addition, HGF/Met signaling in vascular endothelial cells stimulates tumor angiogenesis, facilitating tumor growth for cancers that are growth-limited by hypoxia, and independently promoting tumor metastasis. Hypoxia alone up-regulates MET expression and enhances HGF signaling in cultured cells and mouse tumor models (38,39).


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