The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis.
Hepatocyte growth factor/scatter factor (HGF/SF) can elicit a wide variety of effects upon cells expressing its receptor, the tyrosine kinase proto-oncogene product Met, including mitogenicity, motility, and morphogenesis. Normally, met expression is restricted to epithelial cells and is activated in a paracrine fashion by HGF/SF secreted from cells of mesenchymal origin. In this chapter, we review data showing that: (i) met over-expression in HGF/SF-expressing NIH/3T3 fibroblasts leads to sarcomagenesis and metastasis via an autocrine mechanism; (ii) Met-HGF/SF autocrine signalling occurs to a low level in normal fibroblasts and to a much greater extent in human sarcomas and sarcoma cell lines; (iii) met expression is enhanced as p53-deficient fibroblasts are passaged in vitro and (iv) met and HGF/SF over-expression are selected for during tumorigenesis of p53-deficient late-passage fibroblasts. Thus, loss of p53 predisposes a mesenchymal cell to over-express met and high level Met-HGF/SF autocrine signaling in mesenchymal cells promotes both sarcomagenesis and metastasis through inappropriate induction of the pleiotropic responses to Met-HGF/SF stimulation.
ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, MD 21702, USA.
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Cortner
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Vande Woude
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Rong
D016475:3T3 Cells; D000818:Animals; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D051379:Mice; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D012509:Sarcoma / Q000473:pathology* / Q000503:physiopathology*; D012513:Sarcoma, Experimental / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases