Met Activation And Carcinogenesis

MET is a tyrosine kinase receptor that transduces intracellular signaling to activate the MAPK, PI3K-Akt, and cadherin pathways (among others). In cancer cells, MET is activated upon stimulation by its only ligand, hepatocyte growth factor/scatter factor (HGF/SF), or becomes active due to mutations or amplifications that produce constitutive activation of the MET kinase. The biological consequences of HGF/SF-MET signaling include cell proliferation, cell cycle progression, increased cell motility and invasive activity, and degradation of extracellular matrices, which can lead to oncogenesis. Aberrant MET signaling contributes to the carcinogenesis of hereditary cancers and also plays a major role in the spread of cancer cells; such signaling indicates a poor prognosis for cancer patients. Genetically engineered mouse models are important tools for studying the spontaneous development of tumors mediated by HGF/SF-MET signaling. Such tumors include carcinomas, sarcomas, and lymphomas, demonstrating the breadth of MET signaling as driving force of cancer. In this chapter, we will discuss the role of HGF/SF-MET signaling in carcinogenesis and the animal models used in developing therapeutic strategies that target the HGF/SF-MET signaling pathways.