Abstract 1225: Integration of HGF/Met signaling and hypoxia response in cancer cell invasion and proliferation

Abstract

Abstract The cellular response to hypoxia is a major influence on the aggressiveness of primary tumors, yet much of how this response mechanism integrates with other signaling pathways is unknown. The MET proto-oncogene, which encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), is often overexpressed in cancers and can drive cell proliferation, invasion, and metastasis. Prior studies demonstrate that the Met tyrosine-kinase receptor drives cell invasion and metastasis under hypoxic conditions, and this invasive phenotype is lost if MET expression is inhibited. Hypoxia also has been shown to sensitize Met-activated pathways to drive HGF-induced invasion through an as yet undefined molecular mechanism. The high mortality rate of metastatic cancer makes it crucial to understand the functional integration of these two prevalent drivers of metastasis, hypoxia and Met signaling, and to identify ways to selectively block cancer cell invasiveness. We show that a chemically generated pseudo-hypoxic condition enhanced HGF-mediated cell migration and invasion in the papillary renal cell (PRC) carcinoma cell lines ACHN and UOK112. Enhanced HGF-driven invasiveness was associated with sensitization of the mitogen-activated protein kinase (MAPK) pathway and increased matrix metalloproteinase activity. HGF-stimulated cell proliferation, in contrast, was phosphoinositide 3-kinase (PI3K) pathway dependent and not enhanced under the same pseudo-hypoxic condition. Furthermore, MAPK activation in the presence of HGF and hypoxia negatively regulated HGF-induced Akt activation and mitochondrial reductase enzymes as detected by MTT assay. These data suggest that hypoxia promotes tumor invasion by sensitizing the MAPK pathway to HGF stimulation in PRC-derived cells while limiting and/or suppressing HGF activation of PI3K-mediated cell proliferation. Identifying the specific effectors responsible for the integration these signals will improve our understanding of pro-metastatic invasiveness and potentially identify novels targets for its selective blockade. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1225. doi:1538-7445.AM2012-1225