Our laboratory explores the role of hypoxia-inducible factor (HIF) in tumorigenesis. HIF is a family of transcription factors (HIF1, 2, 3) that plays a central role in physiologic oxygen sensing and is critical for cellular adaptation to hypoxia and low pH, both conditions known to characterize the tumor microenvironment. HIF has been demonstrated to be over expressed in the majority of solid tumors and has been correlated with poor prognosis and resistance to both radio and chemotherapy. These attributes make HIF a likely promoter of solid tumor growth, particularly as tumors outgrow their vascular supply, undergo a phenomenon termed the angiogenic switch, and the process of metastases. While the oncogenic role of HIF, and in particular HIF2 is now well established in renal cell carcinoma we would like to explore the role of HIF in other tumor types. To this end, we have created and characterized a mouse model that will conditionally express a stabilized form of HIF, allowing us to spatially and temporally control its expression. With this mouse in hand we propose to characterize the effects of HIF over expression on the phenotype of several mouse models of human cancer.

Our lab is also investigating the genetic aberrations and signaling pathways that are altered in renal cell carcinoma. Past work has shown that the von Hippel-Lindau tumor suppressor gene is mutated or silenced in up to 70% of sporadic renal cell carcinomas. The protein product of VHL, pVHL, serves as an E3 ubiquitin ligase for HIF. Thus in the absence of pVHL or in hypoxic tissues, HIF is stabilized and allowed to transactivate its downstream target genes, including VEGF, PDGF, Oct4, CA9, TGFa, and Epo. While clinical therapeutic strides have been made based on these observations we hypothesize that there are other oncogenic events that are required for the development and maintenance of kidney cancer and have focused our studies on those that appear to be amenable to pharmacologic inhibition.