Understanding the role of HIF-2alpha in human cancers

Title: Understanding the role of HIF-2alpha in human cancers
Authors: Franovic, Aleksandra
Date: 2009
Abstract: Cancer development is a multi-step process, driven by a series of genetic and environmental alterations, which endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits. The superfluous nature of these pathways is thought to limit therapeutic approaches targeting cell proliferation and so this strategy is often abandoned in favor of inhibiting more systemic hallmarks. Here, we report that genetically diverse cancers converge at a rate-limiting oncogenic axis instigated by HIF-2alpha, a component of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of a panel of highly aggressive human cancer cell lines, irrespective of their mutational status and tissue of origin. We further offer mechanistic evidence that HIF-2alpha exerts its proliferative effects through the translational upregulation and/or activation of select receptor tyrosine kinases, including the EGFR and IGF-IR, and their downstream signaling pathways. Consistently, silencing these receptors or blocking upstream ligand processing events phenocopies the loss of HIF-2alpha activity, abrogating the serum-independent growth of cancer cells in culture and their tumor formation in athymic mice. Taken together, the data presented in this thesis reveal an important role for HIF-2alpha in promoting the persistent proliferation of neoplastic cells and suggest that tumors do share common growth elements that can serve as drug targets in the treatment of a wide range of human cancers.
URL: http://hdl.handle.net/10393/29907
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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