Human cancers converge at the HIF-2α oncogenic axis

Aleksandra Franovic, Chet E. Holterman, Josianne Payette, Stephen Lee

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that 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 [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of antitumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2α, an element of the oxygen-sensing machinery. Inhibition of HIF-2α prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2α exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2α oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data,wepropose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2α as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.

Original languageEnglish (US)
Pages (from-to)21306-21311
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 15 2009
Externally publishedYes


  • Epidermal growth factor receptor
  • Growth signaling
  • Hypoxia-inducible factor
  • Insulin-like growth factor receptor
  • Oncogene

ASJC Scopus subject areas

  • General


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