Grant: Operating Grant

Oxygen homeostasis or balance is a vital organizing principle for human development and physiology. A universal response to compromised oxygen availability involves a protein called hypoxia-inducible factor (HIF), which accumulates during low oxygen levels or hypoxia to trigger the expression of numerous genes including those that promote new blood vessel formation (angiogenesis), anaerobic metabolism, and the production of oxygen-carrying red blood cells. These cellular responses facilitate adaptation and survival in low oxygen environment and help to restore normal oxygen balance. The significance of HIF in cancer is underscored by the finding that HIF is inordinately overexpressed in virtually all human tumours, and the extent of HIF expression correlates with disease aggressiveness, resistance to radiation and chemotherapy, and poor prognosis. Tumour cells express increasing levels of HIF because regions within a growing tumour mass inevitably and progressively become more hypoxic as the diffusional capacity of oxygen from the nearest blood vessel is surpassed. In addition, cancer-causing mutations on critical tumour suppressor genes have been shown to increase the expression of HIF. The objective of this research proposal is to elucidate the molecular mechanisms governing the activity of HIF with the supposition that lessons learned would provide significant insight into the multifaceted adaptive response to hypoxia and advance our fundamental understanding of cancer biology.