Hypoxia-inducible factors and hypoxic cell death in tumour physiology

Hypoxic up-regulation of hypoxia-inducible factors (HIFs) during tumourigenesis presents an interesting paradox with respect to their role in tumour growth. Hypoxia-inducible factor 1 (HIF-1) plays a key role in the adaptive response to hypoxia, trans-activating many genes whose protein products are involved in pathways of angiogenesis, glucose metabolism and cell proliferation, thus facilitating tumour progression. However, it is also emerging that up-regulation of HIF-1 trans-activates anti-proliferative and pro-apoptotic genes (such as BNIP3, NIX and IGFBP3). This makes it unclear as to whether HIF-1 up-regulation provides a selective advantage or disadvantage to neoplastic progression under hypoxia. In addition, vagaries in the hypoxic microenvironment of the tumour such as pH changes, presence of reactive oxygen species and energy availability in the form of adenosine triphosphate (ATP), appear to influence the function of HIF-1 and up-regulated pathways and affect susceptibility to undergo hypoxic cell death. It is apparent that hypoxic cancer cells must be able to select against HIF-1 mediated cell death signals in order to survive and progress towards malignancy. Hypoxia-induced HIF-1 may in itself serve to select for increased malignancy by exerting pressure in the form of anti-proliferative signals that must be escaped. Understanding the mechanisms by which HIF-1 induces cell death and the manner in which the tumour cell can overcome such signals, is critical for our understanding of cancer progression and the development of effective therapeutics.