Hypoxia and hypoxia inducible factors (HIF) as important regulators of tumor physiology.

Abstract

Regions of low oxygen tension are common findings in malignant tumors and are associated with increased frequency of tumor invasion and metastasis. Indeed, the ability to initiate homeostatic responses and adapt to hypoxia, e.g. by induction of angiogenesis, represents an important and crucial aspect in solid tumor growth. A significant advance in our understanding of the hypoxia response stems from the discovery of the hypoxia inducible factors (HIF) which act as key regulators of hypoxia-induced gene expression. Both, low levels of oxygen, apparently via reduced activity of a recently identified class of 2-oxoglutarate dependent oxygenases, and various tumor specific genetic alterations synergistically act to induce the HIF system. A widespread HIF activation can be observed in a variety of malignant tumors including brain tumors. The HIF system induces adaptive responses including angiogenesis, glycolysis, and pH regulation which confer increased resistance towards the hostile tumor microenvironment. Apart from protumorigenic the wide-ranging HIF pathway is known to harbor antitumorigenic components, which may, however, be disabled by tumor specific genetic alterations. Thus, mounting evidence has identified HIF as a crucial regulator of tumor growth and progression constituting an intriguing and novel target for therapeutic intervention.