Hypoxia-inducible factors, hypoxia, and tumor angiogenesis

The transcription factor hypoxia-inducible factor is activated by low oxygen to promote the expression of target genes that allow cellular, tissue, and organismal adaptation to low oxygen. Hypoxia-inducible factor is activated not only by hypoxia but also as a consequence of genetic mutations in a variety of tumors. This review summarizes recent studies on hypoxia-inducible factor-alpha functions in development and tumorigenesis.

Deficiency of the tumor suppressor von Hippel-Lindau leads to constitutively active hypoxia-inducible factor and hypoxia-inducible factor target gene expression. Other genetic lesions, however, e.g. in JunD, can also result in elevated hypoxia-inducible factor levels. The specific functions of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha during development and tumor growth remain incompletely understood. Whereas hypoxia-inducible factor-2alpha seems to be the critical hypoxia factor in renal cell carcinoma, hypoxia-inducible factor-1alpha plays a significant role in the growth of tumors in other tissues. Loss of von Hippel-Lindau is not sufficient for neoplastic transformation, suggesting that hypoxia-inducible factor does not act alone to cause tumors.

It will be important to further characterize the specific roles of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha during tumorigenesis to design therapies targeting the relevant isoform for specific diseases. It is also necessary to investigate the effect of reducing hypoxia-inducible factor levels on other angiogenic factors.