Hypoxia-Inducible Factors, Stem Cells, and Cancer

Abstract

Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation. The hypoxia-inducible factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression.

The role of oxygen availability in embryonic development and stem cell function

“…If so, inhibiting HIF activity could reduce Notch or Oct-4 levels below a threshold required to maintain stem cell identity, and thereby promote tumour dormancy 112 . Hopefully, the recent discovery that hypoxia regulates factors that are crucial for stem/progenitor cell maintenance in normal development and tumour progression will guide the development of novel therapeutics for both tissue regeneration and cancer treatment.…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…As briefly touched upon above, there is experimental support also from other cell systems for a role of HIF-2α during early development and maintenance of a (tumor) stem cell phenotype (reviewed in Keith and Simon 2007). In embryoid bodies, overexpression of HIF-2α results in maintained pluripotency and potentiation of tumorigenic growth (Covello et al 2006).…”

Genome-wide identification and annotation of HIF-1α binding sites in two cell lines using massively parallel sequencing

“…Cancer cells in solid tumors are frequently exposed to limited oxygen environments because aberrantly growing cancer cells can cause a shortage of blood flow (Pouyssegur et al 2006;Harris 2002;Keith and Simon 2007). Hypoxia is a term that is used to describe such cellular environments, which have an oxygen concentration between 0.02 and 3% (Thomas and Johannes 2007).…”

“…For example, ATP metabolism changes from oxidative phosphorylation to anaerobic glycolysis. During this process, glucose uptake is enhanced, angiogenesis is induced to obtain a sufficient blood supply, and cell migration is promoted (Harris 2002;Pouyssegur et al 2006;Gatenby and Gillies 2004;Hirota and Semenza 2006;Keith and Simon 2007). The central regulators of these changes in gene expression, which collectively lead to changes in cellular responses, are the transcription factors hypoxia-inducible factors 1 and 2 (HIF-1/2) (Wang and Semenza 1995;Tian et al 1997).…”