The Role of Hypoxia Inducible Factor (HIF) in Cancers

Dear Colleagues, 

The number of cancer incidences remains a major health problem worldwide and the main goal of development of efficient and safe therapeutic strategies is to allow them to precisely target the complex and multifactorial mechanisms of both tumorigeneses and therapeutic resistance.

Undoubtedly, hypoxia, being a consequence of rapid tumors proliferation that outgrows surrounding vasculature, is a common feature of most cancers, and current understanding of the underlying molecular interactions governing cancers cells’ adaptation to this insult limits their therapeutic utility. 

Tumor cells, while adapting to hypoxia, change their global gene expression profiles to adjust their metabolism and physiology as well as to stimulate angiogenesis. Consequently, the adaptation to hypoxia contributes to plasticity and heterogeneity of tumors and favors more aggressive and resistant phenotypes.

The activation of cellular hypoxia signaling relies on the accumulation of transcriptionally functional complexes of hypoxia-inducible factors (HIF-1 and HIF-2 and HIF-3) that interact with hypoxic-response elements (HREs) in the promoters and enhancers of their numerous target genes and serve as master regulators of cancer growth, metabolism, survival as well as metastasis and invasiveness. Hence, approaches that exploit HIF-based signaling networks are an attractive strategy for the treatment of cancer, however, its utility in therapy has been limited in scope.

Transcriptionally active HIFs are heterodimers that assemble when alpha subunits expression is stabilized due to the inhibition of their oxygen-dependent degradation. Although the HIF-1 (comprised of HIF-1α) is well recognized as the central component of cellular response to hypoxia, the two other HIF-α isoforms have been identified in mammals as well and have been shown to form transcriptionally active HIF-2 and HIF-3 complexes. However, despite all these HIFs isoforms often being overexpressed in human cancers, the most attention has been paid to HIF-1. Notably, besides a large set of overlapping genes, HIF-1 and HIF-2 also govern unique signaling networks and thus may play distinct roles in tumorigenesis. Furthermore, a transition from HIF-1 to 2 signaling called the HIF switch has been observed in cancer cells exposed to prolonged hypoxia. Finally, the HIF-3’s role in cancer cells remains less clear and understudied.

Importantly, in cancer cells, HIFs signaling can be activated and modulated independent of hypoxia by epigenetic changes, mutations as well as in response to the inflammatory pathways. Hence, the development of HIF-targeted treatments requires a better understanding of these pathways' crosstalk.

For this Special Issue of Cancers, “The Role of Hypoxia Inducible Factors (HIFs) in Cancer”, we encourage the submission of review and primary research articles that showcase the molecular mechanisms of HIFs signaling in the cancer cells as well as novel related therapeutic strategies. 

Dr. Rafal Bartoszewski
Guest Editor

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