Review
Hypoxia-inducible factors: Crosstalk between inflammation and metabolism

https://doi.org/10.1016/j.semcdb.2012.04.004Get rights and content

Abstract

Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors that allow adaptation to hypoxic environments. HIFs function in the cellular response to stress: metabolic, hypoxic, or inflammatory. Metabolic changes occur during tumorigenesis that are, in part, under hypoxia and HIF regulation. Additionally, inflammatory signaling and infiltration secondary to hypoxia are clear drivers of tumor progression. HIF-1α and HIF-2α have opposing and occasionally overlapping roles in both tumor cells and inflammatory cells within the tumor microenvironment and crosstalk between these populations has clear effects on tumor metabolism, inflammation, and progression. It is becoming increasingly apparent that HIFs are one common link between hypoxia, chronic inflammation, metabolic adaptation, and tumor progression through its function in macrophages during cancer development.

Highlights

► HIFs function in the cellular response to stress through a variety of pathways. ► HIF-1α and HIF-2α have opposing and overlapping roles in the microenvironment. ► Hypoxia and HIFs contribute to metabolic changes during tumorigenesis. ► The inflammatory response under hypoxia helps drive tumor progression. ► Hypoxia driven crosstalk influences tumor metabolism, inflammation, and malignancy.

Section snippets

Introduction: tumor complexity – hypoxia in the microenvironment

Cellular access to oxygen is a critical component of many physiologic and pathologic processes. While ambient air is 21% O2, the majority of healthy tissues have access to 2–9% O2, and hypoxia is defined as less than 2% O2 [1]. Low O2 tensions are often exhibited by regions of intense inflammation, such as within arthritic joints, atherosclerotic plaques, and notably, domains within solid tumors [2]. Regions within the tumor microenvironment may be characterized by low O2 tensions, or hypoxia,

Hypoxia-inducible factors

Metabolic reprogramming and changes in gene expression are necessary for adaptation to decreased O2 availability. The cellular response to hypoxia is mediated, in part, by hypoxia-inducible factors HIF-1α and HIF-2α [8], [9]. These transcription factors are widely appreciated as key regulators of cellular adaptation to hypoxic stress [3].

HIFs are heterodimeric proteins within the basic helix-loop-helix-PAS (bHLH/PAS) family of transcription factors and are primarily regulated through

Effects of HIF activity on tumor cell metabolism

HIF activity is an important prognostic factor as levels follow closely with poor patient outcomes in a variety of cancers [17]. HIF-1α and HIF-2α have been shown to play important, yet mostly distinct, roles in driving tumor progression [19]. While both factors share common downstream transcriptional targets, such as vascular endothelial growth factor (VEGF), they have also been shown to have different roles in promoting various aspects of cell metabolism and proliferation through opposing

Inflammation-induced tumorigenesis

HIFs have recently come to light as important mediators in myeloid-driven inflammation and tumor progression [14], [31]. Ever since Rudolf Virchow first described infiltrating leukocytes within a solid tumor in 1863, researchers have attempted to explain the relationship between chronic inflammation and tumorigenesis [32], [33], [34]. A complex association between chronic inflammatory states and cancer clearly exists. Although chronic inflammation may be due to a number of inciting agents

Conclusion

HIFs are O2 sensitive transcription factors that allow transcriptional adaptation to hypoxic environments. It is becoming increasingly apparent, however, that HIFs are regulated (both at the level of transcription and post-translationally) by other stress-sensors. HIF regulation incorporates oxygen availability, redox status, nutrient availability, and certain inflammatory signals. In summary, TAMs are recruited to hypoxic regions within the tumor microenvironment where they play a critical

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