Hypoxia-inducible factors: cancer progression and clinical translation

Abstract

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.

Figure 1. HIF target genes that regulate glucose metabolism.

HIF target genes that are induced under hypoxic conditions, leading to increased glycolysis and/or decreased oxidative phosphorylation, are shown in blue. Genes that promote oxidative metabolism are shown in red.

Figure 2. HIF target genes that induce NANOG expression and breast cancer stem cell specification.

HIF target genes are denoted by yellow type in blue rectangles or ovals. Proteins that inhibit NANOG expression and breast cancer stem cell (BCSC) specification are shown in red ovals. Arrows and blocked arrows indicate positive and negative interactions, respectively. Ado, adenosine; Cu, copper; GSH, glutathione; m6A, methylation of adenosine residues in NANOG RNA.

Figure 3. Cells of the adaptive and innate immune systems determine the balance between antitumor immunity and immune suppression.

HIF activity in cancer cells inhibits antitumor immunity and promotes immune suppression.