Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications

Abstract

Hypoxia, a common feature of solid tumors, greatly hinders the efficacy of conventional cancer treatments such as chemo-, radio-, and immunotherapy. The depletion of oxygen in proliferating and advanced tumors causes an array of genetic, transcriptional, and metabolic adaptations that promote survival, metastasis, and a clinically malignant phenotype. At the nexus of these interconnected pathways are hypoxia-inducible factors (HIFs) which orchestrate transcriptional responses under hypoxia. The following review summarizes current literature regarding effects of hypoxia on DNA repair, metastasis, epithelial-to-mesenchymal transition, the cancer stem cell phenotype, and therapy resistance. We also discuss mechanisms and pathways, such as HIF signaling, mitochondrial dynamics, exosomes, and the unfolded protein response, that contribute to hypoxia-induced phenotypic changes. Finally, novel therapeutics that target the hypoxic tumor microenvironment or interfere with hypoxia-induced pathways are reviewed.

Keywords: chemoresistance; hypoxia; hypoxia-inducible factors; metastasis.

Figure 1

The spectrum of effects of hypoxia on cancer cells. Hypoxia affects cancer cell fate, genetics, metabolism, and clinicopathology. ROS: Reactive oxygen species. DNA: Deoxyribonucleic acid.

Figure 2

The Transcriptional-Metabolic Interactions under Hypoxia. A variety of genes upregulated transcriptionally under hypoxia affect cancer cell metabolism and behavior. The balance of glycolysis and oxidative phosphorylation along with the amounts of cholesterol, triacylglycerols, and other metabolites can metabolically “prime” a cancer cell to seed at specific organs during metastasis. HK2: Hexokinase 2; GPI: Glucose-6-phosphate isomerase; PFKP: 6-phosphofructokinase platelet type; ALDOC: Aldolase C; GLUT1: Glucose transporter protein type 1; PGK1: Phosphoglycerate kinase 1; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; ENO1: Enolase 1; LDHA: Lactate dehydrogenase-A; G6PD: Glucose-6-phosphate dehydrogenase; PGLS: 6-phosphogluconolactonase; PGD: 6-phosphogluconate dehydrogenase; TKT: Transketolase; TALDO1: Transaldolase 1; ASCT2: Alanine-serine-cysteine transporter, type-2; OPN: Osteopontin, PLAU: Plasminogen activator urokinase receptor, LOX: Lysyl oxidase; UPR: Unfolded protein response; TCA: Tricarboxylic acid; ATP: Adenosine triphosphate.

Figure 3

A simple schematic of the UPR. The three major arms of the UPR consist of ATF6, PERK, and IRE1. ATF6: activating transcription factor; PERK: PRKR-like endoplasmic reticulum kinase; IRE1: inositol-requiring enzyme 1; eIF2a: eukaryotic initiation factor 2a; NRF2: Nuclear factor erythroid 2-related factor 2; XBP-1: X-box binding protein 1; HSP47: heat shock protein 47.

Figure 4

Mitochondrial dynamics may underlie redox homeostasis and the cellular response to hypoxia.