cells Review Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications Rachel Shi, Chengheng Liao and Qing Zhang * Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
[email protected] (R.S.);
[email protected] (C.L.) * Correspondence:
[email protected]; Tel.: +1-214-645-4671 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 proliferat- ing 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 intercon- nected 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, mitochon- drial 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: hypoxia; metastasis; hypoxia-inducible factors; chemoresistance Citation: Shi, R.; Liao, C.; Zhang, Q. Hypoxia-Driven Effects in Cancer: 1. Introduction Characterization, Mechanisms, and Understanding the mechanisms by which cells sense oxygen and maintain oxygen Therapeutic Implications. Cells 2021, homeostasis is of pivotal importance for science and medicine. Only in recent decades have 10, 678. https://doi.org/10.3390/ breakthrough discoveries of mechanisms for eukaryotic oxygen sensing been made.