Hypoxia’s Function in Cancer

Abstract

Hypoxia is defined as the inadequate supply of oxygen to the tissue that can occur due to a multitude of causes and is called by various names such as hypoxemic, anemic, ischemic, diffusional, and cytotoxic hypoxia. Cancer-induced hypoxia is an interplay of ischemic, diffusional, and anemic hypoxia, and plays an important role as a prognosticator of the disease and also as a target for treatment modalities. The major mediator of hypoxia in tumor cells is hypoxia-inducible factor (HIF), which is a heterodimeric protein that is upregulated in hypoxic conditions. The consequences of HIF action are the activation and upregulation of several enzymes, transporters, and factors that modulate the neoplastic cell’s metabolic functions that result in functional responses to the hypoxic stressor, which resists apoptosis/necrosis, in addition to modifying and refashioning the local microenvironment to suit the neoplastic cell’s survival. Metastasis—one of the most feared outcomes of neoplasm—has almost all of its steps upregulated or controlled by hypoxia and HIF. Hypoxia is also responsible for drug resistance to various chemotherapeutic agents by different mechanisms. This makes it harder to treat neoplasms that are susceptible to these drugs. Therefore, treatment modalities acting by blocking HIF, in addition to the standard chemotherapeutics, target the neoplasm from all aspects, making it more comprehensive and more effective.