Hypoxia and Free Radicals: Role in Tumor Progression and the Use of Engineering-based Platforms to Address These Relationships

Hypoxia is a feature of all solid tumors, contributing to tumor progression and therapy resistance. Through stabilization of the hypoxia-inducible factor 1 alpha (HIF-1α), hypoxia activates the transcription of a number of genes that sustain tumor progression. Since the seminal discovery of HIF-1α as a hypoxia-responsive master regulator of numerous genes and transcription factors, several groups have reported a novel mechanism whereby hypoxia mediates stabilization of HIF-1α. This process occurs as a result of hypoxia-generated reactive oxygen species (ROS), which, in turn, stabilize the expression of HIF-1α. As a result, a number of genes regulating tumor growth are expressed, fueling ongoing tumor progression. In this review, we outline a role for hypoxia in generating ROS and additionally define the mechanisms contributing to ROS-induced stabilization of HIF-1α.We further explore how ROS-induced HIF-1α stabilization contributes to tumor growth, angiogenesis, metastasis, and therapy response. We discuss a future outlook, describing novel therapeutic approaches for attenuating ROS production while considering how these strategies should be carefully selected when combining with chemotherapeutic agents. As engineering-based approaches have been more frequently utilized to address biological questions, we discuss opportunities whereby engineering techniques may be employed to better understand the physical and biochemical factors controlling ROS expression. It is anticipated that an improved understanding of the mechanisms responsible for the hypoxia/ROS/HIF-1α axis in tumor progression will yield the development of better targeted therapies.