A Review of the Role of Hypoxia in Radioresistance in Cancer Therapy

Abstract

Hypoxia involves neoplastic cells. Unlike normal tissue, solid tumors are composed of aberrant vasculature, leading to a hypoxic microenvironment. Hypoxia is also known to be involved in both metastasis initiation and therapy resistance. Radiotherapy is the appropriate treatment in about half of all cancers, but loco-regional control failure and a disease recurrence often occur due to clinical radioresistance. Hypoxia induces radioresistance through a number of molecular pathways, and numerous strategies have been developed to overcome this. Nevertheless, these strategies have resulted in disappointing results, including adverse effects and limited efficacy. Additional clinical studies are needed to achieve a better understanding of the complex hypoxia pathways. This review presents an update on the mechanisms of hypoxia in radioresistance in solid tumors and the potential therapeutic solutions.

Figure 1. Strategies to overcome hypoxia-induced radioresistance

Under hypoxic conditions, the HIF-1α subunit translocates to the nucleus and binds HIF-1β. This results in the transcriptional activation of many genes, which plays a role in tumor progression. Both HIF-1 and HIF-2 stimulate transcription of vascular endothelial growth factor (VEGF), a crucial regulator of vascular development. Different strategies have already been tested to overcome hypoxia-induced radioresistance. (1) The ESCALOX protocol concluded that dose escalation to large parts of the tumor was associated with the risk of more acute and late toxicity. (2) Stereotaxic body radiation therapy showed very encouraging results for very large unresectable tumors. (3) Accelerated radiotherapy induced tumor radiosensitivity. As perspective, in vitro TNP-470, an angiogenesis inhibitor, could increase tumor oxygenation and radiosensitivity. Likewise, HIF-2α (PT2385) inhibition enhanced radiation sensitivity in a cellular model of lung cancer by promoting apoptotic activity via the p53 pathway. The association of radiotherapy and TNP-470 and/or PT2385 should be investigated.