Optimizing antiangiogenic strategies: combining with radiotherapy

Abstract

Tumor response to radiotherapy is influenced by many tumoral intracellular biological factors whose deregulation leads to the modulation of tumor sensitivity to radiotherapy. However, the pathways controlling intracellular radiation resistance are activated by or display common pathways with many factors also controlling the tumoral microenvironment, and particularly angiogenesis. One of the innovative strategies that could improve response to irradiation of aggressive or radiotherapy-insensitive tumors consists of combining radiotherapy with inhibitors of the angiogenesis pathways. This review details four main reasons for this: angiogenic factors control intracellular radioresistance, endothelial cell radiosensitivity controls tumor radiosensitivity, tumor angiogenesis is the cause of hypoxia, a major radiation resistance factor, and stem cells, known to be radiation resistant, are dependent on angiogenic factors. We describe the implication of different factors in the various mechanisms leading to radiation resistance. These factors include vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor 2 (FGF2), along with αvβ3 and αvβ5 integrins as well as their downstream cellular pathways including some small G proteins. The review also explains the radiation-sensitizing effect of the inhibition of these factors by targeted therapies. The optimal sequences of administration between antiangiogenics and radiotherapy are partially elucidated. The success of these combinations will depend on the specific study of the mechanisms of action of antiangiogenic agents and their interaction with ionizing radiations, and on the use in preclinical and clinical studies of metabolic and functional imaging. These techniques represent an essential tool for determining the optimal combination sequence followed by the assessment of these combinations.