Hadrontherapy Interactions in Molecular and Cellular Biology.

The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.

Angiopoietin-2 Combined with Radiochemotherapy Impedes Glioblastoma Recurrence by Acting in an Autocrine and Paracrine Manner: A Preclinical Study.

(1) We wanted to assess the impact of Ang2 in RCT-induced changes in the environment of glioblastoma. (2) The effect of Ang2 overexpression in tumor cells was studied in the GL261 syngeneic immunocompetent model of GB in response to fractionated RCT. (3) We showed that RCT combined with Ang2 led to tumor clearance for the GL261-Ang2 group by acting on the tumor cells as well as on both vascular and immune compartments. (4) In vitro, Ang2 overexpression in GL261 cells exposed to RCT promoted senescence and induced robust genomic instability, leading to mitotic death. (5) Coculture experiments of GL261-Ang2 cells with RAW 264.7 cells resulted in a significant increase in macrophage migration, which was abrogated by the addition of soluble Tie2 receptor. (6) Together, these preclinical results showed that, combined with RCT, Ang2 acted in an autocrine manner by increasing GB cell senescence and in a paracrine manner by acting on the innate immune system while modulating the vascular tumor compartment. On this preclinical model, we found that an ectopic expression of Ang2 combined with RCT impedes tumor recurrence.