1. Angiopoietin-2 Combined with Radiochemotherapy Impedes Glioblastoma Recurrence by Acting in an Autocrine and Paracrine Manner: A Preclinical Study
- Author
-
Myriam Bernaudin, M.M. Leblond, Aurélie Ferré, Edwige Petit, Charly Hélaine, Elodie A. Pérès, Samuel Valable, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Cancer Research ,[SDV]Life Sciences [q-bio] ,Cell ,Inflammation ,chemotherapy ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Immune system ,vascularization ,Medicine ,Macrophage ,Autocrine signalling ,radiotherapy ,Innate immune system ,business.industry ,glioblastoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,microenvironment ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,inflammation ,030220 oncology & carcinogenesis ,Cancer research ,Ectopic expression ,angiopoietin-2 ,radiochemotherapy ,medicine.symptom ,business - Abstract
Simple Summary Glioblastoma (GB) is a highly aggressive brain tumor characterized by poor prognosis and high rate of recurrence in response to conventional treatments consisting of tumor resection and radiochemotherapy (RCT). The reasons for this therapeutic failure are mainly due to the complexity of GB biology and its environment. GB progression is highly dependent on its vascularization and inflammatory status. Besides, evidence showed that RCT also induces vascular change and inflammation. In GB patients, Angiopoietin-2 (Ang2), biomarker of poor prognosis is a crucial angiogenic factor also involved in inflammation. Our aim was to clarify the role of Ang2 in RCT-induced changes in the GB environment. To this end, we generated Ang2-overexpressing GL261 cells and characterized tumor progression, as well as inflammation and vascularization, in response to RCT. We showed that Ang2 delays tumor recurrence and makes a lasting improvement in animal survival when combined with conventional RCT. Abstract (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.
- Published
- 2020