Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts

• Published in: Oncogene Vol. 22; no. 55; pp. 8861 - 8869
• Main Authors: ADER, Isabelle, DELMAS, Caroline, BONNET, Jacques, ROCHAIX, Philippe, FAVRE, Gilles, TOULAS, Christine, COHEN-JONATHAN-MOYAL, Elizabeth
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 04.12.2003; Nature Publishing Group
• Subjects: Angiogenesis; Animals; Biological and medical sciences; Brain cancer; Brain tumors; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Gamma Rays; Gelatinase A; Glioblastoma; Glioblastoma - diagnostic imaging; Glioblastoma - metabolism; Glioma; Glioma cells; Humans; Hypoxia; Ionizing radiation; Medical prognosis; Medical sciences; Metalloproteinase; Mice; Molecular and cellular biology; Neurology; Oxygen - metabolism; Oxygenation; Radiation therapy; Radiography; Radioresistance; Radiosensitivity; Radiosensitization; rho GTP-Binding Proteins - metabolism; Transplantation, Heterologous; Tumor microenvironment; Tumors; Tumors of the nervous system. Phacomatoses; Xenografts; France; Human; Nervous system diseases; Oxygen; Glioblastoma; Environmental factor; Malignant tumor; Heterograft; Carcinogenesis; Malignant glioma; Angiogenesis; MMP; Radiosensitization; Central nervous system disease; Rho; Hypoxia; glioma; Inhibition
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207095

We previously demonstrated in vitro that inhibiting the biological pathways of the small GTPase Rho radiosensitizes the human glioma U87 cell line. The aim of this study was to determine if Rho might be involved in the control of in vivo radiosensitivity altogether by controlling cellular radioresistance and by modifying tumor microenvironment. We demonstrate here that the in vivo induction of the dominant negative of Rho, RhoBN19, in U87 xenografts induces a significant decrease of tumor cell survival after irradiation more important than the one we previously observed in vitro. This in vivo increased effect of RhoBN19 expression is due to the improvement of the tumor oxygenation associated with a significant decrease of the vessel density and of the metalloproteinase 2 (MMP2) expression. Moreover, in vitro RhoBN19 expression in U87 cells leads to the inhibition of MMP2 activity. Our results demonstrate for the first time that inhibiting Rho pathways modifies the in vivo radiosensitivity of human glioma cells by controlling intrinsic radioresistance, hypoxia and angiogenesis. These data strongly suggest that Rho should be a major determinant of cellular resistance to ionizing radiation.