RBIO-01. RADIATION RESPONSES OF 2D AND 3D GLIOBLASTOMA CELLS: A NOVEL, 3D-SPECIFIC RADIOPROTECTIVE ROLE OF VEGF/Akt SIGNALING THROUGH FUNCTIONAL ACTIVATION OF NHEJ

Glioblastoma (GBM) is resistant to conventional treatments with dismal prognosis. . Tumours exhibit inherent resistance to radiation and chemotherapy which has been attributed to a subpopulation of cancer cells termed ‘GBM stem-like cells’ (GSC) characterised by multipotentiality and potent tumorigenic capacity. Anti-VEGF antibody bevacizumab increases progression-free survival of GBM patients in combination with standard radio-chemotherapy. We have previously shown that bevacizumab enhanced radiosensitivity of 3D GSC cultures in clonogenic and neurosphere formation assays, but had no effect on radiation responses of 2D GSC. VEGF deprivation was associated with significant radiosensitisation of 3D GSC but had no effect on 2D GSC confirming previous findings with bevacizumab. A correlation between radiosensitivity, increased gammaH2AX and phospho-DNA-PK nuclear foci and increased number of cells undergoing mitotic catastrophe or with micronuclei following radiation treatment. In contrast, increased numbers of foci of the homologous recombination (HR) repair protein Rad51 were observed in radioresistant populations. Our results show that in the 3D model, VEGF signalling is required for optimal NHEJ activation with fast kinetics. This effect allows access to HR repair proteins at the remaining unrepaired DSBs at later time points, facilitating their repair and conferring radiation protection. Detailed analysis of the signalling pathways demonstrated a radioprote...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: RADIOBIOLOGY Source Type: research