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Infiltration of glioma cells in brain parenchyma stimulated by radiation in the F98/Fischer rat model

Abstract Purpose: In the months following radiotherapy, a rapid recurrence of glioblastoma multiforme occurs in the periphery of the resection cavity. The aim of this study was to assess the contribution of irradiation of the brain in the infiltration profile of glioma cells. Material and methods: Using the F98/Fischer rat glioma model, we either irradiated the brain, the F98 cancer cells, or both to separately investigate the effects of radiation. Inflammatory cytokines and pro-infiltration molecules were measured in irradiated brain. Results: A stimulation of interleukin-1β and transforming growth factor β1 expression 4 h after brain irradiation supported induction of inflammation. Early elevated expression of phospholipase A2 was also measured and was followed by a stimulation of cyclooxygenase-2 from day 5 to 20 after irradiation. This resulted in a biphasic increase of prostaglandins E2 and D2 biosynthesis with maximum at 4 h and 15 days post-irradiation. An important enhancement of F98 cells infiltration was observed when brain was irradiated, which took place at the expense of the growth of the primary tumour and resulted in a decreased median survival of the Fischer rats. This stimulation of F98 cells infiltration was associated with the pro-infiltration molecule, matrix metalloproteinase-2. Conclusion: In the animal model proposed, we demonstrated that irradiation of brain increased the infiltration capacity of F98 cells to the brain, resulting in a reduction of media survival of rats bearing this tumour. This animal model has also allowed identifying inflammatory cytokines and pro-infiltration molecules induced by radiation that can be targeted to prevent this adverse effect of radiation.