Glioblastoma is a primary brain tumor with a poor prognosis despite of many treatment regimens. Radiotherapy significantly prolongs patient survival and remains the most common treatment. Slit2 and Robo1 are evolutionarily conserved proteins involved in axon guidance, migration, and branching of neuronal cells. New studies have shown that Slit2 and Robo1 could play important roles in leukocyte chemotaxis and glioblastoma cell migration. Therefore, we investigated whether the Slit2/Robo1 complex has an impact on the motility of glioblastoma cells and whether irradiation with therapeutic doses modulates this effect. Our results indicate that photon irradiation increases the migration of glioblastoma cells in vitro. qPCR and immunoblotting experiments in two different glioblastoma cell lines (U-373 MG and U-87 MG) with different malignancy revealed that both Slit2 and Robo1 are significantly lower expressed in the cell populations with the highest motility and that the expression was reduced after irradiation. Overexpression of Robo1 significantly decreased the motility of glioblastoma cells and inhibited the accelerated migration of wild-type cells after irradiation. Immunoblotting analysis of migration-associated proteins (fascin and focal adhesion kinase) and of the epithelial-mesenchymal-transition-related protein vimentin showed that irradiation affected the migration of glioblastoma cells by increasing vimentin expression, which can be reversed by the overexpression of Slit2 and Robo1. Our findings suggest that Robo1 expression might counteract migration and also radiation-induced migration of glioblastoma cells, a process that might be connected to mesenchymal-epithelial transition.

Results: Of the 56 patients identified, a total of 52 were included in the study. Four patients were ineligible e 2 were treated with single fraction SRS, and 2 had missing RT details. Median age was 54.3 years (range 29-78). Of those on hormone replacement, 46% were taking T4, 69% steroid, 25% growth hormone, and 38% sex hormones. The most common regimen prescribed was 50.4 Gy in 28 fractions, with 4 patients in the 3D-CRT group and 1 in the IMRT group receiving a higher dose of 54 Gy in 30 fractions. Median GTV volume was 6.9cc, 10.4cc, and 5.7cc, with median PTV volume of 72.7cc, 62.3cc, and 13cc in the 3D-CRT, IMRT, and F-SRS groups respectively, reflecting the tighter GTV to PTV margin in the IMRT/F-SRS groups. There was no difference in acute fatigue levels during RT between groups. Five patients (14%) in the 3D-CRT group had grade 2 or 3 fatigue, compared with 2 (13%) in the more conformal IMRT/F-SRS groups combined. The remainder reported grade 0 or 1 fatigue, and there were no cases of grade 4 fatigue in any patient. At first follow up all patients in the IMRT/F-SRS group (n Z 15) had grade 0 or 1 fatigue, with only 1 patient in the 3D-CRT group reporting ongoing grade 2 or 3 fatigue. There was no association of grade of fatigue with hormone replacement type or number or hormones replaced prior to the commencement of RT. Conclusion: While planning studies have reported lower temporal and normal brain doses with more conformal techniques, in this study, there was no difference at the clinic setting in grade of acute fatigue with RT technique used.

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