Deciphering the response of subventricular zone-nested glioblastoma cells after surgery

Abstract

INTRODUCTION: Glioblastoma (GBM) is the most frequent primary malignant brain tumor in adults, with really poor prognosis, subsequent to systematic recurrences, which occur in 80% of cases in the resection margin of initial tumor. We previously demonstrated that, after experimental striatal xenotransplantation, GBM cells, and particularly GBM-initiating cells (GIC), are able to escape the tumor mass and specifically colonize the sub-ventricular zone (SVZ), a well-known neurogenic zone in adult brains. We also demonstrated that this specific oriented migration is driven by a CXCL12-CXCR4 signalization. In this study, we address the potential implication of SVZ-nested tumor cells in local GBM relapses. MATERIALS AND METHODS: We engrafted in the right striatum of nude mice GBM cells (GB138) from a human primary culture, which are previously transfected with a lentiviral construction in order to express the RFP spontaneously, while they conditionally express eGFP, only in presence of Cre-recombinase. As the GB138 cells reach the SVZ, we injected in the lateral ventricle an Adeno-Associated Viral vector expressing Cre-recombinase, which is able to infect nearby GB138 cells. We finally compared 3 mice that were not operated (control group) with 3 mice that underwent tumor resection (surgery group) and quantify green spots in the tumor mass (TM) and/or resection cavity (RC) every 20 microns thanks to Clarity Lightsheet microscope. RESULTS: We found that the median of green spots for the 3 mice of the control group was respectively 1, 0 and 0 in TM, while the median for the surgery group was 7, 8 and 47 in RC. The Standard Deviation (SD) for the control group was respectively 1.1, 0.4 and 0.6, while SD for the surgery group was respectively 1.5, 1.7 and 16. CONCLUSION: SVZ-nested GBM cells seem to be recruited for tumor relapse after surgery