Integrin-αVβ3 is a fundamental factor in medulloblastoma tumorigenicity and radioresistance: A new game for an old player

Abstract

ABSTRACTMedulloblastoma (MB) is the most frequent solid tumor in children, localized in the brain’s posterior fossa. Its standard of care comprises maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. Relevant targets for naive and recurrent MB are urgently needed. Primary and recurrent MBs are characterized by aggressive invasion into surrounding brain tissue, active angiogenesis, and radioresistance. Integrin-αvβ3 was a major driver of these features in glioblastoma. Nevertheless, such observations have not yet been reported in MB. Integrin-αvβ3 was found to be expressed in a subset of MB patients. We investigated the role of integrin-αvβ3 using MB-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo. Radioresistant MB cell lines were generated and showed increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacological integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/magnetic resonance imaging (MRI) studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This approach offers the prospect of a novel predictive imaging modality in MB. Altogether, our data pave the way for SPECT/MRI-based selection of a subpopulation of MB patients eligible for integrin-αvβ3-directed therapies.SIGNIFICANCEThis study demonstrates integrin-αvβ3’s fundamental role in MB tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.