Intracerebellar administration of the chemokine Cxcl3 prevents the neoplastic transformation of cerebellar precursor cells forcing their migration.

Background: We previously showed, in a medulloblastoma mouse model (Ptch1+/−/Tis21KO), that an increased tumor frequency correlates with a migration defect of cerebellar precursor cells (GCPs), because they remain longer in the proliferative area at the cerebellar surface. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. Methods and Results: To verify whether preneoplastic GCPs (pGCPs) within a medulloblastoma lesion can be induced by Cxcl3 to migrate and differentiate, thus exiting the neoplastic program, we treated 1-month-old Ptch1+/−/Tis21KO mice with Alzet minipumps filled with Cxcl3 or vehicle (cerebrospinal fluid). We observed that intracerebellar administration of Cxcl3 for 4 weeks leads to complete disappearance of the lesions, while a 14 day-treatment is ineffective, indicating that the medulloblastoma suppression is strictly dependent on the duration of Cxcl3 application. By immunohistochemistry we verified that the Cxcl3 treatment causes a massive migration of pGCPs from the lesion to the internal layers, where they differentiate. Conclusions and Significance: Since the tumor lesions present in 2-month-old Ptch1+/−/Tis21KO mice develop invariably into a medulloblastoma, our data represent a proof of concept that the Cxcl3 treatment can reduce medulloblastoma formation. Thus, the pro-migratory chemokine Cxcl3 may represent a novel therapy against medulloblastoma, that exploits the plasticity of pGCPs, forcing their differentiation.