Abstract
Medulloblastoma (MB), tumor of the cerebellum, remains a leading cause of cancer-related mortality in childhood. We previously showed, in a mouse model of spontaneous MB (Ptch1+/-/Tis21-/-), that a defect of the migration of cerebellar granule neuron precursor cells (GCPs) correlates with an increased frequency of MB. This occurs because GCPs, rather than migrating internally and differentiating, remain longer in the proliferative area at the cerebellar surface, becoming targets of transforming insults. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. As it is known that preneoplastic GCPs (pGCPs) can still migrate and differentiate like normal GCPs, thus exiting the neoplastic program, in this study we tested the hypothesis that pGCPs within a MB lesion could be induced by Cxcl3 to migrate and differentiate. We observed that the administration of Cxcl3 for 28 days within the cerebellum of 1-month-old Ptch1+/-/Tis21-/- mice, i.e., when MB lesions are already formed, leads to complete disappearance of the lesions. However, a shorter treatment with Cxcl3 (2 weeks) was ineffective, suggesting that the suppression of MB lesions is dependent on the duration of Cxcl3 application. We verified that the treatment with Cxcl3 causes a massive migration of pGCPs from the lesion to the internal granular layer, where they differentiate. Thus, the induction of migration of pGCPs in MB lesions may open new ways to treat MB that exploit the plasticity of the pGCPs, forcing their differentiation. It remains to be tested whether this plasticity continues at advanced stages of MB. If so, these findings would set a potential use of the chemokine Cxcl3 as therapeutic agent against MB development in human preclinical studies.
Highlights
Medulloblastoma (MB), a neuroepithelial tumor developing in the cerebellum, is the most common pediatric brain cancer and represents about 20% of all cerebral childhood tumors (Roberts et al, 1991; Louis et al, 2007)
This defect of migration is caused by downregulation of the chemokine Cxcl3, whose promoter is directly activated by Tis21 (Farioli-Vecchioli et al, 2012)
In this study we tested the feasibility to reduce the frequency of MB lesions by forcing the preneoplastic granule neuron precursor cells to migrate out of the lesions at the surface of the cerebellum and differentiate, withdrawing from the tumor program, by means of an intracerebellar treatment with the chemokine Cxcl3
Summary
Medulloblastoma (MB), a neuroepithelial tumor developing in the cerebellum, is the most common pediatric brain cancer and represents about 20% of all cerebral childhood tumors (Roberts et al, 1991; Louis et al, 2007). Our recent study demonstrated that a new MB Shh-type mouse model, which lacks the MB-suppressor gene Tis (Ptch1+/−/Tis21−/−), develops MBs with high frequency in consequence of a defect of migration of the GCPs out of the EGL (Farioli-Vecchioli et al, 2007, 2012). This defect of migration is caused by downregulation of the chemokine Cxcl, whose promoter is directly activated by Tis (Farioli-Vecchioli et al, 2012). We revealed the ability of the chemokine Cxcl to cell autonomously induce the migration of the GCPs out of the EGL and, remarkably, to reduce the area of MB lesions in cerebellar slices of the MB Ptch1+/−/Tis21−/− mouse model (Farioli-Vecchioli et al, 2012)
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