Medulloblastoma is one of the most widespread pediatric brain tumors, principally caused by the prolonged mitotic activity of glioma-propagating cells (GCPs) inside the external granular layer (EGL) of the cerebellum, making them potential targets of transforming insults, resulting in gene mutation and tumorigenesis. Medulloblastoma is extremely difficult to treat, in that it is particularly unresponsive to surgical and pharmacological treatments available to date. It is currently treated by surgical removal of the tumor mass, which however is not curative. Adding radiotherapy to the central nervous system may increase the recovery rate, especially when followed by chemotherapy. However the side effects are so serious that the ambition to a satisfying quality of life is compromised. Particularly, radiotherapy has a highly negative effect on the cognitive ability of pediatric patients, as radiations may lead to partial destruction of the neuron precursor supplies in a brain that is not yet completely formed. Therefore, there is a dramatic need of novel therapeutic treatments for medulloblastoma which do not show the abovementioned drawbacks.
A research group of the Institute of Cell Biology and Neurobiology in CNR, have recently shown that it is sufficient to delay the migration of the GCPs from the EGL, forcing them to proliferate for a longer period, to enhance the frequency of the transformation of the GCPs into a neoplastic cell. They demonstrated this in a new mouse model that show a dramatic increase of medulloblastoma frequency, and also an increase of the tumor lesions at the surface of cerebellum. This phenotype is surprisingly not associated to increase of proliferation of GCPs, but rather to a strong decrease of the migration of GCPs from the surface of cerebellum toward the internal layers of cerebellum. They identified by a genome-wide analysis the chemokine Cxcl3 as a novel responsible for the migration of GCPs. In neoplastic GCPs, Cxcl3 is reduced, and this causes a huge increase of the frequency of medulloblastomas in consequence of the reduced migration of GCPs.
The use of Cxcl3 in treating medulloblastoma at an early phase of its development induces the neoplastic GCPs to withdraw from the neoplastic program at a stage when the neoplastic GCP is still able to differentiate. In fact the GCP will be induced by Cxcl3 to migrate outside the neoplastic lesion toward the internal part of cerebellum, where the GCP will differentiate, arresting the neoplastic program. As Cxcl3 is a diffusible chemokine acting through a receptor at the surface of the GCPs, it will be feasible to employ an intrathecal treatment.
The final outcome should be a reduced or arrested development of the tumor.
Considering the side effects of surgical removal of the tumor mass, which need radiotherapy and/or chemotherapy, particularly on the cognitive ability of pediatric patients being between 2 and 7,a novel therapeutic treatments for medulloblastoma which do not show the abovementioned drawbacks could have benefit without any doubts.
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Medulloblastoma treatment, as an alternative to the surgical and pharmacological treatments available to date.
Alessia Naso
