gms | German Medical Science

Objective: The classic (CMB) and the desmoplastic (DMB) subtypes represent the major medulloblastoma variants. In contrast to CMB, DMB display high levels of the low-affinity nerve growth factor receptor p75^NTR. Apoptotic and proliferative functions have been attributed to p75^NTR. Given reports of a better clinical course of DMB we hypothesized that p75^NTR might have a “tumor suppressor” function in DMB, which is lacking in CMB.

Methods: A large panel of medulloblastomas was screened for mutations in the p75^NTR coding region. p75^NTR -mRNA expression and the DNA methylation status of its 5´-region were assessed. We measured p75^NTR-mRNA levels in murine cerebellar granule cell precursors (GCP) after Sonic Hedgehog treatment, simulating tumorigenesis of medulloblastoma in-vitro. p75^NTR immunostainings were performed in wildtype murine cerebella and medulloblastomas arising in patched heterozygous mice. Medulloblastoma cells engineered to express different variants of p75^NTR were characterized flowcytometrically and morphologically by DAPI staining, analyzing the functional role of p75^NTR in medulloblastoma

Results: One CMB displayed a mutation of the p75^NTR coding sequence. p75^NTR mRNA levels clearly delineated DMB and CMB. CpG island hypermethylation was excluded as the cause of low p75^NTR expression in CMB. Sonic Hedgehog-treated GCP showed elevated p75^NTR expression. Strong expression of p75^NTR was detected in the external granule cell layer of wildtype mice and in murine medulloblastomas. CMB cells overexpressing p75^NTR displayed a significant increase of apoptosis in flowcytometric and morphologic analysis.

Conclusions: We could exclude genetic and epigenetic alterations of p75^NTR in MB, being responsible for absent p75^NTR expression in CMB. Moreover we could link activated Hedgehog signaling in DMB with p75^NTR expression and characterize p75^NTR as a biologically relevant inductor of apoptosis in MB. Targeting the p75^NTR might be a valuable target for future therapeutic interventions in MB.