Expression of the Neurotrophin Receptor p75^NTRin Medulloblastomas Is Correlated with Distinct Histological and Clinical Features: Evidence for a Medulloblastoma Subtype Derived from the External Granule Cell Layer

Abstract

Abstract. Medulloblastomas (MBs) are primitive neuroectodermal tumors (PNET) of the cerebellum. They represent the most frequent malignant pediatric brain tumors, but their origin still remains unresolved and controversial. MB cells correspond to different stages of neural development and differentiation as illustrated by their expression of neuronal and glial markers. In the present study, we examined the expression pattern of the common low-affinity neurotrophin receptor p75 NTR in a series of 167 MBs by immunohistochemistry. While p75 NTR was present in only 17% of classic MBs (CMB), we found expression of p75 NTR in all desmoplastic (nodular) MBs (DMB) examined, and in 71% of those MBs with a significant desmoplastic component. Furthermore, both desmoplastic histology and p75NTR expression were present preferentially in those tumors of adolescents and adults that are frequently located laterally in the cerebellar hemispheres. In DMBs, p75NTR was expressed predominantly in the proliferative, reticulin-rich areas, which may show coexpression of GFAP. In the pale islands of DMB, p75NTR was expressed only weakly or was absent. The expression pattern showed an inverse relation to that of the synaptic vesicle protein synaptophysin that was predominant in p75 NTR negative classic MBs. Since the neurotrophin receptor p75 NTR is expressed in cells of the external granule cell layer (EGL) of the fetal cerebellum, our findings suggest that progenitor cells of the EGL are the cellular origin of a distinct subset of MB, namely the desmoplastic variant and MBs with a significant desmoplastic component.

Medulloblastoma Variants: Age-Dependent Occurrence and Relation to Gorlin Syndrome—A New Clinical Perspective

“…Histologically, MBEN contains large nodules with low proliferative activity and advanced neurocytic differentiation, as well as smaller areas with proliferative cells that are embedded in a dense reticulum fiber network. The latter areas resemble the more frequent DMBs, which are believed to arise from granule cell progenitors of the cerebellum and that frequently carry activating mutations of genes encoding for components of the Hedgehog-Patched signaling pathway (14,37). Similar to a previous study (8), our study confirms in greater detail that desmoplastic variants are associated to better prognosis in infants.…”

Loss ofpatchedand disruption of granule cell development in a pre-neoplastic stage of medulloblastoma

“…The same has been postulated for human medulloblastomas, particularly those with a desmoplastic appearance (Buhren et al, 2000;Kadin et al, 1970;Miyata et al, 1998). Desmoplastic tumors -which represent 20-30% of human medulloblastomasfrequently harbor mutations in the Shh pathway, and have a gene expression profile that resembles normal GCPs (Pomeroy et al, 2002).…”

“…Previous studies have suggested that medulloblastoma arises from granule cell precursors (Buhren et al, 2000;Kadin et al, 1970;Miyata et al, 1998). To determine whether preneoplastic cells express markers of the granule cell lineage, we crossed patched +/-mice with Math1-GFP mice (Lumpkin et al, 2003).…”

Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization

“…MB is also found in approximately 20% of offspring from heterozygous transgenic mice carrying a targeted deletion of the Ptch gene that results in constitutive Hh signaling (Goodrich et al, 1997;Wetmore et al, 2001). Both Wnt and Hh signaling pathways play crucial roles in the proliferation and differentiation of cerebellar granule cells, from which MBs are thought to arise (Yokota et al, 1996;Buhren et al, 2000).…”