BIOLOGY OF MEDULLOBLASTOMA FORMATION

From WikiCNS
Jump to: navigation, search
Checkmark.gif This article has been reviewed by the NeuroWiki Editorial Board


Contents

Medulloblastoma may develop as an aberration of cerebellar development

The cerebellum develops from neuronal precursors located in the rhombic lip of the fetal brain. These precursors migrate tangentially to form the external granular cell layer (EGL) of the developing cerebellum. Purkinje neurons and Bergman glia arise from precursors in the subventricular zone and migrate toward the EGL. In the EGL, the granular cell precursors continue to proliferate in the outer zone; postmitotic neurons move to the inner zone of the layer and then migrate along Bergmann glial fibers to finally reside in the internal granular cell layer (IGL). The EGL eventually disappears as cell division ceases and all postmitotic neurons move to the IGL. The sonic hedgehog (SHH), BDNF and Wnt signaling pathways play an essential role in driving both cell migration and cell fate.

Cell of origin lies within the external granular layer

Medulloblastomas are observed to differentiate along glial and neuronal pathways in situ, suggesting that these tumors are derived from primitive, pluripotent, neuroepithelial stem cells. This conclusion is supported by studies of PNET cell lines that demonstrate expression of specific, developmentally regulated proteins in PNETs, as well as by recent work identifying a CD133(+) brain tumor stem-like cell in human medulloblastomas. Medulloblastomas have been demonstrated to express zic, a gene normally expressed only in the EGL of the developing cerebellum and its derivatives, suggesting that medulloblastoma arises from EGL precursor cells. Given the rapid proliferative capacity of EGL precursors and the pattern of gene expression seen, EGL cells and their derivatives seem, by far, the most likely origin of medulloblastoma.

The external granular layer (EGL) of the developing cerebellum. This is the source of the presumed cell of origin of MB, the granule neuron precursor (GNP).

Genetics

Karyotypic abnormalities: An isochromosome 17q is present in about 50% of tumors. The breakpoint has been localized to 17p11.2, but no tumor-specific gene rearrangement has been identified. Despite multiple studies, no tumor-suppressor gene that can be implicated in the development of medulloblastoma has been found on chromosome 17p. Specifically, no alteration in p53 has been identified. Other less common karyotypic abnormalities, including loss of heterozygosity (LOH) on chromosome 9q, have been identified in about 20% of medulloblastomas. Interestingly, the loss of 9q in medulloblastoma has been correlated with the desmoplastic subtype.

Tumor genetics

PDGF and SPARC have been found by immuohistochemical staining to be expressed differentially between metastatic and nonmetastatic tumors. Using Affymetrix HuGene FL array-based gene expression analysis, classic medulloblastomas may be distinguished from desmoplastic medulloblastomas by increased expression in the desmoplastic tumors of genes involved in the SHH/PTC pathway. Genes associated with favorable clinical outcome included TRKC and other genes characteristic of cerebellar differentiation.

Inactivation of the PTCH locus by deletion and mutation has been found in about 10% of sporadic medulloblastomas, suggesting that PTCH functions as a classic tumor suppressor in this subset of tumors. Similarly, APC gene mutations have rarely been identified in spontaneously occurring medulloblastomas. A third genetic alteration found in medulloblastoma is c-myc or N-myc amplification. Amplification of myc genes is rare, occurring in only 4% of medulloblastomas. Interestingly, c-myc amplification appears to correlate with the large cell phenotype, which carries a particularly grim prognosis.

Personal tools