Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma.

Published

Journal Article

Medulloblastoma is the most common malignant brain tumor in children. It is thought to result from the transformation of granule cell precursors (GCPs) in the developing cerebellum, but little is known about the early stages of the disease. Here, we identify a pre-neoplastic stage of medulloblastoma in patched heterozygous mice, a model of the human disease. We show that pre-neoplastic cells are present in the majority of patched mutants, although only 16% of these mice develop tumors. Pre-neoplastic cells, like tumor cells, exhibit activation of the Sonic hedgehog pathway and constitutive proliferation. Importantly, they also lack expression of the wild-type patched allele, suggesting that loss of patched is an early event in tumorigenesis. Although pre-neoplastic cells resemble GCPs and tumor cells in many respects, they have a distinct molecular signature. Genes that mark the pre-neoplastic stage include regulators of migration, apoptosis and differentiation, processes crucial for normal development but previously unrecognized for their role in medulloblastoma. The identification and molecular characterization of pre-neoplastic cells provides insight into the early steps in medulloblastoma formation, and may yield important markers for early detection and therapy of this disease.

Full Text

Cited Authors

  • Oliver, TG; Read, TA; Kessler, JD; Mehmeti, A; Wells, JF; Huynh, TTT; Lin, SM; Wechsler-Reya, RJ

Published Date

  • May 2005

Published In

Volume / Issue

  • 132 / 10

Start / End Page

  • 2425 - 2439

PubMed ID

  • 15843415

Pubmed Central ID

  • 15843415

Electronic International Standard Serial Number (EISSN)

  • 1477-9129

International Standard Serial Number (ISSN)

  • 0950-1991

Digital Object Identifier (DOI)

  • 10.1242/dev.01793

Language

  • eng