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Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma

Robert C Castellino1, Benjamin G Barwick, Matthew Schniederjan

  • 1Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA. rccaste@emory.edu

Plos One
|June 4, 2010
PubMed
Abstract

Insights

PTEN deficiency in mice significantly increases medulloblastoma incidence and decreases survival by activating PI-3 kinase pathways. Low PTEN expression in human tumors correlates with worse survival, suggesting PTEN as a prognostic marker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cross talk between PI-3 kinase and sonic hedgehog pathways is implicated in medulloblastoma pathogenesis.
  • PTEN (Phosphatase and tensin homolog) plays a critical role in cellular signaling.
  • Medulloblastoma is a common malignant brain tumor in children.

Purpose of the Study:

  • To investigate the role of PTEN deficiency in medulloblastoma development.
  • To explore the interplay between PI-3 kinase and sonic hedgehog pathways in PTEN-deficient medulloblastoma.
  • To evaluate PTEN expression as a prognostic marker in human medulloblastoma.

Main Methods:

  • Generated genetically engineered mouse models by crossing SmoA1 mice with Pten deficient mice.
  • Analyzed gene expression profiles, performed Western blotting, and immunohistochemistry on tumor samples.
  • Examined PTEN expression and survival data in human medulloblastoma patient cohorts.

Main Results:

  • Pten deficiency in mice doubled medulloblastoma incidence and reduced survival.
  • Pten deficient tumors showed activation of PI-3 kinase pathway, increased angiogenesis, and altered gene signatures.
  • Low or absent PTEN expression in human medulloblastomas correlated with significantly worse overall survival.

Conclusions:

  • PTEN deficiency promotes medulloblastoma through PI-3 kinase pathway activation.
  • PTEN expression serves as a favorable prognostic marker in medulloblastoma.
  • Mouse models with activated PI-3 kinase pathways are valuable for preclinical drug evaluation.

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