Heterozygosity for Ptenpromotes Tumorigenesis in a Mouse Model of Medulloblastoma

Robert C. Castellino, Benjamin G. Barwick, Matthew Schniederjan, Meghan C. Buss, Oren Becher, Dolores Hambardzumyan, Tobey J. Macdonald, Daniel J. Brat, Donald L. Durden

Research output: Contribution to journalArticle

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Abstract

Background:Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma.&Methodology/Principal Findings:We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/2; Pten +/2 medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/2; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression.&Conclusions/Significance:This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.©2010 Castellino et al.

Original languageEnglish (US)
Article numbere10849
JournalPloS one
Volume5
Issue number5
DOIs
StatePublished - Sep 17 2010

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Medulloblastoma
carcinogenesis
Tumors
heterozygosity
phosphatidylinositol 3-kinase
Carcinogenesis
Genes
animal models
neoplasms
Chemical activation
Phosphatidylinositol 3-Kinases
Erinaceidae
angiogenesis
Hedgehogs
mice
genes
apoptosis
Neoplasms
tumor suppressor genes
Apoptosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Castellino, R. C., Barwick, B. G., Schniederjan, M., Buss, M. C., Becher, O., Hambardzumyan, D., ... Durden, D. L. (2010). Heterozygosity for Ptenpromotes Tumorigenesis in a Mouse Model of Medulloblastoma. PloS one, 5(5), [e10849]. https://doi.org/10.1371/journal.pone.0010849

Heterozygosity for Ptenpromotes Tumorigenesis in a Mouse Model of Medulloblastoma. / Castellino, Robert C.; Barwick, Benjamin G.; Schniederjan, Matthew; Buss, Meghan C.; Becher, Oren; Hambardzumyan, Dolores; Macdonald, Tobey J.; Brat, Daniel J.; Durden, Donald L.

In: PloS one, Vol. 5, No. 5, e10849, 17.09.2010.

Research output: Contribution to journalArticle

Castellino, RC, Barwick, BG, Schniederjan, M, Buss, MC, Becher, O, Hambardzumyan, D, Macdonald, TJ, Brat, DJ & Durden, DL 2010, 'Heterozygosity for Ptenpromotes Tumorigenesis in a Mouse Model of Medulloblastoma', PloS one, vol. 5, no. 5, e10849. https://doi.org/10.1371/journal.pone.0010849
Castellino RC, Barwick BG, Schniederjan M, Buss MC, Becher O, Hambardzumyan D et al. Heterozygosity for Ptenpromotes Tumorigenesis in a Mouse Model of Medulloblastoma. PloS one. 2010 Sep 17;5(5). e10849. https://doi.org/10.1371/journal.pone.0010849
Castellino, Robert C. ; Barwick, Benjamin G. ; Schniederjan, Matthew ; Buss, Meghan C. ; Becher, Oren ; Hambardzumyan, Dolores ; Macdonald, Tobey J. ; Brat, Daniel J. ; Durden, Donald L. / Heterozygosity for Ptenpromotes Tumorigenesis in a Mouse Model of Medulloblastoma. In: PloS one. 2010 ; Vol. 5, No. 5.
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