Cargando…

Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma

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 mic...

Descripción completa

Detalles Bibliográficos
Autores principales: Castellino, Robert C., Barwick, Benjamin G., Schniederjan, Matthew, Buss, Meghan C., Becher, Oren, Hambardzumyan, Dolores, MacDonald, Tobey J., Brat, Daniel J., Durden, Donald L.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877103/
https://www.ncbi.nlm.nih.gov/pubmed/20520772
http://dx.doi.org/10.1371/journal.pone.0010849
_version_ 1782181767025786880
author Castellino, Robert C.
Barwick, Benjamin G.
Schniederjan, Matthew
Buss, Meghan C.
Becher, Oren
Hambardzumyan, Dolores
MacDonald, Tobey J.
Brat, Daniel J.
Durden, Donald L.
author_facet Castellino, Robert C.
Barwick, Benjamin G.
Schniederjan, Matthew
Buss, Meghan C.
Becher, Oren
Hambardzumyan, Dolores
MacDonald, Tobey J.
Brat, Daniel J.
Durden, Donald L.
author_sort Castellino, Robert C.
collection PubMed
description 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+/−; Pten +/− 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+/−; 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.
format Text
id pubmed-2877103
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-28771032010-06-02 Heterozygosity for Pten Promotes 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. PLoS One Research Article 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+/−; Pten +/− 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+/−; 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. Public Library of Science 2010-05-26 /pmc/articles/PMC2877103/ /pubmed/20520772 http://dx.doi.org/10.1371/journal.pone.0010849 Text en Castellino et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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 Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
title Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
title_full Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
title_fullStr Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
title_full_unstemmed Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
title_short Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
title_sort heterozygosity for pten promotes tumorigenesis in a mouse model of medulloblastoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877103/
https://www.ncbi.nlm.nih.gov/pubmed/20520772
http://dx.doi.org/10.1371/journal.pone.0010849
work_keys_str_mv AT castellinorobertc heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT barwickbenjaming heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT schniederjanmatthew heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT bussmeghanc heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT becheroren heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT hambardzumyandolores heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT macdonaldtobeyj heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT bratdanielj heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma
AT durdendonaldl heterozygosityforptenpromotestumorigenesisinamousemodelofmedulloblastoma