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.


RESULTS
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
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.
Department 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
Robert C
RC
Castellino
Benjamin G
BG
Barwick
Matthew
M
Schniederjan
Meghan C
MC
Buss
Oren
O
Becher
Dolores
D
Hambardzumyan
Tobey J
TJ
Macdonald
Daniel J
DJ
Brat
Donald L
DL
Durden
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015536:Down-Regulation; D053823:Hedgehog Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008527:Medulloblastoma / Q000098:blood supply / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000201:enzymology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation
D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse