Abstract
BackgroundRecent 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 FindingsWe 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/SignificanceThis 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.
Highlights
IntroductionMultimodality treatment with surgery, radiation, and chemotherapy cures many patients, but often leaves survivors devastated with long-term toxicities that affect their neurocognitive and growth potential
Medulloblastoma is the most common malignant brain tumor of childhood
When SmoA1 mice were crossed with Pten +/2 mice, 97.9% of the SmoA1 +/2; Pten +/2 offspring followed over the same time interval exhibited symptoms of medulloblastoma
Summary
Multimodality treatment with surgery, radiation, and chemotherapy cures many patients, but often leaves survivors devastated with long-term toxicities that affect their neurocognitive and growth potential. Up to 30% of children with medulloblastoma experience tumor progression or recurrence, for which no curative therapy exists. The lack of more effective, less toxic therapies stems from our imperfect understanding of medulloblastoma tumor biology. Patients diagnosed with medulloblastoma are treated based upon disease stage, age at diagnosis, and extent of resection using a combination of surgery, chemotherapy, and ionizing radiation (IR) [1]. The importance of histology in tumor biology and treatment responsiveness has been controversial. Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma
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