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Apoptosis Suppression by Somatic Cell Transfer of Bcl-2 Promotes Sonic Hedgehog–Dependent Medulloblastoma Formation in Mice

Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah

Requests for reprints: Daniel W. Fults, Department of Neurosurgery, University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT 84132. Phone: 801-581-6908; Fax: 801-581-4385; E-mail: daniel.fults{at}hsc.utah.edu.

Medulloblastomas are malignant brain tumors that arise in the cerebellum in children. Aberrant activation of the Sonic hedgehog (Shh) signaling pathway, which normally stimulates proliferation of granule neuron precursors (GNP) during cerebellar development, induces tumors in mice that closely mimic human medulloblastomas. Shh-dependent medulloblastoma formation is enhanced by hyperactive insulin-like growth factor (IGF) signaling and ectopic expression of Myc oncogenes. This enhanced tumorigenesis stems from the sensitivity of GNPs to IGF and Myc levels in regulating proliferation. An emerging theme in cancer research is that oncogene-induced cell proliferation cannot initiate neoplastic transformation unless cellular programs that mediate apoptosis are disabled. Here, we report a high frequency of medulloblastoma formation in mice after postnatal overexpression of the antiapoptotic protein Bcl-2 in cooperation with Shh. Ectopic expression of Bcl-2 alone or in combination with N-Myc did not induce tumors, indicating that Shh has essential transforming functions in GNPs not supplied by the mitogenic stimulus of N-Myc combined with a strong antiapoptotic signal provided by Bcl-2. Expression of endogenous Bcl-2 was not up-regulated in Shh-induced tumors. Instead, elevated levels of phosphorylated Akt were found, suggesting that activated phosphatidylinositol 3-kinase signaling is one intrinsic mechanism for suppressing apoptosis in Shh-dependent medulloblastomas. Thus, blockade of apoptosis cooperates with Shh-stimulated proliferation to transform GNPs and induce aggressive medulloblastomas. These findings provide insights into the molecular signals that initiate medulloblastoma formation and they support the importance of blocking apoptosis in carcinogenesis. [Cancer Res 2007;67(11):5179–85]

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