Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice.

A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times.

Genetic drivers of metastatic dissemination in sonic hedgehog medulloblastoma.

Leptomeningeal dissemination (LMD), the metastatic spread of tumor cells via the cerebrospinal fluid to the brain and spinal cord, is an ominous prognostic sign for patients with the pediatric brain tumor medulloblastoma. The need to reduce the risk of LMD has driven the development of aggressive treatment regimens, which cause disabling neurotoxic side effects in long-term survivors. Transposon-mediated mutagenesis studies in mice have revealed numerous candidate metastasis genes.

Functional genomics identifies drivers of medulloblastoma dissemination.

Medulloblastomas are malignant brain tumors that arise in the cerebellum in children and disseminate via the cerebrospinal fluid to the leptomeningeal spaces of the brain and spinal cord. Challenged by the poor prognosis for patients with metastatic dissemination, pediatric oncologists have developed aggressive treatment protocols, combining surgery, craniospinal radiation, and high-dose chemotherapy, that often cause disabling neurotoxic effects in long-term survivors. Insights into the genetic control of medulloblastoma dissemination have come from transposon insertion mutagenesis studies.

Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma.

The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh + HGF-driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice.

Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth.

Medulloblastomas are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral neurologic injury. In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas.

Apoptosis suppression by somatic cell transfer of Bcl-2 promotes Sonic hedgehog-dependent medulloblastoma formation in mice.

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.

N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma.

Medulloblastoma is a malignant brain tumor that arises in the cerebellum in children, presumably from granule neuron precursors (GNP). Advances in patient treatment have been hindered by a paucity of animal models that accurately reflect the molecular pathogenesis of human tumors. Aberrant activation of the Sonic hedgehog (Shh) and insulin-like growth factor (IGF) pathways is associated with human medulloblastomas.

Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice.

Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in neural progenitor cells of the cerebellum induces MBs in mice. The incomplete penetrance of tumor formation in mice, coupled with the low frequency of mutations in Shh/Ptc pathway genes in human tumors, suggests that other signaling molecules cooperate with Shh to enhance MB formation.

c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice.

Medulloblastomas are malignant brain tumors that arise in the cerebella of children. The presumed cells-of-origin are undifferentiated precursors of granule neurons that occupy the external granule layer (EGL) of the developing cerebellum. The overexpression of proteins that normally stimulate proliferation of neural progenitor cells may initiate medulloblastoma formation.