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Hepatocyte Growth Factor and Sonic Hedgehog Expression in Cerebellar Neural Progenitor Cells Costimulate Medulloblastoma Initiation and Growth

¹ Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah; Departments of ² Neurology and ³ Pathology and ⁴ Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, Maryland; and ⁵ Galaxy Biotech, LLC, Mountain View, California

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.

Key Words: medulloblastoma • hepatocyte growth factor • scatter factor • mouse model • sonic hedgehog

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. Hepatocyte growth factor (HGF) and its cell surface receptor c-Met are highly expressed in human medulloblastomas, and elevated levels of c-Met and HGF mRNA predict an unfavorable prognosis for patients. HGF is neuroprotective for cerebellar granule cells and promotes growth of human medulloblastoma cells in culture and in murine xenografts. We modeled the ability of HGF to induce medulloblastomas in mice using a version of the RCAS/tv-a system that allows gene transfer to cerebellar neural progenitors during their postnatal expansion phase when these cells are highly susceptible to transformation. Here, we report a high frequency of medulloblastoma formation in mice after postnatal expression of HGF in cooperation with Shh. Some tumors showed neurocytic differentiation similar to that in human nodular medulloblastomas with activated Shh signaling. Systemic administration of a monoclonal antibody against HGF prolonged survival of mice bearing Shh + HGF–induced medulloblastomas by stimulating apoptosis. These findings indicate a role for HGF in medulloblastoma initiation and growth and show efficacy of HGF-targeted therapy in a mouse model of endogenously arising tumors. [Cancer Res 2008;68(19):7838–45]