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Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma

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Abstract

The Hedgehog (Hh) signaling pathway has been implicated in the most common childhood brain tumor, medulloblastoma (MB). Given the toxicity of post-surgical treatments for MB, continued need exists for new, targeted therapies. Based upon our finding that Neuropilin (Nrp) transmembrane proteins are required for Hh signal transduction, we investigated the role of Nrp in MB cells. Cultured cells derived from a mouse Ptch +/−;LacZ MB (Med1-MB), effectively modeled the Hh pathway-related subcategory of human MBs in vitro. Med1-MB cells maintained constitutively active Hh target gene transcription, and consistently formed tumors within one month after injection into mouse cerebella. The proliferation rate of Med1-MBs in culture was dependent upon Nrp2, while reducing Nrp1 function had little effect. Knockdown of Nrp2 prior to cell implantation significantly increased mouse survival, compared to transfection with a non-targeting siRNA. Knocking down Nrp2 specifically in MB cells avoided any direct effect on tumor vascularization. Nrp2 should be further investigated as a potential target for adjuvant therapy in patients with MB.

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Acknowledgments

MHG is supported by a post-doctoral fellowship from the California Institute of Regenerative Medicine (TG2-01159). This work was supported in part by NIH RO1 GM095948, and the Center for Children’s Brain Tumors (CCBT) of the Stanford School of Medicine and Lucile Packard Children’s Hospital. MPS is an Investigator of the Howard Hughes Medical Institute. We appreciate the thoughtful editing of the manuscript by E. Epstein.

Conflict of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

    Melanie G. Hayden Gephart

  2. Department of Developmental Biology, Stanford University School of Medicine, Clark Center, 318 Campus Drive, Stanford, CA, USA

    Melanie G. Hayden Gephart, YouRong Sophie Su, Nicholas Conley, Helen Rayburn, Ljiljana Milenkovic & Matthew P. Scott

  3. Department of Bioengineering, Stanford University School of Medicine, Clark Center, 318 Campus Drive, Stanford, CA, USA

    Melanie G. Hayden Gephart, YouRong Sophie Su, Nicholas Conley, Helen Rayburn, Ljiljana Milenkovic & Matthew P. Scott

  4. Department of Genetics, Stanford University School of Medicine, Clark Center, 318 Campus Drive, Stanford, CA, USA

    Melanie G. Hayden Gephart, YouRong Sophie Su, Nicholas Conley, Helen Rayburn, Ljiljana Milenkovic & Matthew P. Scott

  5. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA

    Samuel Bandara, Feng-Chiao Tsai & Tobias Meyer

  6. Center for Children’s Brain Tumors, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA, USA

    Melanie G. Hayden Gephart, Nicholas Conley, Helen Rayburn & Matthew P. Scott

  7. Department of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    Jennifer Hong

  8. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Ljiljana Milenkovic & Matthew P. Scott

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  1. Melanie G. Hayden Gephart
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  2. YouRong Sophie Su
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Correspondence to Melanie G. Hayden Gephart.

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Hayden Gephart, M.G., Su, Y.S., Bandara, S. et al. Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma. J Neurooncol 115, 161–168 (2013). https://doi.org/10.1007/s11060-013-1216-1

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  • DOI: https://doi.org/10.1007/s11060-013-1216-1

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