title: Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma.
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.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA, mghayden@gmail.com.
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Hayden Gephart
authors.forename: YouRong Sophie
authors.initials: YS
authors.lastname: Su
authors.forename: Samuel
authors.initials: S
authors.lastname: Bandara
authors.forename: Feng-Chiao
authors.initials: FC
authors.lastname: Tsai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hong
authors.forename: Nicholas
authors.initials: N
authors.lastname: Conley
authors.forename: Helen
authors.initials: H
authors.lastname: Rayburn
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Milenkovic
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Scott
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D039943:Neuropilin-2; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D039942:Neuropilin-1
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