title: Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma.
abstract: Invasion and dissemination of medulloblastoma within the central nervous system is the principal factor predicting medulloblastoma treatment failure and death. Netrin-1 is an axon guidance factor implicated in tumor and vascular biology, including in invasive behaviors. We found that exogenous netrin-1 stimulated invasion of human medulloblastoma cells and endothelial cells in contrast to VEGF-A, which promoted invasion of endothelial cells but not medulloblastoma cells. Furthermore, medulloblastoma cells expressed endogenous netrin-1 along with its receptors, neogenin and UNC5B. Blockades in endogenous netrin-1, neogenin, or UNC5B reduced medulloblastoma invasiveness. Neogenin blockade inhibited netrin-1-induced endothelial cells tube formation and recruitment of endothelial cells into Matrigel plugs, two hallmarks of angiogenesis. In patients with pediatric medulloblastoma, netrin-1 mRNA levels were increased 1.7-fold in medulloblastoma tumor specimens compared with control specimens from the same patient. Immunohistochemical analyses showed that netrin-1 was elevated in medulloblastoma tumors versus cerebellum controls. Notably, urinary levels of netrin-1 were 9-fold higher in patients with medulloblastoma compared with control individuals. Moreover, urinary netrin-1 levels were higher in patients with invasive medulloblastoma compared with patients with noninvasive medulloblastoma. Finally, we noted that urinary netrin-1 levels diminished after medulloblastoma resection in patients. Our results suggest netrin-1 is a candidate biomarker capable of detecting an invasive, disseminated phenotype in patients with medulloblastoma and predicting their disease status.
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Surgery.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Akino
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Neurosurgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, PR China.
authors.forename: Xuezhe
authors.initials: X
authors.lastname: Han
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Surgery.
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Surgery.
authors.forename: Brendan
authors.initials: B
authors.lastname: McNeish
authors.affiliation: Anesthesia, and.
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Surgery.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Surgery, Pathology, michael.klagsbrun@childrens.harvard.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.affiliation: Authors' Affiliations: Vascular Biology Program; Departments of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Edward
authors.initials: E
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D001921:Brain / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D000075386:Netrin Receptors; D000075388:Netrin-1; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000652:urine
chemical_list: D015415:Biomarkers; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C532445:UNC5B protein, human; D000075388:Netrin-1; D020928:Mitogen-Activated Protein Kinases