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Cancer Res. 2014 Jul 15;74(14):3716-26. doi: 10.1158/0008-5472.CAN-13-3116. Epub 2014 May 8.

Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma.

Author information

1
Authors' Affiliations: Vascular Biology Program; Departments of Surgery.
2
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.
3
Anesthesia, and.
4
Authors' Affiliations: Vascular Biology Program; Departments of Surgery, Pathology, michael.klagsbrun@childrens.harvard.edu.
5
Authors' Affiliations: Vascular Biology Program; Departments of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; and.

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.

PMID:
24812271
PMCID:
PMC4123751
DOI:
10.1158/0008-5472.CAN-13-3116
[Indexed for MEDLINE]
Free PMC Article

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