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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Biomarkers / metabolism
  • Biomarkers / urine
  • Brain / pathology
  • Cell Line, Tumor
  • Child
  • Endothelial Cells / metabolism
  • Enzyme Activation / drug effects
  • Gene Expression
  • Humans
  • Magnetic Resonance Imaging
  • Medulloblastoma / diagnosis
  • Medulloblastoma / genetics*
  • Medulloblastoma / metabolism
  • Medulloblastoma / pathology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology
  • Nerve Growth Factors / urine
  • Netrin Receptors
  • Netrin-1
  • Prognosis
  • Receptors, Cell Surface / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / pharmacology
  • Tumor Suppressor Proteins / urine


  • Biomarkers
  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • UNC5B protein, human
  • Netrin-1
  • Mitogen-Activated Protein Kinases