Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases

PLoS One. 2014 Mar 19;9(3):e92311. doi: 10.1371/journal.pone.0092311. eCollection 2014.

Abstract

The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / secondary*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Ki-67 Antigen / metabolism
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Netrin-1
  • Prognosis
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Ki-67 Antigen
  • NTN1 protein, human
  • Nerve Growth Factors
  • Tumor Suppressor Proteins
  • Netrin-1

Grant support

The present study was financially supported by the Goethe University Frankfurt am Main, Germany (UCT-Trx program 2012). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.