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

Patrick N. Harter, Jenny Zinke, Alexander Scholz, Julia Tichy, Cornelia Zachskorn, Hans M. Kvasnicka, Benjamin Goeppert, Céline Delloye-Bourgeois, Elke Hattingen, Christian Senft, Joachim P. Steinbach, Karl H. Plate, Patrick Mehlen, Dorothea Schulte, Michel Mittelbronn

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29 Citations (Scopus)


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.

Original languageEnglish
Article numbere92311
JournalPLoS ONE
Issue number3
Publication statusPublished - 19 Mar 2014
Externally publishedYes


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