title: Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases.
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.
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zinke
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Tichy
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zachskorn
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Senckenberg Institute of Pathology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Hans M
authors.initials: HM
authors.lastname: Kvasnicka
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.affiliation: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Delloye-Bourgeois
authors.affiliation: Institute of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.affiliation: Department of Neurosurgery, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Senft
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Schulte
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019394:Ki-67 Antigen; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1