Motility of glioblastoma cells is driven by netrin-1 induced gain of stemness

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Ylivinkka , I , Sihto , H , Tynninen , O , Hu , Y , Laakso , A , Kivisaari , R , Laakkonen , P , Keski-Oja , J & Hyytiäinen , M 2017 , ' Motility of glioblastoma cells is driven by netrin-1 induced gain of stemness ' , Journal of Experimental and Clinical Cancer Research (Online) , vol. 36 , 9 . https://doi.org/10.1186/s13046-016-0482-0

Title: Motility of glioblastoma cells is driven by netrin-1 induced gain of stemness
Author: Ylivinkka, Irene; Sihto, Harri; Tynninen, Olli; Hu, Yizhou; Laakso, Aki; Kivisaari, Riku; Laakkonen, Pirjo; Keski-Oja, Jorma; Hyytiäinen, Marko
Contributor organization: Research Programs Unit
Translational Cancer Biology (TCB) Research Programme
Clinicum
HUS Helsinki and Uusimaa Hospital District
Heikki Joensuu / Principal Investigator
HUSLAB
Department of Pathology
Medicum
Department of Neurosciences
HUS Neurocenter
Neurokirurgian yksikkö
Pirjo Maarit Laakkonen / Principal Investigator
Jorma Keski-Oja Research group
HUS Comprehensive Cancer Center
Date: 2017-01-09
Language: eng
Number of pages: 18
Belongs to series: Journal of Experimental and Clinical Cancer Research (Online)
ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-016-0482-0
URI: http://hdl.handle.net/10138/175531
Abstract: Background: Glioblastoma is an untreatable brain cancer. The tumors contain a population of stem-like cells which are highly invasive and resistant to therapies. These cells are the main reason for the lethality of glioblastoma. Extracellular guidance molecule netrin-1 promotes the invasiveness and survival of various cancer cell types. We have previously found that netrin-1 activates Notch signaling, and Notch signaling associates with cell stemness. Therefore, we have here investigated the effects of netrin-1 on glioblastoma pathogenesis and glioblastoma cell stemness. Methods: Glioma tissue microarrays were stained with immunohistochemistry and the results were used to evaluate the association between netrin-1 and survival of glioma patients. The localization of netrin-1 was analyzed utilizing fresh frozen glioblastoma tissues. The glioma cell invasion was investigated using ex vivo glioma tissue cultures and newly established primary cell cultures in 3D in vitro invasion assays. Intracranial mouse xenograft models were utilized to investigate the effects of netrin-1 on glioblastoma growth and invasion in vivo. Results: Netrin-1 expression associated with poor patient prognosis in grade II-III gliomas. In addition, its expression correlated with the stem-like cell marker nestin. Netrin-1 overexpression in cultured cells led to increased formation of stem-like cell spheroids. In glioblastoma tumor biopsies netrin-1 localized to hypoxic tumor areas known to be rich in the stem-like cells. In xenograft mouse models netrin-1 expression altered the phenotype of non-invasive glioblastoma cells into diffusively invading and increased the expression of glioma stem-like cell markers. Furthermore, a distinct invasion pattern where netrin-1 positive cells were following the invasive stem-like cells was detected both in mouse models and ex vivo human glioblastoma tissue cultures. Inhibition of netrin-1 signaling targeted especially the stem-like cells and inhibited their infiltrative growth. Conclusions: Our findings describe netrin-1 as an important regulator of glioblastoma cell stemness and motility. Netrin-1 activates Notch signaling in glioblastoma cells resulting in subsequent gain of stemness and enhanced invasiveness of these cells. Moreover, inhibition of netrin-1 signaling may offer a way to target stem-like cells.
Subject: Netrin
Glioma
Glioblastoma
Glioblastoma stem-like cell
Cancer stem cell
Notch signalling
Cell invasion
HUMAN GLIOMA
NERVOUS-SYSTEM
EXPRESSION
CANCER
INVASIVENESS
MAINTENANCE
ACTIVATION
SURVIVAL
GROWTH
NESTIN
3122 Cancers
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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