Research Papers:

Association of Notch-1, osteopontin and stem-like cells in ENU-glioma malignant process

Susana Bulnes _, Garazi Bermúdez and José Vicente Lafuente

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Oncotarget. 2018; 9:31330-31341. https://doi.org/10.18632/oncotarget.25808

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Susana Bulnes1, Garazi Bermúdez2 and José Vicente Lafuente1,3,4

1LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Spain

2Neurosurgery Service, Cruces University Hospital, Barakaldo, Spain

3Nanoneurosurgery Group, Institute of Health Research Biocruces, Barakaldo, Spain

4Faculty of Health Science, Universidad Autónoma de Chile, Santiago de Chile, Chile

Correspondence to:

Susana Bulnes, email: [email protected]

Keywords: angiogenesis; glioma stem-like cells; N-ethyl-N-nitrosourea; Notch-1; osteopontin

Received: October 07, 2017     Accepted: July 12, 2018     Published: July 31, 2018


Notch-1 and osteopontin (OPN) mediate angiogenesis and glioma stem-like cell (GSLC) maintenance. However, the relationship between these molecules and GSLCs during the development of glioma is unknown. We investigate the expression of Notch-1, OPN and vascular endothelial growth factor (VEGF) associated to the stemness markers nestin and CD133 in three stages of murine gliomas induced by N-ethyl-N-nitrosourea (ENU).

Notch-1 and OPN overexpress in the intermediate stage (II), which corresponds to the “angiogenesis switch”. Nestin+ cells appear in all stages of ENU-glioma but CD133 only from stage II on. In stage III, neoplastic cells expressing nestin, CD133 and nestin/CD133 reside in spheroid-like aggregates (SAs) and in the neoangiogenic border. These aggregates show Notch-1 and VEGF+ surrounding cells and a significant size and density increase with respect to stage I (3.3 ± 1.5 to 22.4 ± 6.3 μm2, nº = 0.3 ± 0.1 to 4.2 ± 0.9, from stage I to stage III, respectively).

OPN expression increases in correlation to the glioma malignancy from 4.5 ± 1.8% (I) to 12.3 ± 1.2% of OPN+ cells (III). It predominates in astrocyte-like cells of the neoangiogenic border, displaying co-location with VEGF and CD133. The OPN immunopositivity distribution correlates with the CD133 distribution.

In conclusion, OPN co-expressing with CD133 contributes to the identification of GSLCs in the neoangiogenic border, while Notch-1 is present around SAs in advanced stages. The ENU-glioma, mainly in stage II, is a useful tool for assessing new antitumour therapies against these molecules.

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