The impact of tumor nitric oxide production on VEGFA expression and tumor growth in a zebrafish rat glioma xenograft model

Nadhir Yousfi, Benoist Pruvot, Tatiana Lopez, Lea Magadoux, Nathalie Franche, Laurent Pichon, Françoise Salvadori, Eric Solary, Carmen Garrido, Véronique Laurens, Johanna Chluba

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    Abstract

    To investigate the effect of nitric oxide on tumor development, we established a rat tumor xenograft model in zebrafish embryos. The injected tumor cells formed masses in which nitric oxide production could be detected by the use of the cell-permeant DAF-FM-DA (diaminofluorophore 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate) and DAR-4MAM (diaminorhodamine-4M). This method revealed that nitric oxide production could be colocalized with the tumor xenograft in 46% of the embryos. In 85% of these embryos, tumors were vascularized and blood vessels were observed on day 4 post injection. Furthermore, we demonstrated by qRT-PCR that the transplanted glioma cells highly expressed Nos2, Vegfa and Cyclin D1 mRNA. In the xenografted embryos we also found increased zebrafish vegfa expression. Glioma and zebrafish derived Vegfa and tumor Cyclin D1 expression could be down regulated by the nitric oxide scavenger 2-(4-Carboxyphenyl)-4,4,5,5-tetra-methylimidazoline- 1-oxyl-3-oxide or CPTIO.We conclude that even if there is a heterogeneous nitric oxide production by the xenografted glioma cells that impacts Vegfa and Cyclin D1 expression levels, our results suggest that reduction of nitric oxide levels by nitric oxide scavenging could be an efficient approach to treat glioma.

    Original languageEnglish
    Article numbere0120435
    JournalPLoS ONE
    Volume10
    Issue number3
    DOIs
    Publication statusPublished - 13 Mar 2015

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