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ANGIOGENESIS AND INVASION

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INTRODUCTION: Recently, anti-angiogenic therapies have moved into the forefront of GBM targeted therapies, especially following the success of anti-VEGF treatment in increasing progression-free survival and quality of life for patients.However, with the recurrence of GBMs, anti-VEGF treatment seems insufficient at blocking glioma induced angiogenesis single-handedly.Sphingosine-1-phosphate (S1P), a known pro-angiogenic lipid molecule formed by the enzyme sphingosine kinase 1 (Sphk1), has been shown to contribute to breast cancer induced angiogenesis.High SphK1 expression has been shown in two independent studies to predict an unfavorable prognosis in GBM.S1P data in GBM and its role in angiogenesis is limited, therefore requires further research.METHODS: We assessed the levels of SphK1 and S1P in normal grey matter (n ¼ 20), diffuse astrocytomas (n ¼ 26), anaplastic astrocytomas (n ¼ 10), and GBM (n ¼ 20) tissue samples using quantitative PCR and liquid chromatography-mass spectrometry (LC-MS), respectively.Cell based assays examining angiogenesis were performed, targeting SphK1 with siRNA and selective SphK1 inhibitors, including a stereoisomer control.An independent cohort of 50 GBM tissue samples, 35 matched GBM plasma samples, and 20 normal plasma samples were analyzed for S1P using LC-MS, and correlated with patient survival.RESULTS: S1P levels increased, alongside SphK1 expression, as glioma grade increased and compared to normal tissue.Knockdown of SphK1 with siRNA and inhibitor, but not stereoisomer control, affected U87MG induced angiogenesis for HMEC-1 cell lines significantly.S1P in GBM tissue was elevated in short term survivors, but not statistically significant.However, S1P in GBM plasma was elevated compared to normal plasma, and correlated with survival outcome.CONCLUSIONS: S1P is significantly elevated in GBM, a highly vascular tumor, and contributes to U87MG induced angiogenesis independent of VEGF in a cell based assay.The potential role of S1P as a marker for survival requires further validation.However, S1P shows exciting potential as an antiangiogenic target.

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DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.

Titre Crossref
ANGIOGENESIS AND INVASION
Date Crossref
01/11/2013
Éditeur
Oxford University Press (OUP)
Type
journal-article

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Les institutions déclarées

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Les sujets associés

Sphingolipid Metabolism and SignalingAngiogenesis and VEGF in CancerCaveolin-1 and cellular processes

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