A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

Abstract

Background:The sphingolipid metabolite sphingosine 1-phosphate (S1P) is a potent angiogenic factor. Results: S1P content is 9-fold higher in glioblastomas compared with normal brain, and S1P production is necessary for glioblastoma cells to trigger endothelial cell angiogenesis. Conclusion: Excessive S1P synthesis is a major contributor to glioblastoma angiogenesis. Significance: Inhibiting S1P synthesis may be a valuable antiangiogenic approach in glioblastoma.

The Role and Function of Sphingolipids in Glioblastoma Multiforme

“…In GBM cells S1P is able to initiate endothelial cell sprouting, which is representative of a multistep angiogenic process, and SphK1 plays an essential role in regulating paracrine angiogenesis, favoring the early sprouting response of endothelial cells by increasing both number and length of sprouts [ 18 ]. Notably this effect was induced by S1P released by GBM cells, and was not affected by VEGF [ 18 ], suggesting that S1P signaling is required even when potent angiogenic factors such as VEGF are present.…”

“…Indeed, ceramide levels are lower in human GBM tissue compared to normal surrounding brain tissue, and the decrease in ceramide in GBMs is directly related to histological grade and patient survival [ 17 ]. The decrease in total ceramides with increasing glioma grade was found parallel to an increase in S1P content, ceramide and S1P levels being on average twofold lower and ninefold higher, respectively in GBM tissues than in normal gray matter [ 18 ].…”

“…Differences with regard to the fatty acyl chain distributions of ceramides were detected among several glioma cell lines using liquid chromatography tandem mass spectrometry [ 22 ], suggesting heterogeneity in ceramide subfamilies in different GBMs. Of interest, a specifi c reduction in C 18 ceramide was recently shown in human gliomas as a function of their malignancy grade, and, notwithstanding their great heterogeneity, low levels of C 18 ceramide were common to different GBMs [ 18 ]. In head and neck squamous cell carcinoma, C 18 ceramide was found to be the only form of ceramide whose levels were decreased, and its levels inversely correlated with metastasis [ 23 ], suggesting that reduced C 18 ceramide levels may also contribute to GBM malignancy.…”

“…1 ). Indeed, acid ceramidase (A-ceramidase), which converts ceramide to sphingosine, was found to be signifi cantly up-regulated in GBM specimens [ 18 ]. Moreover, Jensen et al [ 27 ] showed that B-cell lymphoma 2-like 13 (Bcl2L13), an atypical member of the Bcl-2 family overexpressed in GBM, acts as ceramide synthase (CerS) inhibitor.…”

“…With regard to the increased level of S1P, a likely explanation should reside in the high expression of both SphK1 and SphK2 in GBMs [ 28 -30 ]. In addition to SphK up-regulation, it was found that the S1P phosphatase 2 (SPP2), a S1P specifi c phosphohydrolase localized to the endoplasmic reticulum (ER) [ 31 ], is signifi cantly downregulated in GBM as compared to normal gray matter samples [ 18 ]. Of note, SPP1 expression has been shown to increase ceramide levels at the ER by the recycling of its product sphingosine [ 32 ], suggesting that the loss of SPP2 expression in GBM not only increases S1P but also drives ceramide levels down.…”