Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

• MeSH
• Lymphoma, Large B-Cell, Diffuse genetics   metabolism   pathology   MeSH
• Endothelial Cells metabolism   MeSH
• Immunohistochemistry MeSH
• Humans MeSH
• Lysophospholipids genetics   metabolism   MeSH
• RNA, Messenger genetics   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neovascularization, Pathologic genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Sphingosine analogs & derivatives   genetics   metabolism   MeSH
• Signal Transduction * MeSH
• Transcriptome * MeSH
• Computational Biology methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Lysophospholipids MeSH
• RNA, Messenger MeSH
• Sphingosine MeSH
• sphingosine 1-phosphate MeSH Browser