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.

Department of Biochemistry and Molecular Biology and Massey Cancer Virginia Commonwealth University School of Medicine Richmond VA USA

Department of Biology San Diego State University San Diego CA USA

Department of Clinical and Molecular Pathology Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Histopathology City Hospital Birmingham UK

Department of Histopathology Heartlands Hospital Birmingham UK

Department of Histopathology Walsall Manor Hospital Walsall UK

Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK

Institute of Immunology and Immunotherapy University of Birmingham Birmingham UK

Institutes of Cardiovascular Sciences and Biomedical Research University of Birmingham Birmingham UK

Section of Experimental Haematology Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

Sheffield Institute of Translational Neuroscience University of Sheffield Sheffield UK

South Egypt Cancer Institute Assiut University Assiut Egypt

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The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma