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Sphingosine-1-phosphate Signalling drives an Angiogenic Transcriptional Programme in Diffuse Large B Cell Lymphoma
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887546/ https://www.ncbi.nlm.nih.gov/pubmed/31097785 http://dx.doi.org/10.1038/s41375-019-0478-9 |
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author | Lupino, Lauren Perry, Tracey Margielewska, Sandra Hollows, Robert Ibrahim, Maha Care, Matthew Allegood, Jeremy Tooze, Reuben Sabbadini, Roger Reynolds, Gary Bicknell, Roy Rudzki, Zbigniew Hock, Ye Lin Zanetto, Ulises Wei, Wenbin Simmons, William Spiegel, Sarah Woodman, Ciaran BJ Rowe, Martin Vrzalikova, Katerina Murray, Paul G |
author_facet | Lupino, Lauren Perry, Tracey Margielewska, Sandra Hollows, Robert Ibrahim, Maha Care, Matthew Allegood, Jeremy Tooze, Reuben Sabbadini, Roger Reynolds, Gary Bicknell, Roy Rudzki, Zbigniew Hock, Ye Lin Zanetto, Ulises Wei, Wenbin Simmons, William Spiegel, Sarah Woodman, Ciaran BJ Rowe, Martin Vrzalikova, Katerina Murray, Paul G |
author_sort | Lupino, Lauren |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6887546 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-68875462019-12-03 Sphingosine-1-phosphate Signalling drives an Angiogenic Transcriptional Programme in Diffuse Large B Cell Lymphoma Lupino, Lauren Perry, Tracey Margielewska, Sandra Hollows, Robert Ibrahim, Maha Care, Matthew Allegood, Jeremy Tooze, Reuben Sabbadini, Roger Reynolds, Gary Bicknell, Roy Rudzki, Zbigniew Hock, Ye Lin Zanetto, Ulises Wei, Wenbin Simmons, William Spiegel, Sarah Woodman, Ciaran BJ Rowe, Martin Vrzalikova, Katerina Murray, Paul G Leukemia Article 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. 2019-05-16 2019-12 /pmc/articles/PMC6887546/ /pubmed/31097785 http://dx.doi.org/10.1038/s41375-019-0478-9 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Lupino, Lauren Perry, Tracey Margielewska, Sandra Hollows, Robert Ibrahim, Maha Care, Matthew Allegood, Jeremy Tooze, Reuben Sabbadini, Roger Reynolds, Gary Bicknell, Roy Rudzki, Zbigniew Hock, Ye Lin Zanetto, Ulises Wei, Wenbin Simmons, William Spiegel, Sarah Woodman, Ciaran BJ Rowe, Martin Vrzalikova, Katerina Murray, Paul G Sphingosine-1-phosphate Signalling drives an Angiogenic Transcriptional Programme in Diffuse Large B Cell Lymphoma |
title | Sphingosine-1-phosphate Signalling drives an Angiogenic
Transcriptional Programme in Diffuse Large B Cell Lymphoma |
title_full | Sphingosine-1-phosphate Signalling drives an Angiogenic
Transcriptional Programme in Diffuse Large B Cell Lymphoma |
title_fullStr | Sphingosine-1-phosphate Signalling drives an Angiogenic
Transcriptional Programme in Diffuse Large B Cell Lymphoma |
title_full_unstemmed | Sphingosine-1-phosphate Signalling drives an Angiogenic
Transcriptional Programme in Diffuse Large B Cell Lymphoma |
title_short | Sphingosine-1-phosphate Signalling drives an Angiogenic
Transcriptional Programme in Diffuse Large B Cell Lymphoma |
title_sort | sphingosine-1-phosphate signalling drives an angiogenic
transcriptional programme in diffuse large b cell lymphoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887546/ https://www.ncbi.nlm.nih.gov/pubmed/31097785 http://dx.doi.org/10.1038/s41375-019-0478-9 |
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