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Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma

L. Lupino, T. Perry, S. Margielewska, R. Hollows, M. Ibrahim, M. Care, J. Allegood, R. Tooze, R. Sabbadini, G. Reynolds, R. Bicknell, Z. Rudzki, Y. Lin Hock, U. Zanetto, W. Wei, W. Simmons, S. Spiegel, CBJ. Woodman, M. Rowe, K. Vrzalikova, PG. Murray,

. 2019 ; 33 (12) : 2884-2897. [pub] 20190516

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20023425

Grantová podpora
10066 Cancer Research UK - United Kingdom
R01 GM043880 NIGMS NIH HHS - United States
C7845/A17723 Cancer Research UK (CRUK) - International

E-zdroje Online Plný text

NLK ProQuest Central od 2000-01-01 do Před 1 rokem
Open Access Digital Library od 1997-01-01
Nursing & Allied Health Database (ProQuest) od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy

PubMed 31097785
DOI 10.1038/s41375-019-0478-9
Knihovny.cz E-zdroje

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.

Citace poskytuje Crossref.org

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