title: Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth.
abstract: Understanding vascular growth and maturation in developing tumors has important implications for tumor progression, spread, and ultimately host survival. Modulating the signaling of endothelial G protein-coupled receptors (GPCRs) in blood and lymphatic vessels can enhance or limit tumor progression. Sphingosine 1-phosphate receptor 1 (S1PR1) is a GPCR for circulating lysophospholipid S1P that is highly expressed in blood and lymphatic vessels. Using the S1PR1- enhanced green fluorescent protein (eGFP) mouse model in combination with intravital imaging and pharmacologic modulation of S1PR1 signaling, we show that boundary conditions of high and low S1PR1 signaling retard tumor progression by enhancing or destabilizing neovasculature integrity, respectively. In contrast, midrange S1PR1 signaling, achieved by receptor antagonist titration, promotes abundant growth of small, organized vessels and thereby enhances tumor progression. Furthermore, in vivo S1PR1 antagonism supports lung colonization by circulating tumor cells. Regulation of endothelial S1PR1 dynamically controls vascular integrity and maturation and thus modulates angiogenesis, tumor growth, and hematogenous metastasis.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California; and.
authors.forename: Gor
authors.initials: G
authors.lastname: Sarkisyan
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California; and.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Gay
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California; and.
authors.forename: Nhan
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California; and.
authors.forename: Brunhilde H
authors.initials: BH
authors.lastname: Felding
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California; and Department of Immunology, The Scripps Research Institute, La Jolla, California hrosen@scripps.edu.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D063065:Organophosphonates / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D047368:Tumor Burden
chemical_list: C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; D000813:Anilides; D063065:Organophosphonates; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: PyMT; S1PR1; angiogenesis; breast cancer; metastasis; vasculature
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