Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth

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 (S1PR(1)) is a GPCR for circulating lysophospholipid S1P that is highly expressed in blood and lymphatic vessels. Using the S1PR(1)-enhanced green fluorescent protein (eGFP) mouse model in combination with intravital imaging and pharmacologic modulation of S1PR(1) signaling, we show that boundary conditions of high and low S1PR(1) signaling retard tumor progression by enhancing or destabilizing neovasculature integrity, respectively. In contrast, midrange S1PR(1) signaling, achieved by receptor antagonist titration, promotes abundant growth of small, organized vessels and thereby enhances tumor progression. Furthermore, in vivo S1PR(1) antagonism supports lung colonization by circulating tumor cells. Regulation of endothelial S1PR(1) dynamically controls vascular integrity and maturation and thus modulates angiogenesis, tumor growth, and hematogenous metastasis.