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 in blood and lymphatic vessels can enhance or limit tumor progression. S1PR₁ is a GPCR for circulating lysophospholipid S1P that is highly expressed in blood and lymphatic vessels. Using the S1PR₁-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, mid-range 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.