Sphingosine-1-phosphate (S1P) is a plasma
lipid mediator with multiple roles in mammalian development, physiology and pathophysiology. It is constitutively produced mostly by erythrocytes by the action of
sphingosine kinase 1 (SphK1), resulting in high (∼0.5 micromolar) steady-state plasma S1P content and steep S1P concentration gradient imposed between plasma/lymph/tissue interstitial fluid. S1P is also locally produced by activated platelets and
tumor cells, in the latter case SphK1 is a downstream target of activated Ras mutant and
hypoxia, and is frequently upregulated especially in advanced stages of
tumors. Most if not all of the S1P actions in vertebrates are mediated through evolutionarily conserved
G protein-coupled
S1P receptor family. Ubiquitously expressed mammalian subtypes S1PR1, S1PR2 and S1PR3 mediate pleiotropic actions of S1P in diverse cell types, through coupling to distinctive repertoire of
heterotrimeric G proteins. S1PR1 and S1PR3 mediate directed cell migration toward S1P through coupling to G(i) and activating Rac, a Rho family
small G protein essential for cell migration. Indeed, S1PR1 expressed in lymphocytes directs their egress from lymph nodes into lymph and recirculation, serving as the target for downregulation by the
immunosuppressant FTY720 (
fingolimod). S1PR1 in endothelial cells plays an essential role in vascular maturation in embryonic stage, and mediates angiogenic and vascular protective roles of S1P which include eNOS activation and maintenance of barrier integrity. It is likely that S1PR1 and SphK1 expressed in host endothelial cells and
tumor cells act in concert in a paracrine loop to contribute to
tumor angiogenesis,
tumor invasion and progression. In sharp contrast, S1PR2 mediates S1P inhibition of Rac at the site downstream of G(12/13)-mediated Rho activation, thus identified as the first
G protein-coupled receptor that negatively regulates Rac and cell migration. S1PR2 could also mediate inhibition of Akt and cell proliferation/survival signaling via Rho-ROCK-PTEN pathway. S1PR2 expressed in
tumor cells mediates inhibition of cell migration and invasion in vitro and
metastasis in vivo. Moreover, S1PR2 expressed in host endothelial cells and
tumor-infiltrating myeloid cells in concert mediates potent inhibition of
tumor angiogenesis and
tumor growth in vivo, with inhibition of
VEGF expression and MMP9 activity. These recent findings provide further basis for
S1P receptor subtype-specific, novel therapeutic tactics for individualized treatment of patients with
cancer.