Plausible mechanism for S1P-mediated lymphangiogenesis. Extracellular S1P, which is derived from tumor or inflammatory cells, binds to its receptor S1P1 and stimulates the activation of coupled G_i proteins. Dissociation of active heterotrimeric G_i proteins from activated S1P1 stimulates PLC, which causes the release of intracellular Ca²⁺, resulting in the stimulation of HLEC migration and differentiation. Extracellular S1P activates lymphatic endothelial cells to induce lymphangiogenesis, as well as vascular endothelial cells to induce angiogenesis, for tumor metastasis or an immune response.