S1P Provokes Tumor Lymphangiogenesis via Macrophage-Derived Mediators Such as IL-1β or Lipocalin-2

Figure 2

Macrophage-derived lipocalin-2 and lymphangiogenesis. Viable and apoptotic tumor cells produce S1P to stimulate the S1PR1 on macrophages. Downstream of S1PR1: there is activation of STAT3 to induce LCN2 mRNA and protein expression. LCN2 promotes EMT and drives lymphangiogenesis by activating its specific receptor, LCN2R, on lymph endothelial cells. The LCN2R activates PI3K, which adds to the production of VEGF-C, provoking a self-amplifying loop via VEGFR3. These signals promote metastasis and tumor progression. Macrophages add to immune suppression by distinct mechanisms. For details, see the text.