Figure 6. A model of PGE₂ and LTB⁴ coordinately regulating angiogenesis in the tumour microenvironment.

Pro-inflammatory prostaglandin E₂ (PGE₂) and/or B₄ LTB₄ promote angiogenesis on at least two levels. First, PGE₂ and/or LTB₄ can directly act on epithelial, endothelial and/or immune cells to induce angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2) and the chemokines CXCL1 and CCL2. In transformed epithelial cells, PGE₂ induces VEGF and CXCL1 secretion through an EP2 or EP4–epidermal growth factor (EGFR)–Erk cascade. In endothelial cells, PGE₂ induces VEGF and FGF2 secretion through a MAPK pathway and LTB₄ also stimulates VEGF expression. Moreover, PGE₂ not only binds to endothelial cells to stimulate cell migration through an αVβ3 integrin–CDC42 and Rac pathway, but also mediates VEGF-and FGF2-induced CXCR4-dependent neovessel assembly in vivo. In immune cells, PGE₂ promotes mast cells to release VEGF and CCL2, and LTB₄ stimulates VEGF expression. Secretion of VEGF and FGF2 from tumour epithelial, endothelial and immune cells promotes endothelial cell proliferation and survival, and the chemokine CXCL1 released from tumour epithelial cells stimulates endothelial cell migration and tube formation in vitro and angiogenesis in vivo. CCL2 can attract endothelial cells to the tumour microenvironment. Interestingly, VEGF and FGF2 induce COX2 and subsequently PGE₂ in endothelial cells, and CCL2 also induces COX2 and PGE₂ in macrophages. Therefore, the effects of PGE₂ on the regulation of VEGF, FGF2 and CCL2 are probably amplified through this positive feedback loop.