FIGURE 7.

Tumor growth and VEGF production are attenuated in Ptger4^−/− mice. A, Ptger4^−/− or wild-type mice were injected with B16 cells into the dorsal subcutaneous tissue. Representative pictures of the subcutaneous tumors on day 9 after injection are shown in the top panel. The arrowheads indicate a subcutaneous solid tumor. The tumor volume was determined, and the data are shown in the bottom panel as mean ± S.E. of the wild-type (n = 9) or Ptger4^−/− (n = 8) mice. *, p < 0.05. N.D., not detected. B, dermal fibroblasts from Ptger4^−/− or wild-type mice were cultured in the presence or absence of PGE₂ (10 μm). After 48 h, the concentration of VEGF-A in the conditioned media was determined by ELISA. Data are mean ± S.E. of three wells. *, p < 0.001. C, schematic of the PGE₂/EP4-depedendent mechanism involved in angiogenesis, tumorigenesis, and osteoclastogenesis. In soft tissues, stromal fibroblasts interact with cancer cells and produce PGE₂ via mPGES-1, and then PGE₂ induces VEGF-A and bFGF production as a result of autocrine/paracrine signaling via EP4. In hard-tissue bone, the interaction with cancer cells elicits mPGES-1-dependent PGE₂ production by osteoblasts, and then PGE₂ induces the expression of RANKL on the surface of osteoblasts to induce osteoclast formation, which is critical for the osteolysis associated with the bone metastasis of cancer. AA, arachidonic acid.