Lysophosphatidic acid (LPA)-induced vascular endothelial growth factor (VEGF) by mesothelial cells and quantification of host-derived VEGF in malignant ascites.

摘要

BACKGROUND: Lysophosphatidic acid (LPA) is a lipid mediator with multiple biological activities that may affect the progression of various cancers. Malignant ascites contains high levels of LPA as well as vascular endothelial growth factor (VEGF). Although LPA receptors are widely expressed in normal as well as cancer cells, little is known about the effect of LPA on host cells. Therefore, we evaluated the effect of LPA specifically on peritoneal mesothelial cells (PMC), and assessed another aspect of LPA in tumor biology mediated through the host cells. MATERIALS AND METHODS: The effect of LPA on the production of VEGF was evaluated by ELISA and northern blotting. Next, we quantified human- and mouse-VEGF separately in ascitic fluid of nude mice inoculated intraperitoneally with a human gastric cancer, MKN45, and thus evaluated the ratio of host-derived VEGF in malignant ascites. RESULTS: Addition of 10 to 80 mum LPA enhanced VEGF production by PMC through gene activation. The effect was strongly inhibited by pre-treatment with PTX or Ki16425, indicating that the effect was mainly dependent on the LPA1 signal. Of the VEGF in ascitic fluid at 3 weeks after tumor inoculation, 12.8% was derived from mouse cells. At 6 weeks, however, the ratio of host-derived VEGF was reduced to 5.0%, suggesting that the ratio of host-derived VEGF may be higher in the earlier phase. CONCLUSION: Because tumor growth is often associated with an increase of LPA concentration in ascites, stimulation of VEGF production in PMC might have an important role in the growth of cancer cells disseminated in the peritoneal cavity.