Ovarian carcinoma cells and IL-1β-activated human peritoneal mesothelial cells are possible sources of vascular endothelial growth factor in inflammatory and malignant peritoneal effusions

Abstract

Objective Inflammatory or malignant peritoneal diseases are associated with high levels of ascitic vascular endothelial growth factor (VEGF). We compared the VEGF secretion by human peritoneal mesothelial cells (HPMC) and ovarian carcinoma (OVCA) cells and its regulation by pro-inflammatory cytokines. Materials and methods VEGF secretion in cultured HPMC, established human OVCA cell lines, and inflammatory or OVCA-associated ascites was determined by enzyme linked immunosorbent assay. Results HPMC constitutively produced VEGF at median levels of 43 ± 7 pg/10 5 cells. Treatment of HPMC with 1 ng/ml IL-1β (567 ± 213 pg/10 5 cells) or TNF-α (89 ± 1 pg/10 5 cells) resulted in a 13-fold ( P < 0.01) or 2-fold ( P < 0.05) elevation of the VEGF secretion. In OVCA, the constitutive VEGF expression was 8-fold higher than VEGF levels in HPMC (364 ± 185 pg/10 5 cells; P < 0.001). VEGF secretion in OVCA cells was also increased by IL-1β (514 ± 105 pg/10 5 cells; P < 0.01) or TNF-α (458 ± 168 pg/10 5 cells; P < 0.01) reaching similar levels as in IL-1β-activated HPMC. Median VEGF levels in malignant ascites (2761 ± 1549 pg/ml) were 11-fold higher compared with levels in inflammatory fluids (244 ± 170 pg/ml; P < 0.01). VEGF levels in both inflammatory- and OVCA-associated fluids correlated with ascitic IL-1β levels ( P < 0.05). Conclusion We identified ovarian cancer cells and/or IL-1β-activated peritoneal mesothelial cells as important sources of ascitic VEGF. The present data indicate that IL-1β-triggered VEGF production by neoplastic and normal cells is a common pathomechanism for ascites formation in both inflammatory and malignant conditions.