(The) role of macrophage on lymphangiogenesis in advanced ovarian cancer

Abstract

Ascites is a build-up of fluid in the abdominal cavity. Under normal conditions, secreted small amount of ascites fluid is absorbed by lymphatic vessels. Lymphatic vessels play an essential role in the maintenance of tissue fluid homeostasis through regulated uptake of protein-rich interstitial fluid into draining lymphatic vessels. Patients with advanced Ovarian cancer most often present symptoms related to ascites including abdominal distension or bloating. Several studies have shown that vascular endothelial growth factor-A (VEGF-A) is the primary molecule responsible for producing ascites in OVCA by inducing vascular permeability very strongly in peritoneal microvessels. However, the underlying mechanism that creates an imbalance between peritoneal vascular leakage and lymphatic drainage is unknown. Here we identified and characterized peritoneal lymphatic vessels in OVCA mice, a model generated by implantation of human OVCA cells into athymic nude mice. The OVCA mice displayed substantial lymphangiogenesis and lymphatic remodeling, massive infiltration of CD11b+/LYVE-1+ macrophages and disseminated carcinomatosis in the mesentery and diaphragm, and progressive ascites formation. Functional assays indicated that the abnormally abundant lymphatic vessels in the diaphragm were not conductive in peritoneal fluid drainage. Moreover, lipid absorbed from the gut leaked out from the aberrant mesenteric lymphatic vessels. VEGF-C, VEGF-D, and VEGF-A from CD11b+ macrophages were directly involved in the OVCA-induced lymphangiogenesis. Accordingly, the combined blockade of VEGF-C/D and VEGF-A signaling with soluble VEGF receptor-3 and VEGF-Trap, respectively, markedly inhibited chylous ascitesformation. These findings provide additional therapeutic targets to ameliorate chylous ascites formation in patients with advanced OVCA.