TGF-beta blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models.

Abstract

Ovarian cancer patients with malignant ascites have poor prognosis. The accumulation of ascites is caused by an imbalance between fluid extravasation from the blood vessels and reabsorption by lymphatic vessels. Whereas, the role of TGF-β in tumor progression has been well studied, the role of TGF-β in lymphatic vessel function is far from understood. Here, we sought to dissect the role of TGF-β blockade in the formation of ascites. We used soluble TGF-β Receptor II (sTβRII) to block TGF-β signaling in two orthotopic human ovarian carcinoma models: SKOV3ip1 and Hey-A8. We measured tumor proliferation, apoptosis, lymphangiogenesis, and angiogenesis by immunohistochemical staining, and examined diaphragm lymphatic vessel network by intraperitoneal injection of a fluorescent dye. Diaphragm lymphatic vessel function was assessed by tracking fluorescent beads in the diaphragm and measuring their drainage rate. TGF-β blockade impaired tumor growth in both models, accompanied by a decreased tumor cell proliferation and angiogenesis. More strikingly, TGF-β blockade almost completely abolished ascites formation. TGF-β blockade significantly inhibited the expression of VEGF, which is the major contributor to ascites formation. At the same time, TGF-β blockade prevent 'abnormalization' of diaphragm lymphatic vessels and improved ascites drainage. TGF-β blockade decreased ascites by both inhibiting ascites formation and improving ascites drainage. Based on our finding, it is reasonable to consider the use of TGF-β blockade as a palliative treatment for symptomatic ascites.