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Profound but Dysfunctional Lymphangiogenesis via Vascular Endothelial Growth Factor Ligands from CD11b⁺ Macrophages in Advanced Ovarian Cancer

¹ National Research Laboratory of Vascular Biology and Biomedical Research Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; ² Laboratory of Liposome Research, Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; ³ Department of Pathology and Obstetrics and Gynecology, Chonbuk University Medical School, Jeonju, Republic of Korea; and ⁴ The Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

Requests for reprints: Gou Young Koh, Biomedical Research Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1, Guseong-dong, Daejeon, 305-701, Republic of Korea. Phone: 82-42-869-2638; Fax: 82-42-869-2610; E-mail: gykoh{at}kaist.ac.kr.

Key Words: OVCA • ascites • VEGF-A • VEGF-Trap • macrophage • diaphragm

Severe ascites is a hallmark of advanced ovarian cancer (OVCA), yet 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 chylous 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. Our results indicate that vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF-A from CD11b⁺ macrophages are responsible for producing OVCA-induced dysfunctional lymphangiogenesis, although other cell types contribute to the increased ascites formation. Accordingly, the combined blockade of VEGF-C/D and VEGF-A signaling with soluble VEGF receptor-3 and VEGF-Trap, respectively, markedly inhibited chylous ascites formation. These findings provide additional therapeutic targets to ameliorate chylous ascites formation in patients with advanced OVCA. [Cancer Res 2008;68(4):1100–9]