Profound but dysfunctional lymphangiogenesis via vascular endothelial growth factor ligands from CD11b+ macrophages in advanced ovarian cancer.
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.
Jeon
Bong-Hyun
BH
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.
Jang
Cholsoon
C
Han
Jinah
J
Kataru
Raghu P
RP
Piao
Lianhua
L
Jung
Keehoon
K
Cha
Hye Ji
HJ
Schwendener
Reto A
RA
Jang
Kyu Yun
KY
Kim
Kwan-Sik
KS
Alitalo
Kari
K
Koh
Gou Young
GY
D000818:Animals; D001202:Ascitic Fluid / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis*; D003964:Diaphragm / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008024:Ligands; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008643:Mesentery / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000096:biosynthesis*
D039481:CD11b Antigen; C509295:ITGAM protein, human; C119248:LYVE1 protein, human; D008024:Ligands; D011993:Recombinant Fusion Proteins; C475927:VEGF-Trap fusion protein, recombinant; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3