Ascites formation associated with neoplasms is most likely due to increased vascular permeability, a process in which vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) plays a pivotal role. We hypothesized that tumor-derived VEGF/VPF modulates ascites formation through a paracrine effect on both tumor and peritoneal vessels. We investigated human vascular endothelial permeability using a newly developed dual-chamber permeability assay by co-culturing human umbilical vein cells with and without ovarian cancer cell lines (OVCAR-3, Hey-A8, and OCC-1) in the presence or absence of a human VEGF monoclonal antibody and VE-cadherin function–blocking antibody. This method permits determination of mechanisms by which substances released from neoplasms and other sources of vascular endothelial cell secretagogues modulate vascular permeability and likely other pathologic states.
MesianoS, FerraraN, JaffeRB. Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization. Am J Pathol153: 1249–1256, 1998.
2.
NagyJA, MasseEM, HerzbergKT, MeyersMS, YeoKT, SioussatTM, DvorakHF. Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res55: 360–368, 1995.
3.
BartonDP, CaiA, WendK, YoungM, GameroA, De CesareS.Angiogenic protein expression in advanced epithelial ovarian cancer. Clin Cancer Res3: 1579–1586, 1997.
4.
KraftS, WeindelK, OchsA, MarthC, ZmijaJ, SchumacherP, UngerC, DieterM, GastlG.Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer85: 178–185, 1999.
5.
BauseroP, CavailleF, MeduriG, FreitasS, Perrot-ApplanatM.Paracrine action of vascular endothelial growth factor in the human endometrium: production and target sites, and hormonal regulation. Angiogenesis2: 167–182, 1998.
6.
JacksonMW, RobertsJS, HeckfordSE, RicciardelliC, StahlJ, ChoongC, HorsfallDJ, TilleyWD. A potential autocrine role for vascular endothelial growth factor in prostate cancer. Cancer Res62: 854–859, 2002.
7.
DejanaE.Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J Clin Invest11:S7–S10, 1997.
8.
BreviarioF, CavedaL, CoradaM, Martin-PaduraI, NavarroP, GolayJ, IntronaM, GulinoD, LampugnaniMG, DejanaE.Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler Thromb Vasc Biol15: 1229–1239, 1995.
ShimaDT, AdamisAP, FerraraN, YeoKT, AllendeR, FolkmanJ, D'amorePA. Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med1: 182–193, 1995.
14.
YonedaJ, KuniyasuH, CrispensMA, PriceJE, BucanaCD, FidlerLT. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst90: 447–454, 1998.
15.
ShifrenJL, TsengJF, ZaloudekCJ, RyanIP, MengYG, FerraraN, JaffeRB, TaylorRN. Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab81: 3112–3118, 1996.
16.
HuL, ZaloudekCJ, FerraraN, JaffeRB. Vascular endothelial growth factor immunoneutralization plus paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol161: 1917–1924, 2002.
17.
ZebrowskiBK, LiuW, RamirezK, AkagiY, MillsGB, EllisLM. Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol6: 373–378, 1999.
18.
TrochaSD, ChristopherGK, ManiciniMG, AlexanderJS. Oran preservation solutions increase endothelial permeability and promote loss of junctional proteins. Ann Surg Oncol230: 105–113, 1999.
BreviarioF, CavedaL, CoradaM, Martin-PaduraI, NavarroP, GolayJ, IntronaM, GulinoD, LampugnaniMG, DejanaE.Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler Thromb Vasc Biol15: 1229–39, 1995.
21.
AliJ, LiaoF, MartensE, MullerWA. Vascular endothelial cadherin (VE-cadherin): cloning and role in endothelial cell-cell adhesion. Microcirculation4: 267–277, 1997.
22.
Martinez-EstradaOM, Rodriguez-MillanE, Gonzalez-DeVicenteE, ReinaM, VilaroS, FabreM.Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability. Eur J Neurosci18: 2538–2544, 2003.
23.
MegardI, GarriguesA, OrlowskiS, JorajuriaS, ClayetteP, EzanE, MabondzoA.A co-culture-based model of human blood-brain barrier: application to active transport of indinavir and in vitro correlation. Brain Res15: 153–167, 2002.
24.
QiuY, RuiYC, LiTJ, ZhangL, YaoPY. Inhibitory effect of extracts of Ginkgo biloba leaves on VEGF-induced hyperpermeability of bovine coronary endothelial cells in vitro. Acta Pharmacol Sin25: 1306–1311, 2004.
25.
StoeltzingO, AhmadSA, LiuW, McCartyMF, WeyJS, ParikhAA, FanF, ReinmuthN, KawaguchiM, BucanaCD, EllisLM. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res63: 3370–3377, 2003.
