title: Does VEGF facilitate local tumor growth and spread into the abdominal cavity by suppressing endothelial cell adhesion, thus increasing vascular peritoneal permeability followed by ascites production in ovarian cancer?
abstract: BACKGROUND
  Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types.
  
  
  METHODS
  Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition.
  
  
  RESULTS
  VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5.
  
  
  CONCLUSIONS
  Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites. These patients may benefit from therapeutic VEGF inhibition.
authors: Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 42, 89075, Ulm, Germany. inga1310@gmx.de.
authors: Inga
authors: I
authors: Bekes
authors: Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 42, 89075, Ulm, Germany. thomas.friedl@uniklinik-ulm.de.
authors: Thomas W P
authors: TW
authors: Friedl
authors: Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 42, 89075, Ulm, Germany. tanja.koehler@uniklinik-ulm.de.
authors: Tanja
authors: T
authors: Köhler
authors: Department of Obstetrics and Gynecology, Klinikum Frankfurt Hoechst, Gotenstraße 6-8, 65929, Frankfurt am Main, Germany. volker.moebus@KlinikumFrankfurt.de.
authors: Volker
authors: V
authors: Möbus
authors: Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 42, 89075, Ulm, Germany. wolfgang.janni@uniklinik-ulm.de.
authors: Wolfgang
authors: W
authors: Janni
authors: Department of Obstetrics and Gynecology, University of Würzburg, Josef-Schneider-Strasse 4, 97080, Würzburg, Germany. woeckel_a@ukw.de.
authors: Achim
authors: A
authors: Wöckel
authors: Department of Obstetrics and Gynecology, University of Würzburg, Josef-Schneider-Strasse 4, 97080, Würzburg, Germany. webmaster@tine-wulff.de.
authors: Christine
authors: C
authors: Wulff
mesh_terms: D034841:Abdominal Cavity / Q000473:pathology*; D000368:Aged; D015703:Antigens, CD; D001201:Ascites / Q000473:pathology*; D015820:Cadherins; D002199:Capillary Permeability; D002448:Cell Adhesion; D049109:Cell Proliferation; D062507:Claudin-5 / Q000378:metabolism; D018920:Coculture Techniques; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology*; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000473:pathology* / Q000601:surgery; D010537:Peritoneum / Q000098:blood supply* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5