VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5. Gynecol Oncol

Department of Obstetrics and Gynecology, Ulm University Medical Centre, Ulm, Germany.
Gynecologic Oncology (Impact Factor: 3.77). 05/2012; 127(1):210-6. DOI: 10.1016/j.ygyno.2012.05.002
Source: PubMed


To evaluate the role of VEGF-dependent Claudin 5 production for the development of ascites via influencing endothelial permeability in peritoneal tissue of ovarian cancer patients.
This study investigates the mechanisms of formation of ascites in ovarian cancer patients, performing RT-PCR, VEGF-ELISA and immunohistochemical dual staining for CD31 and Claudin 5. In addition, in order to analyze the connectivity of VEGF, Claudin 5, and endothelial permeability, an endothelial cell/ovarian cancer cell-co-culture-system was established and evaluated performing Western blot analysis and a permeability assay.
Firstly, VEGF-gene expression was demonstrated for all ovarian cancer and peritoneal biopsies. In addition, quantification of VEGF in the serum and ascites of ovarian cancer patients revealed significantly increased values. We subsequently demonstrated Claudin 5 production in the peritoneal vessels, which was weaker than in the vessels of the controls. Evaluation of endothelial permeability finally showed a VEGF-dependent regulation via Claudin 5 suggesting a mechanism for the development of ascites in ovarian cancer patients.
VEGF induces ascites in ovarian cancer patients. This instance happens due to increased peritoneal permeability, caused by downregulation of the tight junction protein Claudin 5 in the peritoneal endothelium.

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    • "The mechanism by which HCG triggers vascular permeability in OHSS patients is still under investigation, but the vascular endothelial growth factor (VEGF) and its receptors seem to play a key role in this physiological process [4-7]. These observations are strengthened by the findings that the probability of developing OHSS correlates with the concentration of VEGF in serum [8-11] and that, in OHSS patients, the amount of VEGF in the follicular fluid is frequently higher than in individuals not affected by this complication [12]. "
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    ABSTRACT: Background Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of IVF/ICSI therapy. The pathophysiology and etiology of the disease is still not fully clarified. Methods To assess whether polymorphisms of the VEGF/VEGF-receptor system contribute to the occurrence of ovarian hyperstimulation syndrome (OHSS), we performed a retrospective analysis of 116 OHSS patients, and 124 female controls. The following SNPs were genotyped: Rs2071559 (VEGFR2-604); rs2305948 (VEGFR2-1192); rs1870377 (VEGFR2-1719); rs2010963 (VEGF-405); and rs111458691 (VEGFR1-519). Odds ratios (ORs) were estimated with a 95% confidence interval (CI). Linkage disequilibrium (LD) analysis was performed in the three loci of the VEGFR2 gene. Result We found an overrepresentation of the T allele of the VEGFR1-519 polymorphism in OHSS patients (P = 0.02, OR: 3.62, CI: 1.16 – 11.27). By genotype modeling, we found that polymorphism of VEGFR1-519 and VEGF-405 showed significant differences in patients and controls (p = 0.02, OR: 3.79 CI: 1.98 – 11.97 and p = 0.000005, OR: 0.29, CI: 0.17 – 0.50). LD analysis revealed significant linkage disequilibrium in VEGFR2. Conclusion Polymorphisms in the VEGFR2 gene and in the VEGF gene are associated with the occurrence of OHSS. This strengthens the evidence for an important role of the VEGF/VEGF- receptor system in the occurrence of OHSS.
    Full-text · Article · May 2014 · Journal of Ovarian Research
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    • "It is a major mediator of vascular permeability and angiogenesis [36]. Study also indicated VEGF-gene was express in all ovarian cancer and peritoneal biopsies, and it induced ascites in ovarian cancer patients due to increased peritoneal permeability through down-regulating the tight junction protein Claudin 5 in the peritoneal endothelium [37]. Thus, VEGFA might be one of the target genes for diagnosing ovarian cancer. "
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    ABSTRACT: Ovarian cancer is a cancerous growth arising from the ovary. This study was aimed to explore the molecular mechanism of the development and progression of the ovarian cancer. We first identified the differentially expressed genes (DEGs) between the ovarian cancer samples and the healthy controls by analyzing the GSE14407 affymetrix microarray data, and then the functional enrichments of the DEGs were investigated. Furthermore, we constructed the protein-protein interaction network of the DEGs using the STRING online tools to find the genes which might play important roles in the progression of ovarian cancer. In addition, we performed the enrichment analysis to the PPI network. Our study screened 659 DEGs, including 77 up- and 582 down-regulated genes. These DEGs were enriched in pathways such as Cell cycle, p53 signaling pathway, Pathways in cancer and Drug metabolism. CCNE1, CCNB2 and CYP3A5 were the significant genes identified from these pathways. Protein-protein interaction (PPI) network was constructed and network Module A was found closely associated with ovarian cancer. Hub nodes such as VEGFA, CALM1, BIRC5 and POLD1 were found in the PPI network. Module A was related to biological processes such as mitotic cell cycle, cell cycle, nuclear division, and pathways namely Cell cycle, Oocyte meiosis and p53 signaling pathway. It indicated that ovarian cancer was closely associated to the dysregulation of p53 signaling pathway, drug metabolism, tyrosine metabolism and cell cycle. Besides, we also predicted genes such as CCNE1, CCNB2, CYP3A5 and VEGFA might be target genes for diagnosing the ovarian cancer.
    Full-text · Article · Dec 2013 · Journal of Ovarian Research
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    • "Retroviral enforced expression of VEGF in ovarian cancer cells has been shown to dramatically reduce the time of onset of ascites formation (54). One of the mechanisms by which VEGF modulates permeability of peritoneal membranes is by down regulation of tight junction protein claudin 5 in the peritoneal endothelial cells (55). In addition, VEGF has been shown to induce tyrosine phosphorylation of cadherin-catenin complex which results in decreased endothelial junctional strength and increased permeability (56). "
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    ABSTRACT: More than one third of ovarian cancer patients present with ascites at diagnosis, and almost all have ascites at recurrence. The presence of ascites correlates with the peritoneal spread of ovarian cancer and is associated with poor disease prognosis. Malignant ascites acts as a reservoir of a complex mixture of soluble factors and cellular components which provide a pro-inflammatory and tumor-promoting microenvironment for the tumor cells. Subpopulations of these tumor cells exhibit cancer stem-like phenotypes, possess enhanced resistance to therapies and the capacity for distal metastatic spread and recurrent disease. Thus, ascites-derived malignant cells and the ascites microenvironment represent a major source of morbidity and mortality for ovarian cancer patients. This review focuses on recent advances in our understanding of the molecular, cellular, and functional characteristics of the cellular populations within ascites and discusses their contributions to ovarian cancer metastasis, chemoresistance, and recurrence. We highlight in particular recent translational findings which have used primary ascites-derived tumor cells as a tool to understand the pathogenesis of the disease, yielding new insights and targets for therapeutic manipulation.
    Full-text · Article · Sep 2013 · Frontiers in Oncology
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