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?
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?
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DOI：
10.1186/s12943-016-0497-3
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发表时间：
2016-02-12
期刊：
影响因子：
37.3
通讯作者：
Wulff C
中科院分区：
文献类型：
--
作者：
Bekes I;Friedl TW;Köhler T;Möbus V;Janni W;Wöckel A;Wulff C
卵巢癌主要与腹膜血管通透性的病理调节相关，导致腹水。在此，我们研究了血管内皮生长因子 (VEGF) 以及紧密连接蛋白和粘附连接蛋白（VE-钙粘蛋白和密蛋白 5）对内皮通透性的分子调节，与不同卵巢癌类型的肿瘤生物学有关。收集了 68 名卵巢癌患者和 20 名健康对照者手术前后的血清和腹水样本以及腹膜活检样本。通过ELISA测定血清和腹水中的VEGF蛋白。 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.分析 VEGF 水平、VE-钙粘蛋白和密蛋白 5 基因表达的差异与各种肿瘤特征（肿瘤分期、分级、组织学亚型、术后切除状态）的关系，然后与对照进行比较。此外，将人原发性卵巢癌细胞与人脐静脉内皮细胞（HUVEC）共培养，并研究 VEGF 抑制后 VE-cadherin 和 Claudin 5 的变化。与对照组相比，肿瘤患者的 VEGF 显着增加，并在腹水中积聚。在诊断为晚期肿瘤、分化不良的肿瘤或实体/囊性实体瘤组的患者中发现了最高的 VEGF 水平。术后有残留肿瘤的患者在术前和术后的 VEGF 水平均显着高于无肿瘤切除患者。免疫组织化学双染色实验的结果表明 VE-钙粘蛋白和密蛋白 5 在腹膜脉管系统中共定位。与对照组相比，肿瘤患者腹膜血管中VE-cadherin和claudin 5的表达显着受到抑制，但VE-cadherin和claudin 5表达与不同肿瘤特征的关系无显着差异。 A significant positive correlation was found between VE-cadherin and claudin 5 expression.体外 VEGF 抑制与 VE-钙粘蛋白和密蛋白 5 的显着增加相关。我们的结果表明，卵巢癌腹膜通透性增加是由于肿瘤来源的 VEGF 下调粘附蛋白所致。 Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites.这些患者可能受益于治疗性 VEGF 抑制。
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. 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. 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. 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.