Abstract：
At least one-third of patients with epithelial ovarian cancer (OC) present ascites at diagnosis and almost all have ascites at recurrence especially because of the propensity of the OC cells to spread in the abdominal cavity leading to peritoneal metastasis. The influence of ascites on the development of pre-metastatic niches, and on the biological mechanisms leading to cancer cell colonization of the mesothelium, remains poorly understood. Here, we show that ascites weakens the mesothelium by affecting the morphology of mesothelial cells and by destabilizing their distribution in the cell cycle. Ascites also causes destabilization of the integrity of mesothelium by modifying the organization of cell junctions, but it does not affect the synthesis of N-cadherin and ZO-1 by mesothelial cells. Moreover, ascites induces disorganization of focal contacts and causes actin cytoskeletal reorganization potentially dependent on the activity of Rac1. Ascites allows the densification and reorganization of ECM proteins of the mesothelium, especially fibrinogen/fibrin, and indicates that it is a source of the fibrinogen and fibrin surrounding OC spheroids. The fibrin in ascites leads to the adhesion of OC spheroids to the mesothelium, and ascites promotes their disaggregation followed by the clearance of mesothelial cells. Both αV and α5β1 integrins are involved. In conclusion ascites and its fibrinogen/fibrin composition affects the integrity of the mesothelium and promotes the integrin-dependent implantation of OC spheroids in the mesothelium.
摘要：
至少三分之一的上皮性卵巢癌（OC）患者在诊断时出现腹水，几乎所有患者在复发时都有腹水，尤其是因为OC细胞倾向于在腹腔中扩散，导致腹膜转移。腹水对转移前生态位发育的影响，以及导致间皮癌细胞定植的生物学机制，仍然知之甚少。这里,我们发现，腹水通过影响间皮细胞的形态和破坏它们在细胞周期中的分布来削弱间皮。腹水还通过改变细胞连接的组织而导致间皮完整性的不稳定，但不影响间皮细胞合成N-cadherin和ZO-1。此外，腹水诱导局灶性接触的解体，并导致肌动蛋白细胞骨架重组，这可能取决于Rac1的活性。腹水可以使间皮的ECM蛋白致密化和重组，尤其是纤维蛋白原/纤维蛋白，表明它是OC球体周围纤维蛋白原和纤维蛋白的来源。腹水中的纤维蛋白导致OC球状体与间皮粘附，和腹水促进它们的解聚，然后清除间皮细胞。涉及αV和α5β1整合素。总之，腹水及其纤维蛋白原/纤维蛋白成分会影响间皮的完整性，并促进间皮中OC球体的整合素依赖性植入。
