Research paperMalignant ascites determine the transmesothelial invasion of ovarian cancer cells

- Malignant ascites promote invasion of ovarian cancer cells.
- Ascites from type II tumors are more proinvasive than those from type I tumors.
- Ascites deteriorate mesothelial junctions in oxidative stress-dependent mechanism.
- Ascites affect junctional proteins via p38 MAPK- and NF-κB-dependent signaling.

The exact role of malignant ascites in the development of intraperitoneal ovarian cancer metastases remains unclear. In this report we sought to establish if ascites can determine the efficiency of transmesothelial invasion of ovarian cancer cells, and, if so, whether the fluid generated by highly aggressive serous and undifferentiated tumors will promote the invasion more effectively than ascites from less aggressive clear cell and endometrioid cancers. The study showed that the invasion of ovarian cancer cells (SKOV-3 and primary cancer cells) across monolayered peritoneal mesothelial cells was elevated upon mesothelial cell exposure to fluid produced by serous and undifferentiated cancers, as compared with cells subjected to ascites from clear cell and endometrioid tumors. This effect coincided with decreased mesothelial expression of junctional proteins: connexin 43, E-cadherin, occludin, and desmoglein. Moreover, it was accompanied by transforming growth factor β1-dependent overproduction of reactive oxygen species by these cells. The activity of ascites from serous and undifferentiated tumors was mediated by p38 mitogen-activated protein kinase and nuclear factor κB. When the mesothelial cells were protected against oxidative stress, both deterioration of junctional proteins and intensification of cancer cell invasion in response to ascites from serous and undifferentiated tumors were effectively prevented. In conclusion, our findings indicate that the high aggressiveness of some histotypes of ovarian cancer may be related to the ability of malignant ascites generated by these cells to oxidative stress-dependent impairment of mesothelial cell integrity and the resulting increase in their transmesothelial invasion.

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