Abstract
Mechanisms of transmesothelial invasion of ovarian cancer are still poorly understood. Here we examined whether this phenomenon may be determined by an expression of intercellular junctions in peritoneal mesothelial cells (PMCs). Analysis of ovarian tumors showed that cancer cells are localized below an intact layer of PMCs. The PMCs located near the invaded cancer cells displayed low expression of connexin 43, E-cadherin, occludin, and desmoglein, as well as expressed SA-β-Gal, a marker of senescence. Experiments in vitro showed that senescent PMCs exhibited decreased levels of the four tested intercellular junctions, and that the invasion of ovarian cancer cells through the PMCs increased proportionally to the admixture of senescent cells. Intervention studies showed that the expression of connexin 43, E-cadherin, occludin, and desmoglein in senescent PMCs could be restored upon the blockade of p38 MAPK, NF-κB, AKT, JNK, HGF, and TGF-β1. When these molecules were neutralized, the efficiency of the transmesothelial cancer cell invasion was diminished. Collectively, our findings show that the integrity of the peritoneal mesothelium, which is determined by the expression of junctional proteins, is critical for the invasion of ovarian cancer. They also indicate a mechanism by which senescent PMCs may promote the invasive potential of cancer cells.
Highlights
Epithelial ovarian cancer (EOC) remains the most fatal malignancy of the female genital tract
There is a theory that the peritoneal mesothelial cells (PMCs) serve as a mechanical barrier that protects the peritoneal cavity from the entrance of ovarian cancer cells[9]
The PMCs are actively cleared by cancer cells, plausibly via myosin-driven forces, which allows the latter to successfully implant within the peritoneal stroma, where they are encouraged by fibroblasts to multiply and form tumors[10]
Summary
Epithelial ovarian cancer (EOC) remains the most fatal malignancy of the female genital tract. There is a consensus that the interaction between cancer cells that shed from the surface of the ovary, individually or in spheroids, and peritoneal mesothelial cells (PMCs) that cover, as a single layer, the visceral and abdominal surfaces of the peritoneum is the basis of tumor development. This cross-talk includes several individual processes, of which adhesion, migration, proliferation, and invasion are the most critical. Have been found to accumulate within the peritoneal cavity, and their supportive role in the development of an intraperitoneal metastatic niche has been observed in cell culture, laboratory animals, and tumors from EOC patients[7]. The phenomenological aspects of the study were followed with mechanistic insights into the signaling pathways and molecules linked with cellular senescence that could be involved in the senescence-related deterioration of intercellular junctions, leading to intensified cancer cell invasiveness
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