Abstract
The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.
Highlights
One of the most important processes involved in the progression of primary and metastatic tumors is epithelial-mesenchymal transition (EMT)
The conditioned medium (CM) were applied to peritoneal mesothelial cells (PMCs) for 10 days and induced signs of mesenchymal transition (MMT), including a fibroblastic morphology, decreased expression of E-cadherin, increased expression of vimentin, and increased migration
The changes in the MMT-related proteins and the enhancement of PMC migration, were greater in response to the CM generated by the high-grade serous ovarian cancer cells (HGSOCs) than in response to the CM from the A2780 and SKOV-3 cells (Figure 1)
Summary
One of the most important processes involved in the progression of primary and metastatic tumors is epithelial-mesenchymal transition (EMT). This term refers to a process in which cancer cells that typically display a uniform epithelial morphology become spindle-shaped and more invasive. EMT is linked with the repression of the epithelial markers E-cadherin, cytokeratins, and occludin and the increase in the mesenchymal proteins, N-cadherin and vimentin. These changes are regulated by a plethora of signaling molecules, of which Smad, Snail, Slug, miR-200, and TGF-β1 are the most important [1]. The PMCs create a metastatic niche by supporting the critical elements of cancer cell expansion, such as adhesion, proliferation, migration, and neoangiogenesis [2]
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