A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

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.

Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer

“…Moreover, we previously reported compression-induced changes in OvCa multicellular aggregates correlated with upregulation of epithelial-mesenchymal transition (EMT)-associated genes 11 . Together these data suggest that ascites-induced compression may play a role in mesothelial-mesenchymal transition 21 , 44 . A limitation of the current study is the lack of information regarding the uniformity of ascites-induced compression throughout structures of the peritoneal cavity impacted by OvCa metastases.…”

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

“…S3c). While mesenchymal transition of OvCa cells was reported to be caused by several soluble growth factors, 23 this finding indicates that an adhesive molecule may also greatly influence the mesenchymal characteristics of OvCa cells.…”

“…This mesenchymal change in MCs may have been caused by the release of a soluble growth factor from cancer cells as specific studies have already reported that a variety of factors collected from the conditioned media used to culture OvCa cells induced mesenchymal changes in MCs. 23 Notably, TGF-β1 has been recognized as one of the most common mesenchymal inducers of MCs. 16,19,30 An average of 4.62 ng/ml (range: 0.38-22.34 ng/ml) of TGF-β1 was detected in the ascites of patients with malignant ovarian tumors ( Fig.…”

“…Moreover, recent studies have shown that activated MCs play an important role in the development of peritoneal metastasis; these studies further demonstrated that MCs increase the adhesive and proliferative properties of OvCa cells. In fact, mesenchymal transition of MCs was reported to be induced by a variety of soluble factors in malignant ascites, and modification of extracellular matrix (ECM) on the mesothelial cells also promoted peritoneal metastasis of OvCa . These findings suggest that MCs no longer function as simply passive bystanders, but rather act as coordinators for the progression of OvCa.…”

The prognostic value of HGF-c-MET signaling pathway in Gastric Cancer: a study based on TCGA and GEO databases

“…Our prior studies had found multiple genes and signaling pathways participated or play dominant role in tumorigenic process of gastric cancer, such as HGF, which secreted by cancer-associated fibroblasts, could promote vascularization in gastric cancer via activating PI3K/Akt and ERK1/2 signaling pathway [2], and accelerated proliferation, migration and invasion of MET-unamplified gastric cancer cells through activating c-MET/Stat3/twist1 signaling pathway [3]. It was noteworthy that HGF-c-MET signaling pathway is activated in a range of cancer types including gastric cancer, colorectal cancer, head and neck cancer, hepatocellular carcinoma, lung cancer, urothelial carcinoma of bladder, glioblastoma, melanoma and ovarian cancer, among others [2,[4][5][6][7][8][9][10][11], and associated with an aggressive phenotype and poor prognosis in pancreatic cancer [12].…”