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

Abstract

Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell‐to‐cell crosstalk or phenotypic alterations including the acquisition of platinum‐resistance in OvCa cells. Herein, we report how OvCa‐associated mesothelial cells (OCAMs) induce platinum‐resistance in OvCa cells through direct cell‐to‐cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF‐β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum‐sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell‐to‐cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF‐β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell‐to‐cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum‐resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

Screening and identification of key genes and pathways in metastatic uveal melanoma based on gene expression using bioinformatic analysis

“…FN1 has been shown to promote metastasis in various types of tumors. [ 39 – 41 ] Recently, Li et al [ 42 ] reported that FN1 promotes cutaneous melanoma proliferation and metastasis by inhibiting apoptosis and regulating epithelial-to-mesenchymal transition, which is consistent with our results. APOA1 is the main protein constituent of high-density lipoprotein, which shuttles excess cholesterol from organs to the liver for excretion.…”

Ovarian Cancer-Associated Mesothelial Cells: Transdifferentiation to Minions of Cancer and Orchestrate Developing Peritoneal Dissemination

“…Additionally, reports have indicated that these cancer-associated MCs promote OvCa progression via various cell-to-cell crosstalk with OvCa cells [ 9 , 16 , 51 ]. In this context, we comprehensively defined the MCs altered by OvCa as OCAMs and demonstrated their features [ 9 , 15 , 16 , 17 , 19 ]. Based on Dr. Stephen Paget’s theory, seeds of OvCa cells cultivate the soil of MCs for OCAMs of the peritoneum by nourishing them with TGF-β1, which promotes the progression of peritoneal dissemination.…”

“…The changes in OCAMs are mainly due to mesenchymal transition but may also be viewed as transdifferentiation. While there are no unique markers for OCAM, it has been reported that the expression of genes encoding proteins that are known markers of epithelial–mesenchymal transition (EMT), such as E-cadherin decrease and N-cadherin increase, is altered in MCs induced by TGF-β1 [ 9 ]. We speculate that as cancer cells become more malignant as they become more undifferentiated, they may become more closely related to each other as they transdifferentiate.…”

“…It has been reported that in peritoneal metastasis, a subpopulation of CAFs originates from MCs through a mesenchymal transition, predominantly initiated by TGF-β1 [ 13 , 14 , 16 ]. In our previous report, histological analysis of peritoneal dissemination of OvCa revealed the presence of myofibroblasts, consistently associated with peritoneal MCs, suggesting that OCAMs are able to invade the peritoneal tissues together with OvCa cells [ 9 ]. In gastric cancer experiments, cancer-activated MCs were also found to create an invasion front by guiding cancer cells [ 84 ].…”

“…According to the “seed and soil” hypothesis [ 7 , 8 ], the peritoneum offers a highly compatible microenvironment for metastatic OvCa cells [ 9 ]. However, normally the peritoneum is covered by a hyaluronic acid-based anti-adhesion film and serves as a barrier to external stress [ 10 ].…”