Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells

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.

Hyperglycemia aggravates monocyte-endothelial adhesion in human umbilical vein endothelial cells from women with gestational diabetes mellitus by inducing Cx43 overexpression

“…Cx43 expression on membranes mediates the effective signal transduction from extracellular to intracellular. Numerous studies have reported that the NF-κB signaling pathway involves a variety of inflammatory processes that can interact with Cx43 (29,30). Moreover, the NF-κB signaling pathway is also reported to play a key role in regulating the expression of adhesion-related molecules, including ICAM-1 and VCAM-1.…”

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis

“…MCs, which are mesodermal in origin and possess both epithelial and mesenchymal features, are linked by several types of intercellular junctions, including tight junctions (TJs), adherens junctions, desmosomes and gap junctions ( Kastelein et al, 2019 ). SOC cells may disrupt the intercellular junctions within the MCs, favouring transmigration through the mesothelial monolayer ( Pakula et al, 2019a ). In this context, during the metastasis process, a subset of MCs undergoes a mesothelial-to-mesenchymal transition (MMT), a complex and step-wise process that begins with alterations in cellular architecture and include a deep molecular reprogramming with new biochemical instructions ( Pakula et al, 2019b ).…”

Connexins in Cancer: Jekyll or Hyde?

“…Several studies have shown changes in connexin gene expression in response to immortalization [ 108 , 109 , 110 ] but have not investigated the underlying mechanism of connexin function in this situation. A decrease in GJIC with age and with senescence has also been reported [ 111 , 112 , 113 , 114 ], as well as changes in connexin expression during senescence [ 115 ]. In the context of untransformed cells, knockdown of Cx43 in glomerular mesangial cells increased senescence-associated β-galactosidase staining [ 116 ], and Cx43 gene knockout in mesenchymal stem cells also increased cellular senescence.…”