Reprogramming of Mesothelial-Mesenchymal Transition in Chronic Peritoneal Diseases by Estrogen Receptor Modulation and TGF-β1 Inhibition

Abstract

In chronic peritoneal diseases, mesothelial-mesenchymal transition is determined by cues from the extracellular environment rather than just the cellular genome. The transformation of peritoneal mesothelial cells and other host cells into myofibroblasts is mediated by cell membrane receptors, Transforming Growth Factor β1 (TGF-β1), Src and Hypoxia-inducible factor (HIF). This article provides a narrative review of the reprogramming of mesothelial mesenchymal transition in chronic peritoneal diseases, drawing on the similarities in pathophysiology between encapsulating peritoneal sclerosis and peritoneal metastasis, with a particular focus on TGF-β1 signaling and estrogen receptor modulators. Estrogen receptors act at the cell membrane/cytosol as tyrosine kinases that can phosphorylate Src, in a similar way to other receptor tyrosine kinases; or can activate the estrogen response element via nuclear translocation. Tamoxifen can modulate estrogen membrane receptors, and has been shown to be a potent inhibitor of mesothelial-mesenchymal transition (MMT), peritoneal mesothelial cell migration, stromal fibrosis, and neoangiogenesis in the treatment of encapsulating peritoneal sclerosis, with a known side effect and safety profile. The ability of tamoxifen to inhibit the transduction pathways of TGF-β1 and HIF and achieve a quiescent peritoneal stroma makes it a potential candidate for use in cancer treatments. This is relevant to tumors that spread to the peritoneum, particularly those with mesenchymal phenotypes, such as colorectal CMS4 and MSS/EMT gastric cancers, and pancreatic cancer with its desmoplastic stroma. Morphological changes observed during mesothelial mesenchymal transition can be treated with estrogen receptor modulation and TGF-β1 inhibition, which may enable the regression of encapsulating peritoneal sclerosis and peritoneal metastasis.

Comprehensive analysis of EMT-related genes and lncRNAs in the prognosis, immunity, and drug treatment of colorectal cancer

“…cn/ web/ GSCAL ite/). For each CRC patient, the tumor mutation burden (TMB) score is measured as follows: (total mutations/total covered bases) × 10 6 .…”

“…EMT can affect the occurrence and development of CRC, the prognosis of metastasis, and the effect of chemotherapy and immunotherapy [ 6 ]. However, the current research still lacks systematic research on the overall genes that regulate the EMT process and its prognosis and treatment effects with CRC.…”

TGF-β1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-β1 Signaling Pathway

“…First, the PF model using CG may be a very strong fibrosis model, which did not fully prevent injuries byCG, despite SB treatment. Second, PF by intraperitoneally injected CG can be developed through other pathways, such as NF-κB via advanced glycation end products, or IL-1β, or ERK 1/2 via IL-6, or angiotensin, beyond TGF-β and its signaling pathways [29][30][31]. SB525334 can attenuate TGF-β and its downstream pathways, but may not completely prevent changes through other pathways than TGF-β and its signaling pathways.…”

Post-Surgical Peritoneal Scarring and Key Molecular Mechanisms

“…Transitioned cells take on a motile phenotype and display an increase in mesenchymal cytoskeletal markers eventually becoming invasive and fully transitioned into alpha-smooth muscle actin (αSMA)- positive myofibroblasts [ 55 ]. The role of TGF-β1 in promoting MMT is well-documented [ 56 , 57 , 58 ] and several key signalling pathways associated with TGF-β, IL-1β, angiotensin II, HIF-1α, and pleiotrophin have been implicated [ 59 , 60 , 61 , 62 , 63 ]. By inducible genetic fate mapping, Chen and colleagues reported that sodium hypochlorite injured serosa is repaired by mesothelial cells positive for Wilms’ tumour protein 1 (WT1); however, they questioned the role of MMT in mediating peritoneal fibrosis [ 64 ].…”