Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

Sandoval, Pilar; Jiménez‐Heffernan, José A.; Guerra-Azcona, Gonzalo; Pérez-Lozano, María Luisa; Rynne-Vidal, Ángela; Albar-Vizcaíno, Patricia; Gil-Vera, Fernando; Martín, Paloma; Coronado, María José; Bárcena, Carmen; Dotor, Javier; Majano, Pedro L.; Peralta, Abelardo Aguilera; López–Cabrera, Manuel

doi:10.1002/path.4695

Cited by 89 publications

(101 citation statements)

References 64 publications

(93 reference statements)

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“…The MCs loss their protective function and alters their phenotypes. In peritoneal metastases process, although emerging evidences have verified the MMT transition of mesothelium by TGF-β1 factor, no publications report the similar effect of tumor-derived exosomes [14–17]. Herein, our study for the first time demonstrated the transition of mesothelium induced by exosomes.…”

Section: Discussionsupporting

confidence: 48%

Malignant ascites-derived exosomes promote proliferation and induce carcinoma-associated fibroblasts transition in peritoneal mesothelial cells

et al. 2017

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Malignant ascites-derived exosomes have been demonstrated to participate in tumor metastasis. In peritoneal metastasis, normal mesothelial cells (MCs) can be converted into carcinoma-associated fibroblasts (CAFs) by mesothelial-mesenchymal transition (MMT). Herein, we evaluated the effect of malignant ascites-derived exosomes on peritoneal MCs in vitro and in vivo experiments to determine whether exosomes could educate MCs and contribute to peritoneal metastasis.Under the treatment of ascites-derived exosomes, peritoneal MCs showed increased ability to proliferate and migrate. Expression of CAFs specific proteins markers in MCs, including fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA), and fibronectin, were increased after treatment of exosomes. In clinical samples test, TGF-β1 was found to be overexpressed in both malignant ascites and malignant ascites-derived exosomes, and the high volume of TGF-β1 may be responsible for peritoneum fibrosis. In addition, exosomes can increase xenograft tumor growth by suppressing the inhibitive ability on tumor cells by MCs. Besides, CAFs specific proteins markers including FAP, α-SMA, and vimentin were increased in clinical peritoneal biopsies. The immunohistochemical staining for mice tumor biopsies also revealed increased expression of fibronectin and FAP, along with decreased expression of E-cadherin and VCAM-1 after exosomes treatment.Thus, malignant ascites-derived exosomes may be of importance in the development of peritoneal metastasis by facilitating MCs to proliferate and convert into CAFs by TGF-β1 induced MMT.

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Section: Discussionsupporting

confidence: 48%

Malignant ascites-derived exosomes promote proliferation and induce carcinoma-associated fibroblasts transition in peritoneal mesothelial cells

et al. 2017

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“…Another process abundant in peritoneal fibrotic tissue is mesothelial-to-mesenchymal transition (MMT), that mesothelial cells (MCs) in the peritoneal cavity could transform into myofibroblasts under pathological conditions. In mouse model, blockage of TGF-β resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the peritoneal adhesions [68]. …”

Section: Basic Cellular Pathways Promote Emt Process In Endometriosismentioning

confidence: 99%

Epithelial-to-mesenchymal transition in the development of endometriosis

Yang

2017

Oncotarget

121

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Endometriosis, an estrogen-dependent chronic gynecological disease, is common in reproductive-age women and profoundly affects their life quality. Although various pathogenic theories have been proposed, the origin of endometriosis remains unclear. Epithelial to mesenchymal transition (EMT) is a process that epithelial cells lose polarized organization of the cytoskeleton and cell-to-cell contacts, acquiring the high motility of mesenchymal cells. These changes are thought to be prerequisites for the original establishment of endometriotic lesions. However, no study exactly indicates which type of EMT occurs in endometriosis. In this review, we conclude that two different types of EMT may participate in this disease. Besides, two stimulating signals, hypoxia and estrogen, can through different pathways to activate the EMT process in endometriosis. Those pathways involve many cellular factors such as TGF-beta and Wnt, ultimately leading to cell proliferation and migration. As infertility is becoming a serious and intractable issue for women, EMT, during the implantation process, is gaining attention. In this review, we will describe the known functions of EMT in endometriosis, and suggest further studies that may aid in the development of medical therapy.

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“…However, studies dealing with the early stages are often less characterized, although evidence implicates interactions between the mesothelium, fibroblasts, and hematogenous cells. [9][10][11] We recently demonstrated that insult to the surface mesothelium initiates adhesion formation. Abrasion of the peritoneal wall leads to the proliferation of the mesothelial layer through a hypoxia-inducible factor 1a program, upregulation of fetal surface markers such as mesothelin, and an expansive change in gene expression.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil and monocyte kinetics play critical roles in mouse peritoneal adhesion formation

et al. 2019

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Key Points• Upon injury, the mesothelium recruits neutrophils to the peritoneal space, which contributes to adhesion formation.• Neutrophil recruitment and macrophagedepletion kinetics in adhesions differ from the normal innate response.Peritoneal adhesions are pathological fibroses that ensnare organs after abdominal surgery.This dense connective tissue can cause small bowel obstruction, female infertility, and chronic abdominal pain. The pathogenesis of adhesions is a fibrotic response to tissue damage coordinated between mesothelial cells, fibroblasts, and immune cells. We have previously demonstrated that peritoneal adhesions are a consequence of mechanical injury to the mesothelial layer sustained during surgery. Neutrophils are among the first leukocytes involved in the early response to tissue damage. Here, we show that when subjected to mechanical stress, activated mesothelial cells directly recruit neutrophils and monocytes through upregulation of chemokines such as CXCL1 and monocyte chemoattractant protein 1 (MCP-1). We find that neutrophils within the adhesion sites undergo cell death and form neutrophil extracellular traps (NETosis) that contribute to pathogenesis. Conversely, tissue-resident macrophages were profoundly depleted throughout the disease time course.We show that this is distinct from traditional inflammatory kinetics such as after sham surgery or chemically induced peritonitis, and suggest that adhesions result from a primary difference in inflammatory kinetics. We find that transient depletion of circulating neutrophils significantly decreases adhesion burden, and further recruitment of monocytes with thioglycolate or MCP-1 also improves outcomes. Our findings suggest that the combination of neutrophil depletion and monocyte recruitment is sufficient to prevent adhesion formation, thus providing insight for potential clinical interventions.

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Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

Cited by 89 publications

References 64 publications

Malignant ascites-derived exosomes promote proliferation and induce carcinoma-associated fibroblasts transition in peritoneal mesothelial cells

Malignant ascites-derived exosomes promote proliferation and induce carcinoma-associated fibroblasts transition in peritoneal mesothelial cells

Epithelial-to-mesenchymal transition in the development of endometriosis

Neutrophil and monocyte kinetics play critical roles in mouse peritoneal adhesion formation

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