Mesothelial-to-Mesenchymal Transition Contributes to the Generation of Carcinoma-Associated Fibroblasts in Locally Advanced Primary Colorectal Carcinomas.

Carlos H Gordillo,Lucía Pascual-Antón,José A Jiménez-Heffernan,Patricia Muñoz-Hernández,Pilar Sandoval,Manuel López-Cabrera

doi:10.3390/cancers12020499

Abstract

During peritoneal metastasis, cancer cells spread from abdominal solid tumors, disseminate through the peritoneal fluid and attach to and invade through mesothelial cells (MCs) that line the peritoneum. Intestinal adenocarcinomas originating in the mucosa infiltrate the submucosa, muscle layer, and serosa in order to finally colonize the peritoneal cavity. However, the mechanism by which metastatic cells leave the primary tumor and reach the peritoneal cavity has not been previously described. Hence, we investigate whether MCs lining visceral peritoneum, through a mesothelial-to-mesenchymal transition (MMT), are a source of carcinoma-associated fibroblasts (CAFs), which could contribute to cancer progression toward the peritoneal cavity. CAFs detected in biopsies from patients with superficially invasive colorectal cancer differed from locally advanced tumors. An aberrant accumulation of myofibroblasts expressing mesothelial markers was found in the stroma of deeply infiltrative tumors located in the neighborhood of a frequently activated mesothelium. We suggest that MMT is a key event in the early stages of peritoneal dissemination.

Highlights

Epithelial-to-mesenchymal transition (EMT) is a process by which differentiated epithelial cells undergo a deep molecular reprogramming and gradually acquire a mesenchymal phenotype characterized by elongated morphology, enhanced migratory and invasive capacity, and increased production of extracellular matrix (ECM) components
In peritoneal carcinomatosis, secretome of abdominal tumors that have reached the peritoneal cavity modificates the mesothelium in order to abdominal tumors that have reached the peritoneal cavity modificates the mesothelium in order to be colonized via a mesechymal transition (MMT) process
In vitro and ex vivo experiments were combined with a mouse model of peritoneal metastasis in order to obtain a whole picture of the peritoneal carcinomatosis process

Summary

Introduction

Epithelial-to-mesenchymal transition (EMT) is a process by which differentiated epithelial cells undergo a deep molecular reprogramming and gradually acquire a mesenchymal phenotype characterized by elongated morphology, enhanced migratory and invasive capacity, and increased production of extracellular matrix (ECM) components. EMT), wound healing, and organ fibrosis (type II EMT), as well as in metastasis (type III EMT) [1,2,3]. Type II EMT typically acts as a source of fibroblasts in order to reconstruct tissues following an injury. Organ fibrosis occurs when wound healing response persists, in part, due to a continual type II EMT process [4]. We demonstrated that a type II EMT, known as mesothelial-to-mesechymal transition (MMT), occurs after peritoneal damage. Myofibroblast conversion of mesothelial cells (MCs) contributes to peritoneal fibrosis associated with peritoneal dialysis and post-surgical peritoneal adhesions [5,6,7,8]

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Conclusion