The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis

Abstract

Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis. During peritoneal metastasis, cancer cells detach from the primary tumor, such as ovarian or gastrointestinal, disseminate through the peritoneal fluid and colonize the peritoneum. Tumor cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity, then colonizing the submesothelial compact zone where CAFs accumulate. CAFs may derive from different sources depending on the surrounding metastatic niche. In peritoneal metastasis, a sizeable subpopulation of CAFs originates from MCs through a mesothelial-to-mesenchymal transition (MMT), which promotes adhesion, invasion, vascularization and subsequent tumor growth. The bidirectional communication between cancer cells and MC-derived CAFs via secretion of a wide range of cytokines, growth factors and extracellular matrix components seems to be crucial for the establishment and progression of the metastasis in the peritoneum. This manuscript provides a comprehensive review of novel advances in understanding how peritoneal CAFs provide cancer cells with a supportive microenvironment, as well as the development of future therapeutic approaches by interfering with the MMT in the peritoneum.

Keywords: carcinoma-associated fibroblasts; mesothelial cells; mesothelial-to-mesenchymal transition; peritoneal metastasis; therapeutic strategies.

Figure 1

Model for transformation of the pre-metastatic niche by mesothelial-to-mesenchymal transition in the peritoneum: (1) Cancer cells at the primary site secrete an array of exosomes, cytokines, chemokines and growth factors that accumulate in the ascitic fluid. Some of these molecules, such as transforming growth factor-beta1 (TGF-β1) or hepatocyte growth factor (HGF), induce changes in the mesothelial cells (MCs), triggering a mesothelial-to-mesenchymal transition (MMT), through which they lose apico-basal polarity and cell-cell adhesion, and acquire myofibroblastic properties. (2) Cancer cells adhere via β1 integrins to the MCs that line the peritoneum. This adhesion is increased when a MMT has taken place. (3) In later stages of MMT, MCs have converted into carcinoma-associated fibroblasts (CAFs) that represent the invasion front into the stroma, followed by cancer cells. (4) After invading, MC-derived CAFs accumulate in the peritoneal stroma. (5) CAFs produce factors that affect peritoneal implant progression: they induce angiogenesis via secretion of VEGF, among other factors; they transform the extracellular matrix (ECM) by producing collagen, fibronectin and other structural proteins, and they remodel the ECM via matrix metalloproteinases (MMPs); they also stimulate proliferation of cancer cells. (6) The metastatic niche in the peritoneum is created as a result of the clearance of the MC monolayer, myofibroblast conversion of MCs, invasion of MCs and cancer cells, accumulation of CAFs, increased vascularization, ECM remodeling and proliferation of cancer cells. (7) Cancer cells in the new site, together with CAFs, will continue to produce factors that modify the stroma and induce changes in both cancer cells and MCs, thereby creating a positive feedback loop.