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.
Highlights
The majority of tumors are confined to the organ where they first originated and are usually treatable and curable with local therapy
This process is known as peritoneal carcinomatosis and signifies that the disease is at advanced stage, is difficult to treat and, often, there is no prospect of cure
This manuscript focuses on providing a comprehensive review of novel advances in understanding how the peritoneal stroma and, in particular, carcinoma-associated fibroblasts (CAFs) provide cancer cells with a supportive microenvironment for peritoneal implantation
Summary
The majority of tumors are confined to the organ where they first originated and are usually treatable and curable with local therapy. Aggressive surgical tumor removal (tumor cytoreduction) coupled with hyperthermic intraperitoneal chemotherapy (HIPEC) represents the cornerstone of advanced abdominal oncologic surgery The combination of both treatments seems to be encouraging and in colorectal and gynecological cancers provides five-year survival rates of over 40% and 45%, respectively [6,7]. To design new therapeutic approaches it is necessary to improve our knowledge of the mechanisms implicated in tumor progression in the peritoneum This manuscript focuses on providing a comprehensive review of novel advances in understanding how the peritoneal stroma and, in particular, carcinoma-associated fibroblasts (CAFs) provide cancer cells with a supportive microenvironment for peritoneal implantation. The recent description of the mesothelial origin of peritoneal CAFs via mesothelial-to-mesenchymal transition (MMT) opens a new research line to be considered in the treatment of peritoneal metastases that frequently occur in patients with abdominal cancers [9]
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