Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

Abstract

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread.

Keywords: Cytoreductive surgery; Hyperthermic intraperitoneal peroperative chemotherapy; Pathophysiology; Peritoneal carcinomatosis; Peritoneal metastatic cascade; Peritoneum.

Figure 1

Structure of the peritoneum. The peritoneum is composed of a mesothelium supported by a basement membrane that rests on a layer of submesothelium. The mesothelium consists of a monolayer of either flattened, stretch, squamous-like or cuboidal mesothelial cells. The luminal surface of mesothelial cells has numerous microvilli varying in shape, size and density. Cilia have also been identified on the surface of resting mesothelial cells. The basement membrane consists of a thin laminar network containing type I and IV collagen, proteoglycans and glycoproteins. The submesothelium consists of a complex network of extracellular matrix made up of different types of collagen, glycoproteins, glycosaminoglycans and proteoglycans. Blood vessels, lymphatics, and various cells types (fibroblasts, resident tissue macrophages, and mast cells) are also found is this layer. ECM: Extracellular matrix.

Figure 2

Pathophysiology of colorectal peritoneal carcinomatosis: the peritoneal metastatic cascade. The emergence of PC is the result of a molecular crosstalk between tumor cells and host elements, comprising several well-defined steps. A: Individual or clumps of tumor cells detach from the primary tumor and gain access to the peritoneal cavity. Spontaneous exfoliation of tumor cells from the primary tumor can be promoted by the down-regulation of E-cadherin, increased interstitial fluid pressure, and iatrogenically during surgery; B: The free tumor cells become susceptible to the regular peritoneal transport. Peritoneal transport is due to changes in the intra-abdominal pressure during respiration, gravity and peristalsis of the bowel; which results in a clockwise flow from the pelvis, along the right paracolic gutter and to the subdiaphragmatic space and finally towards the pelvis again; C: Attachment of tumor cells to distant peritoneum occurs via two processes, denominated transmesothelial and translymphatic metastasis. During transmesothelial metastasis, loose tumor cells directly adhere to distant mesothelium through adhesion molecules. During translymphatic metastasis, free tumor cells gain access to the submesothelial lymphatics through lymphatic stomata. Preferential tumor growth in the milky spots of the greater omentum has been observed; D: Tumor cells invade the submesothelium. In areas of absent or rounded (cuboidal) mesothelial cells, tumor cells interact with the laminar network of the basement membrane through integrin-mediated adhesion. Subsequent invasion of the submesothelial tissue occurs via degradation by proteases (MMPs); E: Systemic metastasis. PC: Peritoneal carcinomatosis.