Pathophysiology and biology of peritoneal carcinomatosis

Abstract

Peritoneal carcinomatosis represents a devastating form of cancer progression with a very poor prognosis. Its complex pathogenesis is represented by a dynamic process comprising several steps. To the best of our knowledge pathogenesis can be partly explained by 3 major molecular pathways: (1) dissemination from the primary tumor; (2) primary tumor of peritoneum; and (3) independent origins of the primary tumor and peritoneal implants. These are not mutually exclusive and combinations of different mechanisms could occur inside a single case. There are still several aspects which need explanation by future studies. A comprehensive understanding of molecular events involved in peritoneal carcinomatosis is of paramount importance and should be systematically pursued not only to identify novel strategies for the prevention of the condition, but also to obtain therapeutic advances, through the identification of surrogate markers of prognosis and development of future molecular targeted therapies.

Update on Colorectal Carcinomatosis—From Molecular Biology to Diagnosis and Management

“…Presently, our understanding of the molecular events involved in PC is ill-understood [6], future knowledge will permit not only identify novel strategies for PC prevention, but also contribute to therapeutic advances, through the development of molecular targeted therapies [7]. The development of PC involves a complex sequence of continuous and interdependent steps [8][9][10], known as the "peritoneal metastatic cascade" [6]; including cell shedding and transport, adhesion to the mesothelial layer, invasion and proliferation into the submesothelial stroma, and potential access to the systemic circulation [9,10].…”

“…In the Peritoneal Tumour Dissemination step, the tumour cells are release from the primary tumour and gain access to the peritoneal cavity [6,7]. This can occur by several mechanisms namely, spontaneous exfoliation of tumour cells from the primary tumour, by iatrogenic or spontaneous perforation of the primary tumour or from transected lymphatics and blood vessels during tumour surgical resection [7].…”

“…This can occur by several mechanisms namely, spontaneous exfoliation of tumour cells from the primary tumour, by iatrogenic or spontaneous perforation of the primary tumour or from transected lymphatics and blood vessels during tumour surgical resection [7]. After this, cancer cells are seeded in the peritoneal cavity and factors like gravity, peristaltic abdominal viscera movement and the flow of ascitic fluid resulting from the negative pressure exerted by diaphragm movements, contribute for the final destination of tumour cells, that adheres to the mesotelium, in the Mesothelial Adhesion step, and then can penetrate the mesothelial layer, gaining access to the submesothelial connective tissue, in the Mesothelial Invasion step, and then invading the underlying connective tissue; this environment provides the necessary scaffold for tumour proliferation that result in the establishment of metastatic tumour deposit, in the Stromal Invasion and Proliferation step.…”

“…After this, cancer cells are seeded in the peritoneal cavity and factors like gravity, peristaltic abdominal viscera movement and the flow of ascitic fluid resulting from the negative pressure exerted by diaphragm movements, contribute for the final destination of tumour cells, that adheres to the mesotelium, in the Mesothelial Adhesion step, and then can penetrate the mesothelial layer, gaining access to the submesothelial connective tissue, in the Mesothelial Invasion step, and then invading the underlying connective tissue; this environment provides the necessary scaffold for tumour proliferation that result in the establishment of metastatic tumour deposit, in the Stromal Invasion and Proliferation step. The final step involves the Induction of Angiogenesis to sustain tumour proliferation and enable further metastatic growth [6,7].…”

“…In the Peritoneal Tumour Dissemination step, the detachment of cells from the primary tumour, can be mediated by the down-regulation of intercellular adhesion molecules on the tumor cell surface, E-cadherin, namely type I cadherins [7,8,11]. Next, free tumour cells invades the subperitoneal tissue, through matrix metalloproteinases (MMPs), such MMP-7, and directly attach to the submesothelial barrier connective tissue [through interaction with integrins, selectins and CD44, a lymphocyte homing molecules], in the Mesothelial Adhesion step [7,8,11].…”