Molecular biology of peritoneal carcinomatosis

Abstract

Peritoneal carcinomatosis refers to the complex sequence of events by which tumour cells disseminate from their primary organ of origin to establish independent metastatic deposits on the visceral and parietal peritoneal lining of the abdominal cavity. With few exceptions, once peritoneal dissemination occurs the malignant process is deemed non-curative as it is seldom amenable to surgical resection and current chemotherapeutic regimens are merely palliative. An understanding of the molecular events involved in peritoneal carcinomatosis is therefore of paramount importance if we are to advance therapeutic strategies for this devastating form of cancer progression. In order to better understand the events involved in peritoneal carcinomatosis it is necessary to break the process down into a series of steps known as the "peritoneal metastatic cascade". Although this subdivision is analytically useful, it is important to realise that each step in the metastatic cascade does not necessarily occur in isolation, but represents a continuous and interdependent process. Firstly, individual or clumps of tumour cells must break free of the primary tumour mass and gain access to the peritoneal cavity. They are then free to disseminate around the peritoneal cavity, with their ultimate destination being determined by many factors, including gravity, the movement of the abdominal viscera, and the flow of ascitic fluid. The first surface that free tumour cells encounter is the innermost layer of the peritoneum, the mesothelium. The mesothelium forms a cellular monolayer supported by a basement membrane. Adherence of tumour cells to the mesothelium is the second step in the metastatic cascade, which temporarily arrests the tumour cells to their eventual site of metastasis. The third step involves the penetration of the mesothelial monolayer and its basement membrane giving tumour cells access to the submesothelial connective tissue. Invasion of the underlying connective tissue, the fourth step, provides the necessary scaffold for tumour proliferation, and provided tumour-stromal interaction is compatible results in the establishment of a discrete metastatic tumour deposit. The final step involves the induction of angiogenesis to sustain tumour proliferation and enable further metastatic growth The aim of this chapter is to sequentially review each step of the peritoneal metastatic cascade and to highlight the molecular mediators that may be involved.