Metastatic organotropism in peritoneal metastasis: Paget’s hypothesis revisited

Peritoneal metastasis (PM) of solid tumours is a major contributor to cancer-associated mortality and morbidity. The mechanism of PM development encapsulates Paget’s hypothesis of seed and soil, whereby cancer cells remotely prepare a pre-metastatic niche in the peritoneal microenvironment to facilitate transcoelomic cancer progression. The bidirectional communication between cancer cells and host mesothelial cells, endothelial cells, leukocytes, adipocytes, and fibroblasts occurs via exosomes. Exosomes are nano-sized extracellular vesicles that carry cargos of proteins, cytokines, and microRNA. Cancer-derived exosomes enable exfoliated tumour cells to resist anoikis, disseminate, adhere, and implant in the peritoneum. This process involves the degradation of the peritoneal glycocalyx, the transformation of peritoneal mesothelial cells into cancer-associated fibroblasts via mesothelial-mesenchymal transition, and metabolic coupling with omental and subperitoneal adipocytes. Exosomes also enhance ascites and peritoneal immunosuppression. Exosomes promote PM development from mesenchymal subtypes of epithelial cancers, which have a predilection for transcoelomic metastasis compared to other molecular subtypes. Mesenchymal subtypes include diffuse gastric cancer, CMS4 colorectal cancer, and high-grade serous ovarian carcinoma. Understanding the oncogenic roles of exosomal cargo offers potential for future research and therapy in PM.