Abstract
In this project we examined how the presence of human peritoneal mesothelial cells (HPMCs) modifies (supports or inhibits) colorectal and pancreatic cancer cell progression in mice peritoneal cavity. Experiments were performed using primary, omentum-derived HPMCs, commercially available colorectal (SW-480) and pancreatic (PSN-1) cancer cells, and immunocompromised SCID mice. Tumor growth within the peritoneal cavity was monitored using bioluminescence. Adhesion of the cancer cells to HPMCs was examined using a fluorescence-based method, while the incidence of apoptosis was quantified using flow cytometry. Experiments showed that SW480 and PSN-1 cells formed tumors in vivo at higher efficiency when they were injected alone than in the presence of HPMCs. In vitro investigations confirmed that firm adhesion of SW480 and PSN-1 cells to HPMCs is mediated by interactions between ICAM-1 and CD43. They also revealed that IL-6 and TNFα up-regulate the expression of cell-bound ICAM-1 and the secretion of soluble ICAM-1 (sICAM-1). The basal release of sICAM-1 by HPMCs positively correlated with the expression of the cell-bound molecule. sICAM-1 inhibited dose-dependently the adhesion of SW480 and PSN-1 cells to HPMCs. Cancer cells that did not adhere to HPMCs displayed increased activity of caspase-3 and -9, increased incidence of apoptosis, and an inability to re-adhesion, as compared with their intact counterparts not exposed to sICAM-1. Our findings indicate that under certain conditions HPMCs are capable of inhibiting growth of gastrointestinal tumors in a mechanism involving the anti-adhesive capabilities of sICAM-1.