Possible Inhibition of Cancer Cell Adhesion to the Extracellular Matrix in NK4-induced Suppression of Peritoneal Implantation

Milky spots (MS), peritoneal lymphoid tissues, expose the extracellular matrix (ECM) due to a defect of mesothelial cells on their surface, which may explain why peritoneal implantation of cancer cells preferentially takes place at MS. We recently reported that adenovirus vector-mediated intraperitoneal production of NK4 strongly suppressed MS- selective implantation of cancer cells and subsequent peritoneal dissemination, without histological evidence of angiogenesis inhibition. The present study was conducted to clarify the mechanisms underlying the suppressive effects of NK4 on peritoneal implantation. In mice intraperitoneally injected with CT26 cells that were genetically modified to produce NK4 (CT26-NK4), peritoneal dissemination was significantly suppressed with survival prolongation. A decreased cell implantation to omental MS was also detected and evaluated by green fluorescence protein (GFP) imaging. In an in vitro adhesion assay, hepatocyte growth factor-stimulated adhesion to ECM components, such as fibronectin and collagen, was inhibited in CT26-NK4 compared to control cells. These results strongly suggest an inhibition of cancer cell adhesion to the ECM in the suppression of peritoneal implantation by NK4.