Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin

Abstract

Peritoneal carcinomatosis describes cancer metastasis onto the surface of the peritoneum. It is frequently caused by ovarian and colorectal cancer. Once a tumor has penetrated the peritoneum, cancer cells disseminate into the abdominal cavity. Additionally, surgery can account for the spread of free tumor cells. Their subsequent adhesion to mesothelial cells (HMCs) initiates peritoneal carcinomatosis. Therefore, this study analyzed the effect of simvastatin on tumor cell adherence. HMCs were isolated from human greater omentum. Fluorescence-labeled tumor cells (SKOV-3, OvCar-29, OAW42, FraWü; ovarian/HT29; colorectal) were incubated on confluent mesothelial monolayers with 10 µM simvastatin for 48 h. Adhesion was quantified using a fluorescence reader. Expression of the adhesion molecules VCAM-1, ICAM-1 and β1 integrin chain under the influence of simvastatin 0.1-100 µM for 24-72h was analyzed using flow cytometry. Simvastatin significantly reduced the adhesion of all ovarian cancer cells and HT29 to HMCs (P≤0.001). Concomitantly simvastatin decreased the expression of VCAM-1 on HMCs. ICAM-1 and β1 integrin chain expression on ovarian cancer cells was also clearly reduced. By contrast, the expression of the analyzed adhesion molecules on HT29 cells remained unchanged. Simvastatin clearly inhibits tumor cell adhesion to HMCs. In the case of ovarian cancer cell lines it appears to be mediated by decreased expression of both VCAM-1 on HMCs and the integrin α4β1 on tumor cells. As an example of adhesion molecule down-regulating drugs, simvastatin may provide a novel therapeutic approach to the prevention of peritoneal carcinomatosis.