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

Abstract

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 β 1 integrin chain under the influence of simvastatin 0.1-100 µM for 24-72 h 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 β 1 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 α 4 β 1 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.

Carcinoma‐associated fibroblasts derive from mesothelial cells via mesothelial‐to‐mesenchymal transition in peritoneal metastasis

“…SEM analysis reveals that the enhanced adhesion of tumour cells to mesenchymal MCs is not due to a mere exposure of underlying matrix but rather to an increased cell–cell interaction. The tumour cell–mesothelium interaction is mediated, at least in part, by β 1‐integrins , which could reflect that cancer cells bind to mesothelium‐associated ECM and/or to the MC adhesion molecule VCAM‐1 . In agreement with this notion, it has been described that cleavage of MC‐associated matrix proteins fibronectin and vitronectin by MMP‐2 enhances integrin‐mediated carcinoma–mesothelium attachment .…”

Ovarian tumour growth is characterized by mevalonate pathway gene signature in an orthotopic, syngeneic model of epithelial ovarian cancer

“…Retrospective analysis of statin use in ovarian cancer [50, 51], endometrial cancer [51], gliomas [52], colorectal cancer [53], hepatocellular cancer [54], and prostate cancer [55] reveal reduced overall mortality, suggesting that statin therapy may have a protective effect against some cancers. Studies have shown that statins can affect multiple stages of ovarian cancer progression including: metastasis [56, 57], chemoresistance [58], and cytotoxicity [31, 32, 59, 60]. Treating ovarian cancer cells with statins and inhibitors of RhoA resulted in decreased cell dissemination in a NUDE mouse model of ovarian cancer [57].…”

Statins and Colorectal Cancer – A Systematic Review

“…Wagner et al analyzed the effect of simvastatin on colon cancer metastases to the peritoneum. Adhesion to mesothelial cells was significantly reduced by 10 µM simvastatin (P < 0.01) without any change in the expression of adhesion molecules [33].…”