Low density lipoproteins and Lovastatin modulate the organ-specific transendothelial migration of primary and metastatic human colon adenocarcinoma cell lines in vitro

Tumor cell arrest and tumor migration are two of the critical steps in the metastatic cascade. We hypothesized that these steps may be facilitated by the low density lipoprotein (LDL)-induced activation of microvessel endothe lial cells (MVEC), The purpose of our study was to investigate the biologic al effects of an LDL-enriched milieu and the effects of the anticholesterol drug Lovastatin on metastatic behavior. The SW480 and SW620 are primary an d metastatic human colonic adenocarcinoma cell lines derived from the same patient. We investigated the effect of LDL on adhesion and migration of the two tumor cell lines across human brain, lung, liver and dermal endothelia l monolayers, Adhesion and migration assays were done before and after pret reatment of the MVEC or tumor cells with LDL (100 mu g/ml) for 24 h, Althou gh metastatic SW620 cells were more adherent to MVEC compared with primary SW480 cells, LDL pretreatment of SW480 and SW620 cells did not affect tumor cell adhesion to MVEC, In contrast, tumor cell migration was significantly increased across endothelial monolayers when MVEC were pretreated with LDL , Transendothelial cell migration was not significantly affected by pretrea tment of the tumor cells with LDL, Lovastatin is an inhibitor of HMG-CoA re ductase, the rate-limiting enzyme in cholesterol biosynthesis. It has been shown to have anti-tumor activity in vitro. We investigated the effect of L ovastatin on tumor cell kinetics and tumor cell migration across MVEC, Grow th curves and migration assays were done before and after pretreatment of t he tumor cells with Lovastatin (30 mu g/ml). Migration assays were also don e after treatment of unstimulated or LDL-stimulated MVEC (100 mu g/ml) for 24 h with Lovastatin, Lovastatin inhibited the in vitro growth of the metas tatic SW620 cell line to a greater extent than the invasive SW480E cell lin e. On the other hand, pretreatment of tumor cells with Lovastatin (30 mu g/ ml) did not suppress transendothelial tumor cell migration of tumor cells, Finally, Lovastatin given to mice effectively suppressed the number of MCA- 26 tumor colonies in the liver of Balb/c mice compared with untreated mice.