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

Abstract

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 endothelial cells (MVEC). The purpose of our study was to investigate the biological effects of an LDL-enriched milieu and the effects of the anticholesterol drug Lovastatin on metastatic behavior. The SW480 and SW620 are primary and 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 endothelial monolayers. Adhesion and migration assays were done before and after pretreatment of the MVEC or tumor cells with LDL (100 microg/ml) for 24 h. Although 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 pretreatment of the tumor cells with LDL. Lovastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. It has been shown to have anti-tumor activity in vitro. We investigated the effect of Lovastatin on tumor cell kinetics and tumor cell migration across MVEC. Growth curves and migration assays were done before and after pretreatment of the tumor cells with Lovastatin (30 microg/ml). Migration assays were also done after treatment of unstimulated or LDL-stimulated MVEC (100 microg/ml) for 24 h with Lovastatin. Lovastatin inhibited the in vitro growth of the metastatic SW620 cell line to a greater extent than the invasive SW480E cell line. On the other hand, pretreatment of tumor cells with Lovastatin (30 microg/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.

Serum Lipid Profile in Colorectal Cancer Patients with and without Synchronous Distant Metastases

“…Moreover, drugs that inhibit endogenous cholesterol synthesis, i.e. lovastatin or simvastatin, show antimetastatic effects on colon, pancreatic and melanoma cancer cells in vitro and in vivo[ 12, 18, 24, 25]. Moreover, in addition to its greater growth-inhibitory effect on metastatic cancer cells, lovastatin appears to universally reduce transendothelial migration by acting on tumor cells, quiescent endothelial cells and LDL-stimulated cells [12].…”

“…Moreover, experimental evidence of tumor cell accumulation in lesions caused by endothelial inflammation and injury has suggested an increased incidence of metastases in patients with increased LDL-C levels [11]. In addition, recent studies showed that lovastatin, an 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, has antimetastatic effects on human colon adenocarcinoma cell lines as well as other cell lines [12]. …”

The Role of Statins in Cancer Therapy

“…Similarly, atorvastatin has been shown to decrease melanoma cell metastasis [86]. Statins have also been shown to suppress lung metastasis of renal and mammary carcinoma cells [87,88], as well as liver metastasis of colon adenocarcinoma cells [85,89]. However, not all studies have confirmed that statins reduce tumor metastases.…”

“…However, not all studies have confirmed that statins reduce tumor metastases. For example, lovastatin failed to inhibit colon carcinoma and glioblastoma cell migration and invasion [89].…”

Inhibition of <i>ras</i> Oncogene: A Novel Approach to Antineoplastic Therapy

“…An important advantage of LOV is illustrated by in vivo experiments demonstrating its antimetastatic effect. Treatment with LOV induced a decrease or a complete elimination of metastatic growth in different tumor models: xenogeneic with melanoma cells [25], allogeneic with a fibrosarcoma [34] and syngeneic with colon carcinomas [35], mammary adenocarcinoma [2] or lymphoma [33]. Similarly to FT inhibitors, LOV can inhibit tumor cell proliferation, even in those cells with nonmutated ras oncogenes, suggesting its effect on alternative cellular pathways [49].…”