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

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and often is not detected until late stages when cancer cells transcoelomically metastasize to the abdomen and typically become resistant to therapy resulting in very low survival rates. We utilize an orthotopic, syngeneic mouse model to study late stage disease and have discovered that the tumor cells within the abdominal ascites are irreversibly re-programmed, with an increased tumorigenicity and resistance to apoptosis. The goal of this study was to characterize the reprogramming that occurred in the aggressive ascites-derived cells (28-2 cells) compared to the original cell line used for tumor induction (ID8 cells). Microarray experiments showed that the majority of genes upregulated in the 28-2 cells belonged to the mevalonate pathway, which is involved in cholesterol biosynthesis, protein prenylation, and activation of small GTPases. Upregulation of mevalonate appeared to be associated with the acquisition of a p53 mutation in the ascites-derived cells. Treatment with simvastatin to inhibit HMG CoA reductase, the rate limiting enzyme of this pathway, induced apoptosis in the 28-2 cell line. Rescue experiments revealed that mevalonate, but not cholesterol, could inhibit the simvastatin-mediated effects. In vivo, daily intraperitoneal simvastatin treatment significantly regressed advanced stage disease and induced death of metastatic tumor cells. These data suggest that ovarian cancer cells become reprogrammed, with genetic mutations, and upregulation of the mevalonate pathway, which facilitates the development of advanced stage disease. The use of statins to inhibit HMGCR may provide novel therapeutic opportunities for the treatment of advanced stage EOC.

Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer

“…Statins have been shown to have antiproliferative and anti-invasive properties in cell lines and animal models of ovarian cancer. [4][5][6] A metaanalysis of 5 observational studies with 624 ovarian cancer cases reported that statin use was significantly associated with a lower risk of ovarian cancer (relative risk, 0.79 [95% CI, 0.64-0.98]) with no significant evidence of heterogeneity across studies (P value for heterogeneity = 0.67; I 2 = 0.0%). 8 Two sub-sequent case-control studies yielded conflicting findings; a Danish registry-based analysis of 4103 individuals with epithelial ovarian cancer and 58 706 control individuals reported no significant evidence of an association between ever use of statins and cancer risk (OR, 0.98 [95% CI, 0.87-1.10]), but an analysis of the New England Case Control study (2040 individuals with epithelial ovarian cancer and 2100 control individuals) showed a significantly lower odds of ovarian cancer in women who self-reported statin use compared with nonusers (OR, 0.68 [95% CI, 0.54-0.85]).…”

“…3 Laboratory studies have shown that statins can induce apoptosis and inhibit tumor proliferation, invasion, and metastasis. [4][5][6] Observational studies have reported lower rates of ovarian cancer among statin users compared with nonusers. 7,8 However, the clinical relevance of these findings is unclear because of the unknown generalizability of preclinical studies to humans and the susceptibility of conventional observational analyses to residual confounding and other biases.…”

Simvastatin interferes with cancer ‘stem-cell’ plasticity reducing metastasis in ovarian cancer

“…Additionally, new evidence suggests that mut-TP53 is associated with cancer metastasis (Hu et al 2013). Along with changes in TP53 functions, HGS-ovCs seem to acquire a mevalonate pathway gene signature that prompts tumor growth and metastasis (Hu et al 2013, Greenaway et al 2016. This signature is a consequence of metabolic re-programming, an evolutionary adaptation to satisfy the demand of lipid arising from fast dividing and moving HGS-ovC cells (Baenke et al 2013).…”

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer

“…We have shown that lovastatin has an inhibitory effect on growth of ovarian cancer cells in vitro , and antitumor effects such as delayed tumorigenesis and suppression of tumor progression in vivo [ 11 ]. It was also reported that simvastatin inhibited tumor growth in the syngeneic model and reduced cell migration in vitro, resulted to exhibit anti-metastatic and anti-tumorigenic effects in ovarian cancer [ 12 , 13 ]. In this study, we focused on the potentially important role of the mevalonate pathway in progression of ovarian cancer.…”