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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ACM (Cholesterol metabolism as a driver of prostate cancer aggressiveness)

Teaser

Summary

Metabolic syndrome, obesity, and high cholesterol levels have been shown to increase the risk of prostate cancer, one of the malignancies with the highest incidence among man in Europe. However, the data relating cholesterol and prostate cancer is yet controversial and the extent of increased risk varies among studies. This notion is in agreement with the fact that tumour cells reprogram their utilization and biosynthesis of cholesterol, which is frequently elevated in obese individuals. In order to better understand the contribution of obesity to the biology of prostate cancer, we took advantage of genetic mouse models of the disease.

We hypothesized that cholesterol could be a contributing factor to the effect of obesity on prostate cancer pathogenesis. As proof-of-concept, we tested whether anti-cholesterolemic treatment would hamper prostate cancer in the context of obesity. For that we chose one the most commonly used anticholesterolemic drugs, simvastatin. Unexpectedly, simvastatin treatment did not reduce the phenotype, but instead we observed full blown prostate cancer lesions emerging. Next, we evaluated the effect of anticholesterolemic treatment in the absence of obesity and the results also indicated that simvastatin increased prostate cancer therapy resistance and accelerated its appearance.

Moreover, in collaborations with clinicians, we showed that certain subgroup of patients could increase the incidence of prostate cancer when treated with statins.
These results are very relevant socially because although the epidemiological studies didnâ€™t show that statins in general increased the risk to any cancer. However, our results might be uncovering an undesired effect of this treatment on an unknown group of man. For that reason, our objectives are to keep investigating in the mechanisms of this phenomenon to clarify the possible risk of these drugs on the general population.

Work performed

We explored the metabolism of a subpopulation of cancer cells, which led us to discover that prostate cancer were very dependent on cholesterol metabolism. This made us hypothesized that inhibition of cholesterol metabolism with the commonly used drugs statins would be an interesting therapeutic approach. However, unexpectedly, we discovered that treatment of mice susceptible to cancer prostate with statins increased prostate cancer incidence and resistance to castration. Then, we reproduced these results treating prostate cancer cell lines with low doses of simvastatin. Simvastatin pretreated cells formed more colonies, and became more metastatic.

Then we contacted clinicians to validate epidemiologically our data.

Final results

These results are very relevant socially because although the epidemiological studies didnâ€™t show that statins in general increased the risk to any cancer. However, our results might be uncovering an undesired effect of this treatment on an unknown group of man. For that reason, our objectives are to keep investigating in the mechanisms of this phenomenon to clarify the possible risk of these drugs on the general population.