Individual Comparison of Cholesterol Metabolism in Normal and Tumour Areas in Radical Prostatectomy Specimens from Patients with Prostate Cancer: Results of the CHOMECAP Study.

International audienceBACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7alpha-hydroxycholesterol (OHC), 7betaOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders

Persistent organic pollutants promote aggressiveness in prostate cancer

International audienc