Androgen deprivation therapy promotes an obesity-like microenvironment in periprostatic fat

Abstract

Prostate cancer is a leading cause of morbidity and cancer-related death worldwide. Androgen deprivation therapy (ADT) is the cornerstone of management for advanced disease. The use of these therapies is associated with multiple side effects, including metabolic syndrome and truncal obesity. At the same time, obesity has been associated with both prostate cancer development and disease progression, linked to its effects on chronic inflammation at a tissue level. The connection between ADT, obesity, inflammation and prostate cancer progression is well established in clinical settings; however, an understanding of the changes in adipose tissue at the molecular level induced by castration therapies is missing. Here, we investigated the transcriptional changes in periprostatic fat tissue induced by profound ADT in a group of patients with high-risk tumours compared to a matching untreated cohort. We find that the deprivation of androgen is associated with a pro-inflammatory and obesity-like adipose tissue microenvironment. This study suggests that the beneficial effect of therapies based on androgen deprivation may be partially counteracted by metabolic and inflammatory side effects in the adipose tissue surrounding the prostate.

Dissection of prostate tumour, stroma and immune transcriptional components reveals a key contribution of the microenvironment for disease progression

“…This algorithm used a collection of 250 curated publicly available transcriptional profiles (including BLUEPRINT [70], ENCODE [71], GSE89442 [72] and GSE107011 [73]), encompassing transcriptional signatures for 18 hierarchical cell-types (of which nine major cell types were tested for differences) and used those reference signatures to understand the contribution of each cell type to the observed mixed transcriptional signal. This analysis provides tissue composition estimates as well as their association with risk score [69]. Overall, we estimated a median of 88% for epithelial cellular fraction across samples (consistent with public literature [74], Fig.…”

“…a test for difference in cell-type abundance between conditions) based on an independent methodology and independent data. We used a hierarchical Bayesian inference model [69] on an independent cohort of 134 patients from the primary prostate cancer TCGA dataset [7] that included both disease-free survival and CAPRA-S score information. This algorithm used a collection of 250 curated publicly available transcriptional profiles (including BLUEPRINT [70], ENCODE [71], GSE89442 [72] and GSE107011 [73]), encompassing transcriptional signatures for 18 hierarchical cell-types (of which nine major cell types were tested for differences) and used those reference signatures to understand the contribution of each cell type to the observed mixed transcriptional signal.…”

Prostate carcinogenesis: inflammatory storms

“…The GI microbiota, diet, and obesity are all inter-related and have been implicated in the development of aggressive PCa with diet likely altering the microbiome 9,[42][43][44][45][46][47] . Some epidemiologic data link diets high in red meat, charred meat, and saturated fats with the development of PCa 9,10,42 .…”

“…Nevertheless, a growing number of preclinical studies and studies of human prostate tumour samples provide mechanistic insights into the links between adiposity and PCa. These appear to be underscored by metabolic, hormonal and inflammatory processes 44,[52][53][54][55][56][57] . Whilst testosterone levels are decreased in obese and castrate men, adipocytes produce steroid hormones that can activate androgen receptor (AR) or glucocorticoid receptor signaling that can fuel PCa growth 57,58 .…”

“…Interestingly, a clinical study of periprostatic fat collected after neoadjuvant ADT reported induction of a pro-inflammatory transcriptional program in peri-prostatic adipocytes. This included upregulated IL-6/JAK/STAT signalling, CXCL10, myeloid cell nuclear differentiation antigen, toll-like receptor 8 (TLR8), interferon-gamma (IFN-γ), and interferon-alpha (IFN-α) 44 . Some of these cytokines stimulate adaptive immunity; the overall impact of these factors on PCa cell survival needs further study.…”