Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue

Abstract

Background: Periprostatic (PP) adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW) and prostate cancer patients.

Methods: Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean) and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia). Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA) was used to investigate gene ontology, canonical pathways and functional networks.

Results: In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated). Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis), whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH). Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients.

Conclusions: Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for prostate cancer progression.

Figure 1

Reverse transcription PCR analysis of PCA3 in PP adipose tissue samples. GR, gene ruler 100 bp; (+) positive control (prostate tumor sample); (-) negative control (without cDNA); 1-to-6, periprostatic adipose tissue samples of patients with extra prostatic cancer.

Figure 2

Validation of selected genes by real-time PCR. BPH, benign prostatic hyperplasia; EPCa, extra prostatic cancer (≥pT3); Lean (BMI <25 kg/m²); OB/OW, obese/overweight (BMI ≥25 kg/m²). ANGPT1, angiopoietin 1; CFH, complement factor H; CLDN10, claudin 10; FAS, fatty acid desaturase; LEP, leptin; MIRLET7A2, microRNA let-7a-2. The gene expression in lean subjects or BHP was assumed to be 1. *P <0.05 versus lean or BPH groups.

Figure 3

Schematic summary diagram of PP adipose tissue changes in obese/overweight. Genes with altered expression are associated with the regulation of functional biological processes. Altered function likely results in chronic mild immunoinflammatory response and fat mass expansion, which ultimately impacts on prostate cancer progression. Down-regulated genes are depicted in green while up-regulated genes are shown in red. ASCs, adipose-derived stem cells; E-M-T, epithelial-to-mesenchymal transition.

Figure 4

Schematic summary diagram of changes in PP adipose tissue of patients with prostate cancer. Periprostatic adipose tissue of patients bearing prostate cancer likely reveals the interactions between tumor cells and adipose tissue cells. The functional repercussions of altered genes in patients with prostate cancer prompt PP adipose tissue to increased hypercellularity and decreased immunosurveillance. The resulting influence of this favorable microenvironment is to foster prostate cancer progression. Down-regulated genes are depicted in green while up-regulated genes are shown in red. ASCs, adipose-derived stem cells.