Tumor Cell-educated Periprostatic Adipose Tissue Acquires an Aggressive Cancer-promoting Secretory Profile

Abstract

Background/Aims: The microenvironment produces important factors that are crucial to prostate cancer (PCa) progression. However, the extent to which the cancer cells stimulate periprostatic adipose tissue (PPAT) to produce these proteins is largely unknown. Our purpose was to determine whether PCa cell-derived factors influence PPAT metabolic activity. Methods: Primary cultures of human PPAT samples from PCa patients (adipose tissue organotypic explants and primary stromal vascular fraction, SVF) were stimulated with conditioned medium (CM) collected from prostate carcinoma (PC3) cells. Cultures without CM were used as control. We used multiplex analysis and ELISA for protein quantification, qPCR to determine mitochondrial DNA (mtDNA) copy number and zymography for matrix metalloproteinase activity, in order to evaluate the response of adipose tissue explants and SVFs to PC3 CM. Results: Stimulation of PPAT explants with PCa PC3 CM induced adipokines associated with cancer progression (osteopontin, tumoral necrosis factor alpha and interleukin-6) and reduced the expression of the protective adipokine adiponectin. Notably, osteopontin protein expression was 13-fold upregulated. Matrix metalloproteinase 9 activity and mitochondrial DNA copy number were higher after stimulation with cancer CM. Stromovascular cells from PPAT in culture were not influenced by tumor-derived factors. Conclusion: The modulation of adipokine expression by tumor CM indicates the pervasive extent to which tumor cells command PPAT to produce factors favorable to their aggressiveness.

Human Periprostatic Adipose Tissue: its Influence on Prostate Cancer Cells

“…Particularly, PCa microenvironment maybe influenced by PPAT and could affect tumorigenesis and possibly even aggressiveness' [8]. For example, the regulation of adipokine expression by tumor CM indicates to what extent tumor cells are capable of inducing PPAT to produce factors that could favor their aggressiveness [9].…”

“…Finley et al [8] screened cj^okines and growth factors, such as IL-6, in conditioned medium of PPAT from PCa patients; Ribeiro et al [9] determined that PCa cell derived factors influence PPAT metabolic activity in patients with PCa. However, up to date, no study has compared the role of PPAT in patients with benign prostatic hyperplasia (BPH) and PCa patients.…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Moreover, in prostate cancer, gene expression signatures are different in tumours from obese versus lean cohorts [69]. Cultured media from prostate cancer cells stimulated adipokine production (osteopontin, TNF-/, and IL-6) from periprostatic adipose tissue, which in turn promoted tumour proliferation and invasiveness [70]. In oesophageal cancer, cells co-cultured with fat from viscerally obese patients showed differential gene expression, including genes associated with EMT [71].…”

Fat and Lipid Partitioning: Phenotyping Beyond BMI

“…Recent findings also suggest the involvement of periprostatic adipose tissue in prostate cancer progression [63], and of bone marrow adipose tissue in hematopoiesis regulation and in the pathophysiology of myeloma and bone metastases [64].…”