Endocrine Abstracts

JOINT1904

Prostate cancer (PCa) is a hormone-dependent tumor and one of the most prevalent cancers in men worldwide. PCa progression is influenced by its interaction with the surrounding tumor-microenvironment, highlighting the role of periprostatic adipose tissue (PPAT), which is a mediator of PCa microenvironmental regulation through the secretion of bioactive molecules (e. g., adipokines). Yet, the nature/influence of this complex secretion derived from PPATs remains to be fully elucidated. Herein, we investigated the potential dysregulation of the expression and secretion profile of PPAT adipokines in PCa patients. Specifically, by integrating transcriptomic (on PPATs) as well as proteomic and metabolomic (in PPAT-secretome) approaches on a well-characterized cohort of PPAT-samples [75 PCa-patients vs 22 benign-prostate-hyperplasia (BPH) control-subjects], we identified a significant signature of dysregulated adipokines in PCa patients. Subsequent unsupervised clustering analyses allowed the identification of two distinct molecular phenotypes of PCa patients with a unique fingerprint of alterations in adipokines (T1 and T2) that presented distinctive clinical-metabolic alterations (i. e., BMI, diabetes, and dyslipidemia), being lipocalin-2 (LCN2) the only adipokine showing consistent differences at transcriptomic- and proteomic-levels. Functional approaches in different prostate cell models [normal-like (PNT2) and PCa (DU145, LnCaP and 22Rv1)] revealed that exogenous LCN2 treatment did not alter proliferation, apoptosis, or colony formation in any of the prostate cell models, but migration was significantly increased in PNT2 and decreased in DU145, wherein a differential expression profile of LCN2 receptors (especially SLC22A17), may directly contribute to this differential effects observed across cell models. Molecularly, LCN2 treatment was associated with alteration in critical oncogenic/metabolic-pathways, including neutrophil-degranulation, inflammation, and autophagy, suggesting a connection with the inflammasomes. Further analyses revealed a weight-dependent association pattern between LCN2 and individual inflammasome components. Additionally, arachidonic acid (prostaglandin precursor) in PPAT-secretome positively correlated with LCN2 levels specifically in the obese PCa-patients, suggesting a metabolic link to LCN2-mediated effects. Our findings highlight LCN2 as a potential key player in the interaction between PPAT, obesity and PCa-microenvironment, with a potential influence on inflammation and tumor cell behavior.