Abstract
Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabolic impairment, and certain features of prostate cancer (PCa) aggressiveness. AT thromboinflammation, mediated by the proteolytic activation of protease‐activated receptors (PARs) particularly by thrombin and Factor Xa (FXa), drives AT dysfunction. Nevertheless, the contribution of PPAT thromboinflammation to early prostatic neoplastic alterations has not been investigated. Here, we utilized a non‐obese prediabetic rat model to assess prostatic neoplasia in association with PPAT thromboinflammation. Mild hypercaloric diet (MHC)‐fed rats exhibited hyperinsulinemia, hypertriglyceridemia, a lower metabolic efficiency, and a higher fat/lean ratio in comparison to regular chow‐fed rats. When compared to regular chow‐fed rats, MHC‐fed rats exhibited PPAT with larger adipocytes, enhanced oxidative stress and increased immune cell influx. Concurrently, prostates from MHC‐fed rats displayed higher number of prostatic intraepithelial neoplasia (PIN), enhanced expression of the proliferation markers Ki67 and PCNA, enhanced expression of cytokeratin 8 (CK8), pronounced fibrosis and increased immune cell influx. Further profiling of macrophage polarization in PPAT and the prostate is underway. Importantly, these prostatic and adipocytic manifestations were attenuated in MHC‐fed rats treated with non‐hemorrhagic doses of rivaroxaban, a direct FXa inhibitor. Ongoing in vitro investigation demonstrates that rivaroxaban reduces the migratory potential of murine prostate cancer cells (Plum‐AD); and the effect of rivaroxaban on the colony forming and sphere forming capacities of Plum‐AD cells are being studied. Further investigation is ongoing to delineate the molecular underpinnings of rivaroxaban‐associated amelioration of PPAT inflammation and the associated prostatic neoplastic alterations.
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