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Insulin signaling, androgen receptor and PSMA immunohistochemical analysis by semi-automated tissue microarray in prostate cancer with diabetes (DIAMOND study)

      In the last years, many studies have highlighted the hypothesis that diabetes and hyperglycemia could be relevant for prostate cancer (PC) development and progression. We aimed to identify the prognostic value of tissue expression of androgen receptor (AR), Prostate-Specific Membrane Antigen (PSMA), Ki-67, insulin receptors (IR)  α and β, insulin growth factor-1 (IGF-1) receptor, in patients with PC and to evaluate their association with diabetes. We retrospectively collected data from 360 patients who underwent radical prostatectomy for PC or surgery for benign prostatic hyperplasia (BPH), between 2010 and 2020. We constructed tissue microarray for immunohistochemistry (IHC) analysis. In the final cohort (76 BPH and 284 PC), 57 (15.8%) patients had diabetes, 17 (22.37%) in BPH and 40 (14.08%) in PC (P = 0.08). IR-α was more expressed in patients with PC compared to the BPH Group (95.96% vs 4.04%; P <0.01). We found that AR was associated with increased risk of International Society of Urological Pathology (ISUP) score ≥4 (OR: 2.2; P <0.05), higher association with Ki-67 (OR: 2.2; P <0.05) and IR-α (OR: 5.7; P <0.05); IGF-1 receptor was associated with PSMA (OR: 2.8; P <0.05), Ki-67 (OR: 3.5; P <0.05) and IR-β (OR: 5.1; P <0.05). Finally, IGF-1 receptor was predictive of ISUP ≥ 4 (OR: 16.5; P =0.017) in patients with PC and diabetes. In the present study we highlighted how prostate cancer patients have a different protein expression in the tissue. This expression, and in particular that relating to IGF-1R, is associated with greater tumor aggressiveness in those patients with diabetes. We suppose that these results are attributable to an alteration of the insulin signal which therefore determines a greater mitogenic activity that can influence tumor progression.
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