Utilidad de la expresión de Ki67 en las biopsias preoperatorias para predecir la recidiva bioquímica del cáncer de próstata después de la prostatectomía radical

Background Apalutamide (APA) is a next-generation androgen receptor antagonist for the treatment of advanced prostate cancer. We have previously shown that upregulation of autophagy is one of the mechanisms by which prostate cancer (PC) cells survive APA anti-tumor treatment in vitro. Therefore, we investigated the characteristics of the autophagic response to APA treatment, alone and in combination with autophagy inhibition, in an in vivo model. Methods Tumor cells were injected into previously castrated nude mice. Four groups of mice bearing LNCaP xenografts were treated with daily intraperitoneal (i.p.) injections of vehicle (control), APA (10 mg/kg), APA (10 mg/kg) + Chl (Chloroquine, 10 mg/kg) or Chl (10 mg/kg). The animals of each treatment group (3/treatment) were kept for the duration of 2 and 3 weeks. At the end of the experiments, the animals were sacrificed and all samples assessed for tumor weight and size, histological analysis, immunoblotting (WES) and immunofluorescence. Results The tumor weight was significantly reduced in mice treated with APA + Chl (203.2 ± 5.0, SEM, P = 0.0066) compared to vehicle control (380.4 ± 37.0). Importantly, the combined treatment showed a higher impact on tumor weight than APA (320.4 ± 45.5) or Chl (337.9 ± 35) alone. The mice treated with the combination of APA + Chl exhibited a reduced expression of ATG5 (autophagy-related five protein), Beclin 1 and LC3 punctuations and an increase in P62 as visualized by immunofluorescence and WES. In addition, Ki-67 nuclear staining was detected in all samples however reduced in APA + Chl (58%) compared to vehicle control (100%). The reduction in Ki-67 protein was associated with an increase in caspase 3 and endothelial CD31 protein expression. Conclusion These data demonstrate that a treatment with APA + Chl leads to reduced autophagy levels and to tumor suppression compared to the APA monotherapy. Hence, the increased antitumor effect of APA in combination with autophagy inhibitors might provide a new therapeutic approach potentially translatable to patients.

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Expression of p27(Kip1), cyclin D3 and Ki67 in BPH, prostate cancer and hormone-treated prostate cancer cells

Nikoleishvili

Pertia

Trsintsadze

et al. 2008

Int Urol Nephrol

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p27((Kip1)), cyclin D3 and Ki67 are the markers of DNA damage and cell proliferation. The goal of the current study was to analyze expression of the markers in benign and malignant prostate cancer tissues. Activity of p27((Kip1)), cyclin D3 and Ki67 was immunohistochemically evaluated in different cells of BPH, prostate cancer (PCa) and hormonally treated prostate cancer (HTPCa) tissues. The tissue samples were derived by means of TURP or radical prostatectomy. Intensity of the expression was compared between the groups, and association was sought with clinical parameters. Total expression of p27((Kip1)) was significantly higher in BPH as compared with PCa. Epithelial marker expression was higher in HTPCa than in PCa. Intensity of the expression in epithelial, vascular and ductal cells was negatively associated with the tumor stage and Gleason grades. Total Ki67 activity was positively correlated with patient age and serum PSA level. There was significantly higher expression in PCa and hormone-escaped PCa (HEPCa) as compared with BPH. Epithelial and vascular marker expression was positively associated with tumor stage and Gleason grades. There was a positive correlation between cyclin D3 and serum PSA level. With the increase of Gleason grades, cyclin D3 expression increased significantly. Expression of p27((Kip1)) negatively correlated with Ki67 and cyclin D3, while the latter two markers correlated positively. p27((Kip1)) is down-regulated, whereas Ki67 and cyclin D3 are up-regulated in PCa. Intensity of the markers' expression is associated with tumor stage and grades. Hormonotherapy of PCa causes activation of p27((Kip1)). HEPCa is characterized by increased Ki67 expression.

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Utilidad de la expresión de Ki67 en las biopsias preoperatorias para predecir la recidiva bioquímica del cáncer de próstata después de la prostatectomía radical

Cited by 14 publications

References 32 publications

Ki67 staining index and neuroendocrine differentiation aggravate adverse prognostic parameters in prostate cancer and are characterized by negligible inter-observer variability

Ki67 staining index and neuroendocrine differentiation aggravate adverse prognostic parameters in prostate cancer and are characterized by negligible inter-observer variability

Apalutamide and autophagy inhibition in a xenograft mouse model of human prostate cancer

Expression of p27(Kip1), cyclin D3 and Ki67 in BPH, prostate cancer and hormone-treated prostate cancer cells

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