Ledderose Stephan, Rodler Severin, Eismann Lennert, Ledderose Georg, Rudelius Martina, Junger Wolfgang G, Ledderose Carola
Institute of Pathology, Ludwig Maximilian University, 80337 Munich, Germany.
Department of Urology, Ludwig Maximilian University, 81377 Munich, Germany.
Cancers (Basel). 2023 Apr 16;15(8):2321. doi: 10.3390/cancers15082321.
Bladder cancer is amongst the most common causes of cancer death worldwide. Muscle-invasive bladder cancer (MIBC) bears a particularly poor prognosis. Overexpression of purinergic P2X receptors (P2XRs) has been associated with worse outcome in several malignant tumors. Here, we investigated the role of P2XRs in bladder cancer cell proliferation in vitro and the prognostic value of P2XR expression in MIBC patients. Cell culture experiments with T24, RT4, and non-transformed TRT-HU-1 cells revealed a link between high ATP concentrations in the cell culture supernatants of bladder cell lines and a higher grade of malignancy. Furthermore, proliferation of highly malignant T24 bladder cancer cells depended on autocrine signaling through P2X receptors. P2X1R, P2X4R, and P2X7R expression was immunohistochemically analyzed in tumor specimens from 173 patients with MIBC. High P2X1R expression was associated with pathological parameters of disease progression and reduced survival time. High combined expression of P2X1R and P2X7R increased the risk of distant metastasis and was an independent negative predictor of overall and tumor-specific survival in multivariate analyses. Our results suggest that P2X1R/P2X7R expression scores are powerful negative prognostic markers in MIBC patients and that P2XR-mediated pathways are potential targets for novel therapeutic strategies in bladder cancer.
膀胱癌是全球癌症死亡的最常见原因之一。肌层浸润性膀胱癌（MIBC）的预后特别差。嘌呤能P2X受体（P2XRs）的过表达与几种恶性肿瘤的较差预后相关。在此，我们研究了P2XRs在体外膀胱癌细胞增殖中的作用以及P2XR表达在MIBC患者中的预后价值。用T24、RT4和未转化的TRT-HU-1细胞进行的细胞培养实验揭示了膀胱细胞系细胞培养上清液中高ATP浓度与更高恶性程度之间的联系。此外，高恶性T24膀胱癌细胞的增殖依赖于通过P2X受体的自分泌信号传导。对173例MIBC患者的肿瘤标本进行了P2X1R、P2X4R和P2X7R表达的免疫组化分析。高P2X1R表达与疾病进展的病理参数和生存时间缩短相关。P2X1R和P2X7R的高联合表达增加了远处转移的风险，并且在多变量分析中是总生存和肿瘤特异性生存的独立负性预测指标。我们的结果表明，P2X1R/P2X7R表达评分是MIBC患者强有力的负性预后标志物，并且P2XR介导的途径是膀胱癌新治疗策略的潜在靶点。
