Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Br J Cancer. 2014 Apr 29;110(9):2217-23. doi: 10.1038/bjc.2014.158. Epub 2014 Apr 8.
Radiotherapy provides high-cure rates in prostate cancer. Despite its overall slow clinical growth, high proliferation rates documented in a subset of tumours relate to poor radiotherapy outcome. This study examines the role of anaerobic metabolism in prostate cancer growth and resistance to radiotherapy.
Biopsy samples from 83 patients with prostate cancer undergoing radical hypofractionated and accelerated radiotherapy were analysed for MIB1 proliferation index and for lactate dehydrogenase isoenzyme LDH5, a marker of tumour anaerobic metabolism. Ninety-five surgical samples were in parallel analysed. Correlation with histopathological variables, PSA and radiotherapy outcome was assessed. Dose-response experiments were performed in PC3 and DU145 cancer cell lines.
High MIB1 index (noted in 25% of cases) was directly related to Gleason score (P<0.0001), T3-stage (P=0.0008) and PSA levels (P=0.03). High LDH5 (noted in 65% of cases) was directly related to MIB1 index (P<0.0001), Gleason score (P=0.02) and T3-stage (P=0.001). High Gleason score, MIB1, LDH5 and PSA levels were significantly related to poor BRFS (P=0.007, 0.01, 0.03 and 0.01, respectively). High Gleason score (P=0.04), LDH5 (P=0.01) and PSA levels (P=0.003) were significantly related to local recurrence. MIB1 and T-stage did not affect local control. Silencing of LDHA gene in both prostate cancer cell lines resulted in significant radiosensitisation.
LDH5 overexpression is significantly linked to highly proliferating prostate carcinomas and with biochemical failure and local relapse following radiotherapy. Hypoxia and LDHA targeting agents may prove useful to overcome radioresistance in a subgroup of prostate carcinomas with anaerobic metabolic predilection.
放射治疗可为前列腺癌提供高治愈率。尽管其总体临床进展缓慢，但在肿瘤亚群中记录的高增殖率与放疗效果差有关。本研究探讨了无氧代谢在前列腺癌生长和对放疗抵抗中的作用。
对 83 例接受根治性低分割和加速放疗的前列腺癌患者的活检样本进行了 MIB1 增殖指数和乳酸脱氢酶同工酶 LDH5（肿瘤无氧代谢的标志物）分析。对 95 例手术样本进行了平行分析。评估了与组织病理学变量、PSA 和放疗结果的相关性。在 PC3 和 DU145 癌细胞系中进行了剂量反应实验。
高 MIB1 指数（在 25%的病例中发现）与 Gleason 评分（P<0.0001）、T3 期（P=0.0008）和 PSA 水平（P=0.03）直接相关。高 LDH5（在 65%的病例中发现）与 MIB1 指数（P<0.0001）、Gleason 评分（P=0.02）和 T3 期（P=0.001）直接相关。高 Gleason 评分、MIB1、LDH5 和 PSA 水平与不良 BRFS（P=0.007、0.01、0.03 和 0.01）显著相关。高 Gleason 评分（P=0.04）、LDH5（P=0.01）和 PSA 水平（P=0.003）与局部复发显著相关。MIB1 和 T 期与局部控制无关。沉默两种前列腺癌细胞系中的 LDHA 基因可显著增加放射敏感性。
LDH5 的过表达与高度增殖的前列腺癌显著相关，并与放疗后的生化失败和局部复发相关。缺氧和 LDHA 靶向药物可能有助于克服具有无氧代谢倾向的前列腺癌亚群的放射抵抗。
