Stark Timothy W, Hensley Patrick J, Spear Amanda, Pu Hong, Strup Stephen S, Kyprianou Natasha
Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky.
Department of Pathology, University of Kentucky College of Medicine, Lexington, Kentucky.
Prostate. 2017 Dec;77(16):1583-1591. doi: 10.1002/pros.23435. Epub 2017 Oct 23.
Epithelial-mesenchymal-transition (EMT) has been previously identified as a contributor to prostate cancer progression to metastasis and therapeutic resistance to antiandrogens and radiotherapy. In this study we conducted a retrospective analysis to investigate the significance of radiation-induced EMT and consequential changes to the tumor microenvironment in biochemical recurrence and response to radiotherapy in prostate cancer patients.
Expression profiling and localization for EMT effectors, E-Cadherin, N-Cadherin, β-catenin and Vimentin was assessed in human prostate tumor specimens pre- and post-radiotherapy and correlated with biochemical recurrence. In addition, immunoreactivity of the DNA repair enzyme, polymerase (PARP-1) and the cytoskeletal-remodeling regulator, cofilin was evaluated in prostate tumor specimens pre- and post-radiotherapy and correlated with pre-treatment prostate-specific antigen levels (PSA).
Our findings identified that characteristic changes associated with the EMT phenotype and its reversal to mesenchymal-epithelial-transition (MET) within the tumor microenvironment correlate with biochemical recurrence and resistance to radiotherapy among prostate cancer patients. Moreover, elevated PARP-1 expression among the tumor cells undergoing EMT implicates that DNA repair mechanisms may potentially reverse the cytotoxic effects of radiotherapy-induced DNA breaks.
Our results suggest that EMT programming effectors, integrated with the actin cytoskeleton regulator cofilin and mesenchymal PARP-1 expression profile provide a signature of potential predictive significance of therapeutic response to radiotherapy in a subset of prostate cancer patients.
上皮-间质转化（EMT）先前已被确定为前列腺癌进展至转移以及对抗雄激素和放疗产生治疗抵抗的一个因素。在本研究中，我们进行了一项回顾性分析，以探讨辐射诱导的EMT及肿瘤微环境的相应变化在前列腺癌患者生化复发及放疗反应中的意义。
在放疗前后的人前列腺肿瘤标本中评估EMT效应分子E-钙黏蛋白、N-钙黏蛋白、β-连环蛋白和波形蛋白的表达谱及定位，并将其与生化复发相关联。此外，在放疗前后的前列腺肿瘤标本中评估DNA修复酶聚（ADP-核糖）聚合酶-1（PARP-1）和细胞骨架重塑调节因子丝切蛋白的免疫反应性，并将其与治疗前前列腺特异性抗原水平（PSA）相关联。
我们的研究结果表明，肿瘤微环境中与EMT表型相关的特征性变化及其向间质-上皮转化（MET）的逆转与前列腺癌患者的生化复发及放疗抵抗相关。此外，经历EMT的肿瘤细胞中PARP-1表达升高表明DNA修复机制可能潜在地逆转放疗诱导的DNA断裂的细胞毒性作用。
我们的结果表明，EMT编程效应分子与肌动蛋白细胞骨架调节因子丝切蛋白以及间质PARP-1表达谱相结合，为一部分前列腺癌患者放疗治疗反应提供了具有潜在预测意义的特征。
