Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy:: prognostic significance of p21/WAF1/CIP1 expression
Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy:: prognostic significance of p21/WAF1/CIP1 expression
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DOI：
10.1038/sj.bjc.6690390
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发表时间：
1999-05-01
影响因子：
8.8
通讯作者：
Löhrs, U
中科院分区：
文献类型：
--
作者：
Baretton, GB;Klenk, U;Löhrs, U
前列腺癌(PC)雄激素非依赖性生长的分子机制尚不清楚。雄激素剥夺疗法(ADT)在生理上导致细胞增殖减少和程序性细胞死亡(PCD)/凋亡增加。我们研究的目的是为了更深入地了解前列腺癌在ADT前后的这些过程。为此，对档案材料进行雄激素受体(AR)分子、Ki-67抗原、bcl2癌蛋白、P53蛋白及其生理效应蛋白p21/WAF1的免疫组织化学染色。酶促DNA片段化检测显示PCD。对69例胰腺癌患者ADT后标本与组织病理学及预后的关系进行了研究。在42例患者中，可对比分析未经治疗的原发肿瘤的相应肿瘤组织。ADT前组织学分级与Ki-67指数(P<；0.0001，Spearman相关)和PCD发生率(P<；0.05，Spearman相关)相关。Ki-67指数与PCD发生率(P<；0.05，Spearman相关)和p21/WAF1表达(P<；0.01，Fisher‘s精确检验)相关。P21/waf1的表达是唯一有统计学意义的影响较短生存期的预后因素(P<；0.002，对数等级检验)。P21/WAF1阳性病例均表现为高Ki-67指数和高组织学分级。ADT后AR表达缺失与高Ki-67指数相关，而组织学退行性征象与Ki-67指数负相关(P<；0.001，Pearson chi(2)检验)。P21/WAF1表达显著增加(P<；0.02，McNemar检验)，并与P53积聚相关(P<；0.0001，Pearson chi(2)检验)。常规ADT后最显著的预后参数是p21/WAF1的高表达(50%的肿瘤细胞；P<；0.00001，对数等级检验)。这项研究表明，ADT前后p21/WAF1的过度表达是晚期PC的一个亚群，具有反常的高增殖率和显著更差的临床预后。这一发现可能在临床上对这些患者的治疗计划有帮助。
The molecular mechanisms leading to androgen-independent growth in prostate cancer (PC) are poorly understood. Androgen deprivation therapy (ADT) results physiologically in a decrease in proliferation and an increase in programmed cell death (PCD)/apoptosis. The aim of our study was to get more insight into these processes in prostatic carcinomas before and after ADT. For this purpose; immunohistologic staining for the androgen receptor (AR) molecule, the Ki-67 antigen, the bcl-2 oncoprotein, the p53 protein and its physiologic effector, p21/WAF1, was performed on archival material. PCD was visualized by enzymatic detection of DNA fragmentation. Specimens from 69 PC patients after ADT were studied in correlation to histopathology and prognosis. In 42 cases, corresponding tumour tissue from the untreated primary tumours could be analysed comparatively. Before ADT, histologic grade was associated with Ki-67 index (P < 0.0001, Spearman correlation) and PCD rate(P < 0.05, Spearman correlation). Ki-67 index correlated with PCD rate (P < 0.05, Spearman correlation) and p21/WAF1 expression (P < 0.01, Fisher's exact test). p21/WAF1 expression was the only statistically significant prognostic factor for shorter survival (P < 0.002, log-rank test). All p21/WAF1-positive cases showed high Ki-67 index and high histologic grade. After ADT, loss of AR expression was associated with high Ki-67 index, whereas histologic signs of regression correlated negatively with Ki-67 index (P < 0.001, Pearson chi(2) test). p21/WAF1 expression increased significantly (P < 0.02, McNemar test) and correlated with p53 accumulation (P < 0.0001, Pearson chi(2) test). Most significant prognostic parameter after conventional ADT was high-rate p21/WAF1 expression (> 50% of tumour cells; P < 0.00001, log-rank test). This study demonstrates that p21/WAF1 overexpression before and after ADT characterizes a subgroup of advanced PC with paradoxically high proliferation rate and significantly worse clinical outcome. This finding might be clinically useful for planning therapy in these patients.