Romanenko Alina M, Morimura Keiichirou, Kinoshita Anna, Wanibuchi Hideki, Takahashi Satoru, Zaparin Wadim K, Vinnichenko Wladimir I, Vozianov Alexander F, Fukushima Shoji
Department of Pathology, Academy of Medical Sciences of Ukraine, Kiev, Ukraine.
Cancer Sci. 2006 Nov;97(11):1168-74. doi: 10.1111/j.1349-7006.2006.00309.x. Epub 2006 Sep 5.
The present study was carried out in order to examine the molecular status of selected growth factor receptors (GFR) in urinary bladder lesions, recently described by our group as representing 'Chernobyl cystitis'. Fibroblast growth factor receptor 3 (FGFR3), epidermal growth factor receptor 1 (EGFR1), EGFR2neu (a member of the same family), p53 and Raf-1 serine/threonine kinase expression were evaluated immunohistochemically in urinary bladder biopsies from 22 men with benign prostate hyperplasia (group 1). For comparison, 16 men with benign prostate hyperplasia and five women with chronic cystitis living in non-radio-contaminated areas of the country were also investigated as controls (group 2). Additionally, 14 patients with dysplasia, carcinoma in situ (CIS) and primary urothelial carcinoma (UC) operated before the Chernobyl accident as well as 23 patients with UC living in the radio-contaminated areas were included as pre- and post-Chernobyl UC groups 1 and 2, respectively. Chronic proliferative atypical cystitis ('Chernobyl cystitis') was observed in group 1 patients. Foci of dysplasia and CIS were found in 22 (100%) and 19 (86%) of the 22 cases, respectively; moreover, two small UC were also detected. Elevated levels of FGFR3, EGFR2/neu, p53 and to a lesser extent EGFR1 and Raf-1 expression in the urothelial dysplasia and CIS were evident for patients of group 1. Statistically significant differences in immunohistochemical scores for FGFR3, EGFR1, p53 and Raf-1 were observed between groups 1 and 2 and between group 1 and the post-Chernobyl UC group 2, where a change in expression of EGFR2/neu was also noted. A significant decrease in FGFR3 expression in additional pre-Chernobyl UC group 1 with dysplasia, CIS and UC compared with group 1 Chernobyl cystitis cases was detected. Our findings suggest that FGFR and EGFR signaling pathways, associated with p53 and Raf-1 activation, may contribute to multistage urothelial carcinogenesis caused by irradiation, through autocrine or paracrine growth stimulation.
本研究旨在检测膀胱病变中所选生长因子受体(GFR)的分子状态,我们小组最近将这些病变描述为“切尔诺贝利膀胱炎”。对22例良性前列腺增生男性患者(第1组)的膀胱活检组织进行免疫组织化学评估,检测成纤维细胞生长因子受体3(FGFR3)、表皮生长因子受体1(EGFR1)、EGFR2neu(同一家族成员)、p53和Raf-1丝氨酸/苏氨酸激酶的表达。作为对照,还对16例良性前列腺增生男性患者和5例居住在该国非放射性污染地区的慢性膀胱炎女性患者进行了研究(第2组)。此外,将14例在切尔诺贝利事故前接受手术的发育异常、原位癌(CIS)和原发性尿路上皮癌(UC)患者以及23例居住在放射性污染地区的UC患者分别纳入切尔诺贝利事故前和事故后的UC第1组和第2组。在第1组患者中观察到慢性增殖性非典型膀胱炎(“切尔诺贝利膀胱炎”)。在22例病例中,分别有22例(100%)和19例(86%)发现发育异常灶和CIS;此外,还检测到2例小的UC。第1组患者的尿路上皮发育异常和CIS中FGFR3、EGFR2/neu、p53水平升高,EGFR1和Raf-1表达也有一定程度升高。在第1组和第2组之间以及第1组和切尔诺贝利事故后的UC第2组之间,观察到FGFR3、EGFR1 p53和Raf-1免疫组织化学评分的统计学显著差异,并注意到EGFR2/neu表达的变化。与第1组切尔诺贝利膀胱炎病例相比,在额外的切尔诺贝利事故前伴有发育异常、CIS和UC的UC第1组中,检测到FGFR3表达显著降低。我们的研究结果表明,与p53和Raf-1激活相关的FGFR和EGFR信号通路可能通过自分泌或旁分泌生长刺激,促成辐射引起的尿路上皮多阶段致癌过程。