Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Cancer. 2010 Dec 1;116(23):5517-26. doi: 10.1002/cncr.25502. Epub 2010 Oct 11.
Bladder urothelial carcinoma has high rates of mortality and morbidity. Identifying novel molecular prognostic factors and targets of therapy is crucial. Mammalian target of rapamycin (mTOR) pathway plays a pivotal role in establishing cell shape, migration, and proliferation.
Tissue microarrays were constructed from 132 cystectomies (1994-2002). Immunohistochemistry was performed for Pten, c-myc, p27, phosphorylated (phos)Akt, phosS6, and 4E-BP1. Markers were evaluated for pattern, percentage, and intensity of staining.
Mean length of follow-up was 62.6 months (range, 1-182 months). Disease progression, overall survival (OS), and disease-specific survival (DSS) rates were 42%, 60%, and 68%, respectively. Pten showed loss of expression in 35% of bladder urothelial carcinoma. All markers showed lower expression in invasive bladder urothelial carcinoma compared with benign urothelium with the exception of 4E-BP1. Pten, p27, phosAkt, phosS6, and 4E-BP1 expression correlated with pathologic stage (pathological stage; P<.03). Pten, 4E-BP1, and phosAkt expression correlated with divergent aggressive histology and invasion. phosS6 expression inversely predicted OS (P=.01), DSS (P=.001), and progression (P=.05). c-myc expression inversely predicted progression (P=.01). In a multivariate analysis model that included TNM stage grouping, divergent aggressive histology, concomitant carcinoma in situ, phosS6, and c-myc expression, phosS6 was an independent predictor of DSS (P=.03; hazard ratio [HR], -0.19), whereas c-myc was an independent predictor of progression (P=.02; HR, -0.38). In a second model substituting organ-confined disease and lymph node status for TNM stage grouping, phosS6 and c-myc remained independent predictors of DSS (P=.03; HR, -0.21) and progression (P=.03; HR, -0.34), respectively.
We found an overall down-regulation of mTOR pathway in bladder urothelial carcinoma. phosS6 independently predicted DSS, and c-myc independently predicted progression.
膀胱癌具有较高的死亡率和发病率。鉴定新的分子预后因素和治疗靶点至关重要。哺乳动物雷帕霉素靶蛋白（mTOR）途径在建立细胞形态、迁移和增殖方面发挥着关键作用。
从 132 例膀胱切除术（1994-2002 年）中构建组织微阵列。进行免疫组织化学染色以检测 Pten、c-myc、p27、磷酸化（phos）Akt、phosS6 和 4E-BP1。评估标志物的模式、百分比和染色强度。
平均随访时间为 62.6 个月（范围，1-182 个月）。疾病进展、总生存率（OS）和疾病特异性生存率（DSS）分别为 42%、60%和 68%。35%的膀胱癌中 Pten 表达缺失。除 4E-BP1 外，所有标志物在浸润性膀胱癌中的表达均低于良性尿路上皮，且与病理分期（病理分期；P<.03）相关。Pten、4E-BP1 和 phosAkt 的表达与不同的侵袭性组织学和浸润相关。phosS6 的表达与 OS（P=.01）、DSS（P=.001）和进展（P=.05）呈负相关。c-myc 的表达与进展呈负相关（P=.01）。在包括 TNM 分期分组、不同侵袭性组织学、同时性原位癌、phosS6 和 c-myc 表达的多变量分析模型中，phosS6 是 DSS 的独立预测因子（P=.03；风险比[HR]，-0.19），而 c-myc 是进展的独立预测因子（P=.02；HR，-0.38）。在替代 TNM 分期分组的器官局限性疾病和淋巴结状态的第二个模型中，phosS6 和 c-myc 仍然是 DSS（P=.03；HR，-0.21）和进展（P=.03；HR，-0.34）的独立预测因子。
我们发现膀胱癌中 mTOR 途径总体下调。phosS6 独立预测 DSS，而 c-myc 独立预测进展。
