Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas
Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas
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DOI：
10.1016/j.humpath.2012.01.009
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发表时间：
2012-12-01
期刊：
影响因子：
3.3
通讯作者：
Netto, George J.
中科院分区：
文献类型：
--
作者：
Chaux, Alcides;Schultz, Luciana;Netto, George J.
在透明细胞肾细胞癌中一致发现了哺乳动物雷帕霉素靶点的失调和缺氧诱导的途径。然而，非透明细胞肾细胞癌亚型的经验是缺乏的。在这项研究中，我们评估了免疫组化表达的上游（PTEN和磷酸化AKT）和下游（磷酸化S6和4 EBP 1）的哺乳动物靶雷帕霉素途径，以及相关的细胞周期蛋白（p27和c-MYC），和缺氧诱导途径（HIF-1 α）的成员在54例乳头状肾细胞癌患者接受肾切除术治疗。PTEN在肿瘤中的表达低于正常肾组织，48%的患者PTEN表达缺失。在肿瘤组织中，磷酸化S6、4 EBP 1和HIF-1 α高于正常肾脏。相反，p27在肿瘤中的评分低于正常肾脏。最后，c-MYC和磷酸化AKT的评分在肿瘤和正常肾脏中相似。总死亡率和癌症特异性死亡率分别为24%和11%。在17%的患者中观察到肿瘤进展。测试的生物标志物都不能预测癌症特异性死亡率或肿瘤进展。正如预期的那样，高T期肿瘤患者的癌症特异性死亡率（风险比，6.9）和肿瘤进展（风险比，6.7）的风险比更高。Fuhrman分级越高的患者，癌症特异性死亡率（风险比，11.4）和肿瘤进展（风险比，4.5）的风险也越高。总之，我们的研究提供了乳头状肾细胞癌中雷帕霉素哺乳动物靶点和缺氧诱导通路失调的证据。在我们的队列中，雷帕霉素通路哺乳动物靶点成员和HIF-1 α的免疫组化缺乏预后意义。(C)2012 Elsevier Inc. All rights reserved.
Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1 alpha) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1 alpha were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1 alpha lacked prognostic significance in our cohort. (C) 2012 Elsevier Inc. All rights reserved.