Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma.
Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma.
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Caveolin-1和活化的AKT/MTOR途径的结合表达预测，临床上受限制的肾细胞癌中无病生存率降低。
DOI：
10.1038/sj.bjc.6604243
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发表时间：
2008-03-11
影响因子：
8.8
通讯作者：
Griffiths, D. F. R.
中科院分区：
文献类型：
--
作者：
Campbell, L.;Jasani, B.;Edwards, K.;Gumbleton, M.;Griffiths, D. F. R.
我们以前报道过，肿瘤相关的小窝蛋白-1是肾细胞癌（RCC）的一个潜在的生物标志物，其过表达可预测临床局限性疾病手术切除后的转移。最近，许多注意力集中在AKT/mTOR通路在一些恶性肿瘤，包括RCC。由于小窝蛋白-1和AKT/mTOR信号级联被独立地证明是肿瘤血管生成的重要调节因子，我们假设小窝蛋白-1与AKT/mTOR通路相互作用以驱动RCC中的疾病进展和转移。本研究的目的是确定（i）活化的AKT/mTOR通路组分（磷酸化形式）在RCC中的表达状态和（ii）当与小窝蛋白-1组合时它们的预后价值。对174例临床局限性RCC的组织微阵列进行小窝蛋白-1、pAKT、pmTOR、pS 6和p4 E-BP 1的免疫组化。当小窝蛋白-1与pAKT（2.95 vs 6.14年）、pmTOR（3.17 vs 6.28年）、pS 6（1.45 vs 6.62年）或p4 E-BP 1（2.07 vs 6.09年）共表达时，观察到平均无病生存期显著降低，而不是单独表达任何一种生物标志物。在多变量分析中，“小窝蛋白-1/AKT”的协变量（两者都不是有影响的协变量）是无病生存率差的重要影响指标，风险比为2.13（95%CI：1.15-3.92），高于血管浸润。共表达小窝蛋白-1和激活mTOR成分的肿瘤更可能更大，级别更高，并显示血管浸润。我们的研究结果提供了第一个临床证据，即caveolin-1与癌症中激活的AKT/mTOR通路合作，并可能在疾病进展中发挥重要作用。我们的结论是，在原发性肾脏肿瘤的“小窝蛋白-1/AKT/mTOR轴”的评价将确定RCC患者的子集，需要更大的术后监测和更密集的治疗。
We previously reported that tumour-associated caveolin-1 is a potential biomarker in renal cell carcinoma (RCC), whose overexpression predicts metastasis following surgical resection for clinically confined disease. Much attention has recently focused on the AKT/mTOR pathway in a number of malignancies, including RCC. Since caveolin-1 and the AKT/mTOR signalling cascade are independently shown to be important regulators of tumour angiogenesis, we hypothesised that caveolin-1 interacts with the AKT/mTOR pathway to drive disease progression and metastasis in RCC. The aims of this study were to determine (i) the expression status of the activated AKT/mTOR pathway components (phosphorylated forms) in RCC and (ii) their prognostic value when combined with caveolin-1. Immunohistochemistry for caveolin-1, pAKT, pmTOR, pS6 and p4E-BP1 was performed on tissue microarrays from 174 clinically confined RCCs. Significantly decreased mean disease-free survival was observed when caveolin-1 was coexpressed with either pAKT (2.95 vs 6.14 years), pmTOR (3.17 vs 6.28 years), pS6 (1.45 vs 6.62 years) or p4E-BP1 (2.07 vs 6.09 years) than when neither or any one single biomarker was expressed alone. On multivariate analysis, the covariate of ‘caveolin-1/AKT’ (neither alone were influential covariates) was a significant influential indicator of poor disease-free survival with a hazard ratio of 2.13 (95% CI: 1.15–3.92), higher than that for vascular invasion. Tumours that coexpressed caveolin-1 and activated mTOR components were more likely to be larger, higher grade and to show vascular invasion. Our results provide the first clinical evidence that caveolin-1 cooperates with an activated AKT/mTOR pathway in cancer and may play an important role in disease progression. We conclude that evaluation of the ‘caveolin-1/AKT/mTOR axis’ in primary kidney tumours will identify subsets of RCC patients who require greater postoperative surveillance and more intensive treatment.
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