Department of Urology, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
J Cancer Res Clin Oncol. 2019 Jan;145(1):153-163. doi: 10.1007/s00432-018-2775-5. Epub 2018 Oct 27.
Impaired regulation of the Akt/mammalian target of rapamycin (mTOR) pathway has been implicated in mechanisms related to neoplastic transformation in renal cell cancer (RCC) through enhancement of cell proliferation and survival and mTOR activation has been reported to occur due to phosphorylation of mTOR. To further determine the relevance of mTOR expression and activation and to analyze their putative role as a biomarker for systemic treatment in metastatic RCC, we investigated the expression of mTOR and phospho(p)-mTOR in primary RCC and metastases and correlated levels with pathological variables and clinical outcome.
Tissue microarrays (TMA) from paraffin-embedded tissue from 342 patients with primary clear cell renal cell carcinoma and 90 patients undergoing surgical resection for metastases were immunohistochemically stained for mTOR and p-mTOR and expression was quantified with immunoreactivity scores. Clinical patient characteristics and follow-up were recorded. Comparative evaluation of protein expression levels and association of expression with clinical variables and survival was performed.
mTOR staining revealed differential expression in benign, primary and RCC metastasis (average staining score: 1.64, 0.78, and 1.44, respectively). Average staining of p-mTOR was 0.99 in benign kidney tissue, 0.73 in primary RCC and 1.14 in RCC metastasis tissue. Elevated mTOR expression in primary RCC tissue was associated with the presence of tumor necrosis, while a high level of p-mTOR was significantly correlated with advanced T-stage, high Fuhrman grade, the presence of tumor necrosis and sarcomatoid features. An elevated ratio of p-mTOR/mTOR was significantly correlated with advanced stage and sarcomatoid histology. mTOR expression was not predictive of overall survival (OS), while high p-mTOR levels were associated with impaired OS (p = 0.0046) and cancer-specific survival (p = 0.0067). In univariate analysis, advanced stage (HR 3.78), high Fuhrman grade (HR 4.0), the presence of tumor necrosis (HR 1.99), and sarcomatoid features (HR 5.12) were significant predictors of OS. Moreover, elevated levels of p-mTOR (HR 1.67) and an elevated ratio of p-mTOR/mTOR ratio (HR 1.73) were significantly predictive of OS. In the multivariate regression model only the presence of locally advanced tumors (HR 2.44) was of independent prognostic value for OS, while there was a trend for impaired OS for patients with a high p-mTOR (HR 1.27, p = 0.21).
Phosphorylated mTOR is differentially expressed in localized RCC and metastasis. Elevated phosphorylation of mTOR is associated with aggressive pathologic features and unfavorable outcome. Whether these findings portend to relevance for mTOR inhibition treatment for metastatic RCC should be objective of further investigations.
在肾细胞癌（RCC）中，Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路的调节失调通过增强细胞增殖和存活而与肿瘤转化的相关机制有关，并且已经报道 mTOR 的激活是由于 mTOR 的磷酸化。为了进一步确定 mTOR 表达和激活的相关性，并分析它们作为转移性 RCC 全身治疗的生物标志物的潜在作用，我们研究了原发性 RCC 和转移灶中 mTOR 和磷酸化（p）-mTOR 的表达，并将水平与病理变量和临床结果相关联。
对 342 例原发性透明细胞肾细胞癌患者和 90 例接受转移切除术的患者的石蜡包埋组织的组织微阵列（TMA）进行 mTOR 和 p-mTOR 的免疫组织化学染色，并通过免疫反应性评分定量表达。记录临床患者特征和随访情况。对蛋白表达水平进行比较评估，并对表达与临床变量和生存的关系进行分析。
mTOR 染色显示良性、原发性和 RCC 转移组织中的差异表达（平均染色评分分别为 1.64、0.78 和 1.44）。良性肾脏组织中 p-mTOR 的平均染色为 0.99，原发性 RCC 为 0.73，RCC 转移组织为 1.14。原发性 RCC 组织中 mTOR 的高表达与肿瘤坏死有关，而高 p-mTOR 水平与晚期 T 分期、高 Fuhrman 分级、肿瘤坏死和肉瘤样特征显著相关。升高的 p-mTOR/mTOR 比值与晚期分期和肉瘤样组织学显著相关。mTOR 表达与总生存期（OS）无关，而高 p-mTOR 水平与 OS 受损（p=0.0046）和癌症特异性生存（p=0.0067）相关。在单因素分析中，晚期分期（HR 3.78）、高 Fuhrman 分级（HR 4.0）、肿瘤坏死（HR 1.99）和肉瘤样特征（HR 5.12）是 OS 的显著预测因素。此外，p-mTOR 水平升高（HR 1.67）和 p-mTOR/mTOR 比值升高（HR 1.73）均显著预测 OS。在多变量回归模型中，只有局部晚期肿瘤的存在（HR 2.44）对 OS 具有独立的预后价值，而高 p-mTOR 患者的 OS 受损存在趋势（HR 1.27，p=0.21）。
磷酸化 mTOR 在局限性 RCC 和转移灶中差异表达。mTOR 的磷酸化升高与侵袭性病理特征和不良预后相关。这些发现是否预示着对转移性 RCC 的 mTOR 抑制治疗具有相关性，应该是进一步研究的目标。
