Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Am J Surg Pathol. 2011 Oct;35(10):1549-56. doi: 10.1097/PAS.0b013e31822895e5.
The need for effective targeted therapies for renal cell carcinomas (RCCs) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC), tissue microarrays were constructed from 135 primary and 41 metastatic ccRCCs. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCCs compared with benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4E-binding protein-1 (4EBP1) were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared with benign tissues (P<0.001). c-MYC levels were higher in metastatic ccRCC (P<0.0001), and incremental p27 levels were observed in benign, primary ccRCC, and metastatic ccRCC (P<0.0001). HIF-1α levels were significantly higher in primary and metastatic ccRCCs compared with benign tissues (P<0.0001). In primary ccRCC, levels of all mTOR and hypoxia-induced pathway members were significantly associated with pT stage (P≤0.036), p27 levels with Fuhrman grade (P=0.031), and 4EBP1, p27, and HIF-1α levels with tumor size (P≤0.025). Tumor size, HIF-1α, and phos-S6 levels were associated with disease-specific survival (DSS) (P≤0.032) and tumor progression (P≤0.043). In conclusion, both mTOR and hypoxia-induced pathways were activated in primary and metastatic ccRCC. PTEN loss seems to be an early event during tumorigenesis. Tumor size, HIF-1α, and phos-S6 expression were found to be independent predictors of both DSS and tumor progression in primary ccRCC.
为了寻找有效的靶向治疗方法来治疗肾细胞癌（RCC），人们对参与肾脏肿瘤发生的分子途径产生了浓厚的兴趣。本研究旨在分析 mTOR 和缺氧诱导途径成员在透明细胞肾细胞癌（ccRCC）患者中的表达状态和预后意义，为此构建了 135 例原发性和 41 例转移性 ccRCC 的组织微阵列。比较免疫表达水平，并将其与临床病理参数和结果相关联。与良性组织相比，原发性和转移性 ccRCC 中的 PTEN 水平显著降低（P<0.001）。转移性 ccRCC 中磷酸化 AKT、磷酸化 S6 和 4E 结合蛋白-1（4EBP1）的水平较高（P≤0.001）。对于磷酸化 S6 和 4EBP1，与良性组织相比，原发性 ccRCC 中的水平更高（P<0.001）。转移性 ccRCC 中的 c-MYC 水平较高（P<0.0001），良性、原发性和转移性 ccRCC 中 p27 的递增水平较高（P<0.0001）。与良性组织相比，原发性和转移性 ccRCC 中的 HIF-1α 水平显著升高（P<0.0001）。在原发性 ccRCC 中，所有 mTOR 和缺氧诱导途径成员的水平均与 pT 分期显著相关（P≤0.036），p27 水平与 Fuhrman 分级相关（P=0.031），而 4EBP1、p27 和 HIF-1α 水平与肿瘤大小相关（P≤0.025）。肿瘤大小、HIF-1α 和磷酸化 S6 水平与疾病特异性生存率（DSS）（P≤0.032）和肿瘤进展（P≤0.043）相关。总之，原发性和转移性 ccRCC 中均激活了 mTOR 和缺氧诱导途径。PTEN 缺失似乎是肿瘤发生过程中的早期事件。肿瘤大小、HIF-1α 和磷酸化 S6 的表达被发现是原发性 ccRCC 中 DSS 和肿瘤进展的独立预测因素。
