Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Hum Pathol. 2014 May;45(5):984-93. doi: 10.1016/j.humpath.2013.12.012. Epub 2014 Jan 8.
The Akt/mammalian target of rapamycin (mTOR) pathway plays important roles in modulating cellular function in response to extracellular signals such as growth factors and cytokines. The Akt/mTOR signaling pathway is activated in certain kinds of sarcomas. Myxofibrosarcoma is a soft tissue sarcoma, characterized by abundant myxoid stroma and frequent local recurrence. Here, we conducted a large-scale examination of the clinicopathological and activation statuses of the Akt/mTOR pathways in myxofibrosarcoma. The phosphorylation status of Akt, mTOR, S6 ribosomal protein, and the eukaryotic translation initiation factor 4E-binding protein, and mitogen-activated protein kinase were assessed by immunohistochemistry in 101 formalin-fixed, paraffin-embedded samples, including 68 primary tumors in myxofibrosarcoma. Immunohistochemical expressions were confirmed by Western blotting with 20 frozen samples, which were paired with normal tissue samples. PIK3CA and AKT1 gene mutations were also analyzed using 12 primary tumor frozen samples. Immunohistochemically, phosphorylations of Akt, mTOR, S6 ribosomal protein, 4E-binding protein, and mitogen-activated protein kinase 1/2 were observed in 64.7%, 45.6%, 42.6%, 63.2%, and 64.7% of samples. Phosphorylated Akt/mTOR pathway proteins were correlated with one another and were also correlated with the phosphorylation of these proteins in the concordant recurrent tumors. Immunoblotting showed a high degree of phosphorylation in tumor samples, compared with that in normal tissue samples. Activation of the Akt/mTOR pathway was correlated with histologic grade and tumor progression. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots. Activation of the Akt/mTOR pathway was associated with histologic malignancy and tumor progression in primary and recurrent myxofibrosarcoma.
Akt/哺乳动物雷帕霉素靶蛋白 (mTOR) 途径在调节细胞功能方面发挥重要作用，以响应细胞外信号，如生长因子和细胞因子。Akt/mTOR 信号通路在某些肉瘤中被激活。黏液纤维肉瘤是一种软组织肉瘤，其特征是丰富的黏液样基质和频繁的局部复发。在这里，我们对黏液纤维肉瘤中的 Akt/mTOR 途径的临床病理和激活状态进行了大规模检查。通过免疫组织化学方法评估了 101 例福尔马林固定、石蜡包埋样本中的 Akt、mTOR、S6 核糖体蛋白和真核翻译起始因子 4E 结合蛋白以及丝裂原活化蛋白激酶的磷酸化状态，包括 68 例原发性黏液纤维肉瘤。使用 20 个冷冻样本通过 Western 印迹验证了免疫组织化学表达，这些样本与正常组织样本配对。还使用 12 个原发性肿瘤冷冻样本分析了 PIK3CA 和 AKT1 基因突变。免疫组织化学检测显示，磷酸化 Akt、mTOR、S6 核糖体蛋白、4E 结合蛋白和丝裂原活化蛋白激酶 1/2 在 64.7%、45.6%、42.6%、63.2%和 64.7%的样本中观察到。磷酸化 Akt/mTOR 途径蛋白相互之间相关，并且与在一致复发性肿瘤中这些蛋白的磷酸化相关。免疫印迹显示肿瘤样本中的磷酸化程度明显高于正常组织样本。Akt/mTOR 途径的激活与组织学分级和肿瘤进展相关。突变分析未能发现热点周围的 PIK3CA 或 AKT1 突变。Akt/mTOR 途径的激活与原发性和复发性黏液纤维肉瘤中的组织学恶性和肿瘤进展相关。
