Cutcliffe Colleen, Kersey Donna, Huang Chiang-Ching, Zeng Yong, Walterhouse David, Perlman Elizabeth J
Department of Pathology and Laboratory Medicine, Division of Hematology/Oncology, Children's Memorial Hospital, Chicago, Illinois 60614, USA.
Clin Cancer Res. 2005 Nov 15;11(22):7986-94. doi: 10.1158/1078-0432.CCR-05-1354.
Clear cell sarcoma of the kidney (CCSK), the second most common renal tumor in children, poses significant diagnostic challenges. No positive diagnostic markers are available, and the pathogenesis of CCSK remains an enigma. To address these challenges, the gene expression patterns of 14 CCSKs were compared with 15 Wilms tumors and 3 fetal kidney samples using oligonucleotide arrays.
Using unsupervised methods, the gene expression profile of CCSK was distinctive: differentially expressed genes could largely be grouped into four categories: (a) a wide variety of neural markers, (b) members of the Sonic hedgehog pathway, (c) members of the phosphoinositide-3-kinase/Akt cell proliferation pathway, and (d) known therapeutic targets. Corresponding changes in critical proteins using Western blot and/or immunohistochemistry confirmed the up-regulation of these pathways and proteins. In particular, CD117 and epidermal growth factor receptor are up-regulated at the protein level in many CCSKs, providing potential therapeutic targets. One of the neural markers, nerve growth factor receptor, represents a promising diagnostic tool for CCSK.
This study suggests that CCSKs arise within a renal mesenchymal cell that shows a wide variety of neural markers. As such, it seems to be susceptible to genetic changes also seen in a variety of other neuroectodermal and neuronal tumors, including activation of Sonic hedgehog and phosphoinositide-3-kinase/Akt pathways. Involvement of these pathways in CCSKs implicates their widening role in tumorigenesis.
肾透明细胞肉瘤（CCSK）是儿童第二常见的肾肿瘤，带来了重大的诊断挑战。目前尚无阳性诊断标志物，CCSK的发病机制仍是个谜。为应对这些挑战，使用寡核苷酸阵列将14例CCSK的基因表达模式与15例肾母细胞瘤和3例胎儿肾脏样本进行了比较。
采用无监督方法，CCSK的基因表达谱具有独特性：差异表达基因大致可分为四类：（a）多种神经标志物；（b）音猬因子信号通路成员；（c）磷酸肌醇-3-激酶/蛋白激酶B细胞增殖通路成员；（d）已知的治疗靶点。使用蛋白质印迹法和/或免疫组织化学对关键蛋白的相应变化进行确认，证实了这些信号通路和蛋白的上调。特别是，许多CCSK中CD117和表皮生长因子受体在蛋白水平上调，提供了潜在的治疗靶点。神经标志物之一神经生长因子受体是CCSK一种很有前景的诊断工具。
本研究表明，CCSK起源于显示多种神经标志物的肾间充质细胞。因此，它似乎易发生在多种其他神经外胚层和神经元肿瘤中也可见的基因变化，包括音猬因子和磷酸肌醇-3-激酶/蛋白激酶B信号通路的激活。这些信号通路在CCSK中的参与暗示了它们在肿瘤发生中作用的扩大。
