Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition
Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition
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DOI：
10.1016/j.humpath.2011.06.019
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发表时间：
2012-05-01
期刊：
影响因子：
3.3
通讯作者：
Johansson, Martin E.
中科院分区：
文献类型：
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作者：
Bostrom, Anna-Karin;Moller, Christina;Johansson, Martin E.
大约8%的肾透明细胞癌病例包含完全不同形态的区域，表现出组织学上类似肉瘤的间充质外观。这种双相性肿瘤称为肉瘤样透明细胞肾细胞癌。肉瘤样透明细胞肾细胞癌患者由于转移倾向增加，预后相当差。在本研究中，我们调查是否肉瘤样转化透明细胞肾细胞癌可以解释为与上皮间质转化的过程。使用6双相透明细胞肾细胞癌的情况下，我们发现肉瘤样透明细胞肾细胞癌的特点标志物与传统的透明细胞肾细胞癌的von Hippel-Lindau肿瘤抑制基因的损失，也表现出显着较高的增殖指数。此外，与肾透明细胞癌对应物相比，肉瘤样成分表现出上皮-间充质转化相关间充质标记物的表达增强。我们进一步选择了一个有代表性的病例，临床上证明肉瘤样成分直接过度生长到肝脏和结肠，进行扩展的免疫组化表征，导致进一步的一组阳性和阴性上皮-间质转化标志物以及明显的转化生长因子β阳性，表明肉瘤样透明细胞肾细胞癌可能与上皮-间质转化有关。体外培养的原代肾透明细胞癌细胞暴露于转化生长因子β 1导致细胞采用类似肉瘤样肾透明细胞癌的间充质形态。还观察到关键上皮-间充质转化标志物的RNA水平的相应变化。因此，我们认为肉瘤样透明细胞肾细胞癌的形态学和免疫化学可能代表了一个完整的上皮间质转化和转化生长因子β 1可能是一个重要的驱动力在肉瘤样透明细胞肾细胞癌的转分化。(C)2012 Elsevier Inc. All rights reserved.
Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor beta positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor beta 1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor beta 1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma. (C) 2012 Elsevier Inc. All rights reserved.