Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis.
Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis.
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发表时间：
2010
影响因子：
2.2
通讯作者：
S. Sethi;J. Macoska;Wei Chen;F. Sarkar
中科院分区：
文献类型：
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作者：
S. Sethi;J. Macoska;Wei Chen;F. Sarkar
前列腺癌(PCa)有骨转移的倾向。在发生转移之前，定植的上皮癌细胞通过一个重要的、但短暂的过程转变为移动性和侵袭性的间充质表型，称为上皮间充质转化(EMT)。由这一过程引发的一系列分子事件具有临床意义，因为它们与癌症干细胞(CSC)、衰老减少和最终的耐药表型相关。我们利用存档的患者样本询问了一些与前列腺癌的原发和骨转移有关的EMT标记物。采用免疫组织化学方法检测E-钙粘素、波形蛋白、ZEB1、Notch-1、PDGFR-D和NF-κB的表达。显微镜下用强度(0，+1，+2，+3)和阳性细胞百分比对病例进行评分。数据采用Fisher‘s Exact检验进行统计学分析。E-钙粘素、波形蛋白、血小板衍生生长因子-D、核因子-κB、Notch-1和ZEB1在前列腺癌和骨转移瘤组织中均有异常表达。肿瘤内不同部位的异常表达模式不同，侵袭性肿瘤前沿(ITF)的表达高于肿瘤中心。骨转移癌组织中Noch-1的表达显著高于原发PCa组织(p=0.057)。其余标记物在PCa和骨转移中的表达水平、强度和阳性细胞百分率均无统计学意义。综上所述，蛋白质表达分析揭示了前列腺癌和骨转移中EMT表型的存在。侵袭性肿瘤前沿异常表达模式的变化提示EMT标记物在肿瘤侵袭中的作用。我们的结果提示Notch-1可能在前列腺癌的骨转移中起作用。在这些EMT分子标记可以转化为临床使用之前，需要在更大的患者队列中进行研究。
Prostate cancer (PCa) has a predilection to metastasize to bone. Before metastasis can occur there is transition of the sessile epithelial cancer cells to become motile and invasive mesenchymal phenotypes by an important albeit transient process called Epithelial-to-Mesenchymal Transition (EMT). The cascade of molecular events triggered by this process is clinically relevant as they are associated with cancer stem-like cells (CSC), decreased senescence and eventual drug resistance phenotype. We interrogated some EMT markers that have been implicated in primary and bone metastasis of PCa using archived patient samples. Using an immunohistochemical approach, E-cadherin, Vimentin, ZEB1, Notch-1, PDGF-D and NF-κB were analyzed. Cases were microscopically scored using intensity (0, +1, +2, +3) and percentage of positive cells. Data was statistically analyzed using Fisher's Exact Test. Aberrant expression of EMT markers E-cadherin, Vimentin, PDGF-D, NF-κB, Notch-1 and ZEB1 was observed in PCa (primary tumor specimen) and bone metastasis tissues. The aberrant expression pattern varied according to the location within the tumor with higher expression was observed more at the invasive tumor front (ITF) vs. the center of the tumor. Notch-1 was significantly over-expressed in bone metastasis compared to primary PCa (p=0.057). The expression levels, intensity and % of positive cells of the remaining markers were not statistically significant in PCa vs. bone metastasis. In conclusion, protein expression analysis revealed the existence of EMT phenotype in the PCa and bone metastasis. Variation in the aberrant expression patterns at the invasive tumor front indicates the role of EMT markers in tumor invasion. Our results suggest that Notch-1 could play a role in PCa bone metastasis. Studies in larger patient cohorts are warranted before these EMT molecular markers can be translated to the clinical use.