Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer.
Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer.
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DOI：
10.1002/pros.22625
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Huang TH
中科院分区：
文献类型：
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作者：
Chen CL;Mahalingam D;Osmulski P;Jadhav RR;Wang CM;Leach RJ;Chang TC;Weitman SD;Kumar AP;Sun L;Gaczynska ME;Thompson IM;Huang TH
前列腺癌将循环中的肿瘤细胞(CTC)送入血液。越来越多的证据表明，转移性前列腺癌中经常存在CTC，可以作为疾病概况和预测的替代来源。在这里，我们假设，表达与上皮-间充质转化(EMT)相关基因的CTC是转移性前列腺癌的强烈预测因素。基于没有CD45白细胞标记的大上皮样细胞的大小选择，使用微滤系统从外周血中捕获CTC。使用原子力显微镜对用显微操作装置分别取出的这些细胞的细胞膜物理性质进行评估。此外，来自8名前列腺癌患者的38个CTC被用于使用基于微流控的PCR系统来确定84个EMT相关基因和参考基因的表达谱。与非癌细胞相比，CTC的细胞弹性和膜平整度增加，突出了它们在外周循环中的潜在侵袭性和流动性。尽管单个CTC的表达模式不同，但在这些细胞中普遍观察到促进间充质向更恶性状态转变的基因，包括IGF1、IGF2、EGFR、FOXP3和TGFB3。另外一组EMT相关基因(例如，PTPRN2、ALDH1、ESR2和Wnt5A)在去势抵抗癌症的CTCs中表达，但在去势敏感癌症中表达较少。这项研究表明，CTC中EMT相关基因的增加表达与转移性去势抵抗癌症有关。尽管CTCs代表了一组高度异质性的细胞，但它们独特的EMT相关基因特征为晚期前列腺癌患者的靶向抑制剂个体化治疗提供了新的机会。
Prostate tumors shed circulating tumor cells (CTCs) into the blood stream. Increased evidence shows that CTCs are often present in metastatic prostate cancer and can be alternative sources for disease profiling and prognostication. Here we postulate that CTCs expressing genes related to epithelial-mesenchymal transition (EMT) are strong predictors of metastatic prostate cancer. A microfiltration system was used to trap CTCs from peripheral blood based on size selection of large epithelial-like cells without CD45 leukocyte marker. These cells individually retrieved with a micromanipulator device were assessed for cell membrane physical properties using atomic force microscopy. Additionally, 38 CTCs from eight prostate cancer patients were used to determine expression profiles of 84 EMT-related and reference genes using a microfluidics-based PCR system. Increased cell elasticity and membrane smoothness were found in CTCs compared to noncancerous cells, highlighting their potential invasiveness and mobility in the peripheral circulation. Despite heterogeneous expression patterns of individual CTCs, genes that promote mesenchymal transitioning into a more malignant state, including IGF1, IGF2, EGFR, FOXP3, and TGFB3, were commonly observed in these cells. An additional subset of EMT-related genes (e.g., PTPRN2, ALDH1, ESR2, and WNT5A) were expressed in CTCs of castration-resistant cancer, but less frequently in castration-sensitive cancer. The study suggests that an incremental expression of EMT-related genes in CTCs is associated with metastatic castration-resistant cancer. Although CTCs represent a group of highly heterogeneous cells, their unique EMT-related gene signatures provide a new opportunity for personalized treatments with targeted inhibitors in advanced prostate cancer patients.