Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer.
Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer.
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DOI：
10.1186/1476-4598-13-223
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发表时间：
2014-09-27
期刊：
影响因子：
37.3
通讯作者：
ENITEC Consortium
中科院分区：
文献类型：
--
作者：
Alonso-Alconada L;Muinelo-Romay L;Madissoo K;Diaz-Lopez A;Krakstad C;Trovik J;Wik E;Hapangama D;Coenegrachts L;Cano A;Gil-Moreno A;Chiva L;Cueva J;Vieito M;Ortega E;Mariscal J;Colas E;Castellvi J;Cusido M;Dolcet X;Nijman HW;Bosse T;Green JA;Romano A;Reventos J;Lopez-Lopez R;Salvesen HB;Amant F;Matias-Guiu X;Moreno-Bueno G;Abal M;ENITEC Consortium
大约20%的子宫内膜癌（EC）患者被认为是预后不良的高危人群。在欧洲EC个体化治疗网络（ENITEC）的框架内，我们研究了高危EC患者中循环肿瘤细胞（CTC）的存在和表型特征。使用两种方法在来自34名患者（范围从3级IB期至IV期癌症和复发）和27名健康对照的外周血样品中进行CTC分离。使用CELLection™ Epithelial Enrich试剂盒（Invitrogen，Dynal）对样品进行基于EpCAM的免疫分离，然后进行RTqPCR分析。询问了子宫内膜CTC的表型决定因素，包括发病机制、激素受体途径、干细胞标志物和上皮间质转化（EMT）驱动因素。使用Kruskal-Wallis分析和Dunn事后检验进行组间比较。统计学显著性设定为p < 0.05。基于EpCAM的免疫隔离在高危子宫内膜癌患者中阳性检测到CTC。CTC表征表明由EMT标志物ETV 5、NOTCH 1、SNAI 1、TGFB 1、ZEB 1和ZEB 2的表达定义的显著可塑性表型。此外，ALDH和CD 44的表达表明与干性相关，而CTNNB 1、STS、GDF 15、RELA、RUNX 1、BRAF和PIK 3CA的表达提示了潜在的治疗靶点。我们通过在EC细胞系中ETV 5的上调进一步概括了在子宫内膜CTC中发现的EMT表型，并在全身性传播的动物模型中验证了这些CTC在完成转移中的倾向。我们的研究结果将CTC的存在与高风险EC相关联。基因表达谱特征的CTC可塑性表型与干性和EMT功能。最后，我们通过在EC细胞系Hec 1A中过表达ETV 5来重现这种CTC表型，并在CTC传播和归巢的体内小鼠模型中证明了促进转移的优势。本文的在线版本（doi：10.1186/1476-4598-13-223）包含补充材料，可供授权用户使用。
About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn’s post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing. The online version of this article (doi:10.1186/1476-4598-13-223) contains supplementary material, which is available to authorized users.
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影响因子：
3.8
作者：
Obermayr E;Sanchez-Cabo F;Tea MK;Singer CF;Krainer M;Fischer MB;Sehouli J;Reinthaller A;Horvat R;Heinze G;Tong D;Zeillinger R
通讯作者：
Zeillinger R
影响因子：
3.3
作者：
Mirantes, Cristina;Espinosa, Inigo;Matias-Guiu, Xavier
通讯作者：
Matias-Guiu, Xavier
影响因子：
158.5
作者：
Cristofanilli, M;Budd, GT;Hayes, DF
通讯作者：
Hayes, DF
影响因子：
11.2
作者：
Monge, Marta;Colas, Eva;Abal, Miguel
通讯作者：
Abal, Miguel
影响因子：
6.6
作者：
Sorolla, Anabel;Yeramian, Andree;Matias-Guiu, Xavier
通讯作者：
Matias-Guiu, Xavier