Functional Heterogeneity of Cancer-Associated Fibroblasts from Human Colon Tumors Shows Specific Prognostic Gene Expression Signature
Functional Heterogeneity of Cancer-Associated Fibroblasts from Human Colon Tumors Shows Specific Prognostic Gene Expression Signature
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DOI：
10.1158/1078-0432.ccr-13-0694
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发表时间：
2013-11-01
影响因子：
11.5
通讯作者：
Pena, Cristina
中科院分区：
文献类型：
--
作者：
Herrera, Mercedes;Islam, Abul B. M. M. K.;Pena, Cristina
目的：癌症相关成纤维细胞（CAF）积极参与与肿瘤细胞和微环境中其他细胞类型的相互交流，有助于肿瘤允许的邻居并促进肿瘤进展。本研究的目的是表征如何从原发性人类结肠肿瘤CAF促进结肠癌celles.Experimental设计迁移：原代CAF培养物从15个原发性人类结肠肿瘤建立。通过各种上皮和肌成纤维细胞特异性标志物的表达来评估它们在CAFs中的富集。进行原代CAF与不同结肠肿瘤细胞的共培养测定，以评估促迁移CAF衍生的对癌细胞的作用。基因表达谱的发展，以进一步调查CAF的characteristics.Results：共培养试验显示成纤维细胞来源的旁分泌promigrating对癌细胞的影响显着差异。此外，观察到CAF对癌细胞的促迁移作用与经典成纤维细胞活化或干性标志物之间的关联。通过微阵列分析CAF基因表达谱，以鉴定不同前迁移CAF中的失调基因。鉴定了来自最促肿瘤发生的CAF的基因表达特征。有趣的是，这种“CAF特征”显示出对结肠癌患者临床结果的显著预后价值。此外，通过定量实时PCR（qRT-PCR），在142例结肠癌患者的独立系列中验证了该预后价值，其中一组四个基因包括在“CAF标签”中。结论：总之，这些研究首次显示了原发性CAFs对结肠癌细胞迁移影响的异质性。CAF基因表达特征能够将结肠癌患者分为高风险组和低风险组。(C)2013年AACR。
Purpose: Cancer-associated fibroblasts (CAF) actively participate in reciprocal communication with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive neighborhood and promoting tumor progression. The aim of this study is the characterization of how CAFs from primary human colon tumors promote migration of colon cancer cells.Experimental design: Primary CAF cultures from 15 primary human colon tumors were established. Their enrichment in CAFs was evaluated by the expression of various epithelial and myofibroblast specific markers. Coculture assays of primary CAFs with different colon tumor cells were performed to evaluate promigratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics.Results: Coculture assays showed significant differences in fibroblast-derived paracrine promigratory effects on cancer cells. Moreover, the association between CAFs' promigratory effects on cancer cells and classic fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs. The gene expression signature, derived from the most protumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. Moreover, this prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR (qRT-PCR), with a set of four genes included in the "CAF signature."Conclusions: In summary, these studies show for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high-and low-risk groups was identified. (C) 2013 AACR.