Authors' Affiliations: Departments of Medical Oncology and Pathology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda; Functional Proteomics Laboratory, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid; Programa de Recerca en Càncer, IMIM-Hospital del Mar, Barcelona, Spain; and Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.
Clin Cancer Res. 2013 Nov 1;19(21):5914-26. doi: 10.1158/1078-0432.CCR-13-0694. Epub 2013 Sep 19.
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.
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.
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."
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.
癌相关成纤维细胞（CAF）积极参与与肿瘤细胞以及微环境中其他细胞类型的相互交流，促进肿瘤微环境的形成并促进肿瘤的进展。本研究的目的是研究原发性人结肠肿瘤中的 CAF 如何促进结肠癌细胞的迁移。
从 15 个人类原发性结肠肿瘤中建立了原发性 CAF 培养物。通过表达各种上皮和成纤维细胞特异性标志物来评估它们在 CAF 中的富集程度。进行原发性 CAF 与不同结肠肿瘤细胞的共培养实验，以评估 CAF 衍生的促迁移作用对癌细胞的影响。开发基因表达谱进一步研究 CAF 的特征。
共培养实验显示 CAF 对癌细胞的旁分泌促迁移作用存在显著差异。此外，还观察到 CAFs 对癌细胞的促迁移作用与经典成纤维细胞激活或干性标志物之间的关联。通过微阵列分析 CAF 的基因表达谱，以鉴定不同促迁移 CAF 中的失调基因。从最具促瘤性的 CAFs 中鉴定出基因表达特征。有趣的是，该“CAF 特征”对结肠癌患者的临床结局具有显著的预后价值。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，其中包含在“CAF 特征”中的四个基因。
综上所述，这些研究首次表明原发性 CAF 对结肠癌细胞迁移的影响存在异质性。鉴定出一种能够将结肠癌患者分为高风险和低风险组的 CAF 基因表达特征。
