The Campbell Family Institute for Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7160-5. doi: 10.1073/pnas.1014506108. Epub 2011 Apr 7.
The tumor microenvironment strongly influences cancer development, progression, and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene-expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-β signaling pathway. We have identified a subset of 11 genes (13 probe sets) that formed a prognostic gene-expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene-expression changes revealed prominent involvement of the focal adhesion and MAPK signaling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture-microdissected corresponding primary tumor stroma compared with the matched normal lung. Six of these 14 genes could be induced by TGF-β1 in NF. The results establish the prognostic impact of CAF-associated gene-expression changes in NSCLC patients.
肿瘤微环境强烈影响癌症的发生、发展和转移。癌相关成纤维细胞（CAFs）在这些过程中的作用及其临床影响在非小细胞肺癌（NSCLC）中尚未得到系统研究。我们从 15 例切除的 NSCLC 中建立了 CAFs 和匹配的正常成纤维细胞（NFs）的原代培养物。我们证明 CAFs 比 NFs 具有更强的增强肺癌细胞系致瘤性的能力。对 15 对匹配的 CAF 和 NF 细胞系进行的微阵列基因表达分析鉴定出 46 个差异表达基因，这些基因编码的蛋白质显著富集于 TGF-β 信号通路调节的细胞外蛋白。我们已经确定了一组 11 个基因（13 个探针集），它们形成了一个预后基因表达特征，在多个独立的 NSCLC 微阵列数据集得到了验证。使用这些基因和已发表的癌症基质相关基因表达变化的蛋白质-蛋白质相互作用分析进行功能注释，揭示了粘着斑和 MAPK 信号通路的显著参与。46 个基因中有 14 个（30%）在与匹配的正常肺相比的激光捕获微切割的相应原发性肿瘤基质中也存在差异表达。这 14 个基因中的 6 个可以在 NF 中被 TGF-β1 诱导。结果确立了 CAF 相关基因表达变化在 NSCLC 患者中的预后影响。
