Characterization of heterotypic interaction effects in vitro to deconvolute global gene expression profiles in cancer.
Characterization of heterotypic interaction effects in vitro to deconvolute global gene expression profiles in cancer.
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DOI：
10.1186/gb-2007-8-9-r191
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发表时间：
2007
期刊：
影响因子：
12.3
通讯作者：
Brown PO
中科院分区：
文献类型：
--
作者：
Buess M;Nuyten DS;Hastie T;Nielsen T;Pesich R;Brown PO
在努力去卷积全球基因表达谱，一些乳腺癌细胞和间质成纤维细胞之间的相互作用被发现诱导干扰素反应，这可能与肿瘤进展的倾向更大。细胞间相互作用的扰动是癌症的一个关键特征。然而，关于细胞间相互作用对癌症中整体基因表达的系统性影响知之甚少。我们使用体外模型来模拟肿瘤间质相互作用，通过系统地共培养乳腺癌细胞与间质成纤维细胞，并用cDNA微阵列确定相关基因表达变化。在上皮-间质相互作用的复杂图景中，一个突出的特征是在癌细胞亚群中诱导干扰素应答基因（IRGs）。在这些癌细胞附近，成纤维细胞分泌I型干扰素，这反过来又诱导肿瘤细胞中IRGs的表达。与此模型相似，对人乳腺癌组织的免疫组织化学分析显示，STAT 1，IRG的关键转录激活因子，本身也是一种IRG，在癌症的一个亚组中表达，在接近基质的癌细胞中具有显著的表达升高模式。在体内，IRGs的表达是非常一致的，为将295例早期乳腺癌分为两组提供了基础。IRGs表达水平高的肿瘤与IRGs表达水平低的肿瘤相比，总生存期显著缩短; 10年时为59% vs 80%（对数秩p = 0.001）。在努力deconvolute全球基因表达谱的乳腺癌的系统特性的异型相互作用的影响，在体外，我们发现，一些乳腺癌细胞和间质成纤维细胞之间的相互作用可以诱导干扰素反应，这种反应可能与更大的倾向，肿瘤进展。
In an effort to deconvolute global gene-expression profiles, an interaction between some breast cancer cells and stromal fibroblasts was found to induce an interferon response, which may be associated with a greater propensity for tumor progression. Perturbations in cell-cell interactions are a key feature of cancer. However, little is known about the systematic effects of cell-cell interaction on global gene expression in cancer. We used an ex vivo model to simulate tumor-stroma interaction by systematically co-cultivating breast cancer cells with stromal fibroblasts and determined associated gene expression changes with cDNA microarrays. In the complex picture of epithelial-mesenchymal interaction effects, a prominent characteristic was an induction of interferon-response genes (IRGs) in a subset of cancer cells. In close proximity to these cancer cells, the fibroblasts secreted type I interferons, which, in turn, induced expression of the IRGs in the tumor cells. Paralleling this model, immunohistochemical analysis of human breast cancer tissues showed that STAT1, the key transcriptional activator of the IRGs, and itself an IRG, was expressed in a subset of the cancers, with a striking pattern of elevated expression in the cancer cells in close proximity to the stroma. In vivo, expression of the IRGs was remarkably coherent, providing a basis for segregation of 295 early-stage breast cancers into two groups. Tumors with high compared to low expression levels of IRGs were associated with significantly shorter overall survival; 59% versus 80% at 10 years (log-rank p = 0.001). In an effort to deconvolute global gene expression profiles of breast cancer by systematic characterization of heterotypic interaction effects in vitro, we found that an interaction between some breast cancer cells and stromal fibroblasts can induce an interferon-response, and that this response may be associated with a greater propensity for tumor progression.
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影响因子：
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通讯作者：
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