Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers
Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers
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DOI：
10.1073/pnas.0909797107
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Fitzgerald, Rebecca C.
中科院分区：
文献类型：
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作者：
Saadi, Amel;Shannon, Nicholas B.;Fitzgerald, Rebecca C.
基质区室越来越多地被认为在癌症中发挥作用。然而，其在从预侵袭性疾病向侵袭性疾病转变中的作用尚不清楚。大多数胃肠道肿瘤都有明确的癌前阶段，Barrett食管（BE）是一个理想的研究模型。来自显微切割的间质的基因表达谱的监督聚类确定了可以区分BE化生、异型增生和食管腺癌（EAC）的基因特征。过表达从该基质标签鉴定的五种基因（TMEPAI、JMY、TSP 1、FAPa和BCL 6）中的任何一种的EAC患者具有显著较差的结果。基因本体分析确定了BE疾病进展中的强炎症组分，并且关键途径包括精氨酸-细胞因子受体相互作用和TGF-β。与侵袭前阶段相比，EAC中炎症相关基因的蛋白水平显著上调，这在独立样本的基质中得到证实，体外试验证实了这些基因的功能相关性。外部数据集的基因集富集分析表明，基质签名也与胃、结肠和胰腺的侵袭前向侵袭性转变有关。这些数据表明胃肠道癌症发生中的炎症途径，这可能会影响预后。
The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett's esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPa, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine-cytokine receptor interactions and TGF-beta. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis.