Proteome Profiling of Cancer-Associated Fibroblasts Identifies Novel Proinflammatory Signatures and Prognostic Markers for Colorectal Cancer
Proteome Profiling of Cancer-Associated Fibroblasts Identifies Novel Proinflammatory Signatures and Prognostic Markers for Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-13-1130
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发表时间：
2013-11-01
影响因子：
11.5
通讯作者：
Ignacio Casal, J.
中科院分区：
文献类型：
--
作者：
Torres, Sofia;Bartolome, Ruben A.;Ignacio Casal, J.
目的：癌症相关成纤维细胞（CAF）是基质的重要组成部分，在癌症进展中起关键作用。本研究的目的是确定新的CAFs标记，可能有助于结肠直肠cancer.Experimental Design的侵袭和预后：azoxymethane/葡聚糖硫酸钠小鼠模型散发性结肠癌的CAFs和正常成纤维细胞的分离代表了足够的来源。采用组织块培养技术，从结肠组织中分离纯化CAFs和正常成纤维细胞。通过串联质谱法对全细胞提取物和上清液进行深入的定量蛋白质组学分析。进一步验证的上调蛋白在CAFs进行了趋化因子微阵列和免疫组化分析小鼠和人体tissues.Results：使用1.4或更多的倍数变化，我们发现132和125差异表达的蛋白在全细胞提取物和上清液中，分别。我们发现了CAFs相关的促炎和促纤维增生特征。促炎信号由几种细胞因子组成。其中，CCL 2和CCL 8引起结直肠癌KM 12细胞的迁移和侵袭增加。促结缔组织增生标志物由30种分泌蛋白组成。在小鼠和人样品中，LTBP 2、CDH 11、OLFML 3，特别是FSTL 1的表达在肿瘤间质中显著增加，而在癌上皮细胞中没有显著表达。CALU和CDH 11间质表达的组合显示出显着的无病生存率和不良预后association.Conclusion：我们已经确定LTBP 2，CDH 11，OLFML 3，和FSTL 1作为选择性的肿瘤间质的生物标志物，和CALU和CDH 11作为候选间质的生物标志物的预后意义在结肠癌。(C)2013年AACR。
Purpose: Cancer-associated fibroblasts (CAF) are essential components of the stroma that play a critical role in cancer progression. This study aimed to identify novel CAFs markers that might contribute to the invasion and the prognosis of colorectal cancer.Experimental Design: The azoxymethane/dextran sodium sulfate mouse model of sporadic colon cancer represents an adequate source for the isolation of CAFs and normal fibroblasts. By using the explants technique, we purified CAFs and normal fibroblasts from colon tissues. Whole-cell extracts and supernatants were subjected to in-depth quantitative proteomic analysis by tandem mass spectrometry. Further validations of upregulated proteins in CAFs were carried out by chemokine microarray and immunohistochemical analyses of mouse and human tissues.Results: Using a fold-change of 1.4 or more, we found 132 and 125 differentially expressed proteins in whole-cell extracts and supernatants, respectively. We found CAFs-associated proinflammatory and desmoplastic signatures. The proinflammatory signature was composed of several cytokines. Among them, CCL2 and CCL8 caused an increase in migration and invasion of colorectal cancer KM12 cells. The desmoplastic signature was composed of 30 secreted proteins. In mouse and human samples, expression of LTBP2, CDH11, OLFML3, and, particularly, FSTL1 was significantly increased in the tumoral stroma, without significant expression in the cancer epithelial cells. The combination of CALU and CDH11 stromal expression showed a significant association with disease-free survival and poor prognosis.Conclusion: We have identified LTBP2, CDH11, OLFML3, and FSTL1 as selective biomarkers of cancer stroma, and CALU and CDH11 as candidate stromal biomarkers of prognostic significance in colon cancer. (C) 2013 AACR.