Colorectal cancer candidate biomarkers identified by tissue secretome proteome profiling
Colorectal cancer candidate biomarkers identified by tissue secretome proteome profiling
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DOI：
10.1016/j.jprot.2014.01.001
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发表时间：
2014-03-17
影响因子：
3.3
通讯作者：
Fijneman, Remond J. A.
中科院分区：
文献类型：
--
作者：
de Wit, Meike;Kant, Huub;Fijneman, Remond J. A.
结直肠癌（CRC）是一个主要的健康问题。与癌细胞中分子变化相关的生物标志物可以帮助早期检测、诊断、预后、治疗选择和疾病监测。肿瘤组织分泌体是候选生物标志物的丰富来源。为了鉴定CRC蛋白质生物标志物，通过GeLC-MS/MS分析了四对人CRC组织和患者匹配的正常结肠组织样品的分泌组，以及五种CRC细胞系的分泌组。随后的数据分析基于无标记光谱计数、Incluity Pathway Analysis、Secretome/SignalP、STRING和Cytoscape，导致组织分泌组中的2703种蛋白质鉴定，其中409种蛋白质在CRC样品中比在对照中显著更多地存在。76种候选生物标志物的选择是基于与对照相比，癌症分泌组中一致且丰富的过度表达以及推测的肿瘤起源。与先前获得的数据集的重叠分析揭示了21种适合早期检测CRC的生物标志物。免疫组织化学证实了一种候选标志物（MCM 5）在CRC中的过表达。总之，鉴定了76种候选生物标志物的人类参考数据集，我们说明了与现有临床前数据集的组合允许预先选择用于基于血液或粪便的测定的生物标志物，以支持CRC的临床管理。组织分泌组蛋白质组是一个丰富的候选生物标志物来源，其生物学意义有待进一步的验证研究。已经从临床前体外和体内结直肠癌（CRC）模型系统中获得了几个分泌组蛋白质组数据集，产生了在明确定义的实验控制条件下获得的有希望的CRC生物标志物。然而，这些生物标志物蛋白中的哪一种实际上由人类CRC样品分泌尚不清楚。据我们所知，这是第一项直接比较临床相关的人类CRC组织与患者匹配的正常结肠组织的分泌组蛋白质组的研究。我们鉴定了76种人类CRC蛋白质生物标志物，这些生物标志物可能有助于基于血液或基于粪便的检测开发，以支持CRC的临床管理。与来自明确定义的临床前研究的数据集的重叠分析有助于确定哪些临床应用最适合这些人类CRC生物标志物，即CRC的早期检测、诊断、预后、治疗选择和/或疾病监测。这在CRC小鼠模型数据集中得到了证实，揭示了21种适合早期检测CRC的人类CRC生物标志物。(C)2014爱思唯尔有限公司版权所有。
Colorectal cancer (CRC) is a major health problem. Biomarkers associated with molecular changes in cancer cells can aid early detection, diagnosis, prognosis, therapy selection, and disease monitoring. Tumor tissue secretomes are a rich source of candidate biomarkers. To identify CRC protein biomarkers, secretomes of four pairs of human CRC tissue and patient-matched normal colon tissue samples, and secretomes of five CRC cell lines were analyzed by GeLC-MS/MS. Subsequent data analysis was based on label-free spectral counting, Ingenuity Pathway Analysis, Secretome/SignalP, STRING and Cytoscape, resulting in 2703 protein identifications in the tissue secretomes, of which 409 proteins were significantly more present in CRC samples than in controls. Biomarker selection of 76 candidates was based on consistent and abundant over-representation in cancer-compared to control-secretomes, and presumed neoplastic origin. Overlap analysis with previously obtained datasets revealed 21 biomarkers suited for early detection of CRC. Immunohistochemistry confirmed overexpression in CRC of one candidate marker (MCM5). In conclusion, a human reference dataset of 76 candidate biomarkers was identified for which we illustrate that combination with existing pre-clinical datasets allows pre-selection of biomarkers for blood- or stool-based assays to support clinical management of CRC. Further dedicated validation studies are required to demonstrate their clinical applicability.Biological significanceTissue secretome proteomes are a rich source of candidate biomarkers. Several secretome proteome datasets have been obtained from pre-clinical in vitro and in vivo colorectal cancer (CRC) model systems, yielding promising CRC biomarkers obtained under well-defined experimentally controlled conditions. However, which of these biomarker proteins are actually secreted by human CRC samples was not known. To our knowledge, this is the first study that directly compares secretome proteomes from clinically relevant human CRC tissues to patient-matched normal colon tissues. We identified 76 human CRC protein biomarkers that may facilitate blood-based or stool-based assay development to support clinical management of CRC. Overlap analysis with datasets from well-defined pre-clinical studies helps to determine what clinical application suits these human CRC biomarkers best, i.e. early detection, diagnosis, prognosis, therapy selection, and/or disease monitoring of CRC. This is demonstrated for a CRC mouse model dataset, revealing 21 human CRC biomarkers suited for early detection of CRC. (C) 2014 Elsevier B.V. All rights reserved.