Differential exoprotease activities confer tumor-specific serum peptidome patterns
Differential exoprotease activities confer tumor-specific serum peptidome patterns
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DOI：
10.1172/jci26022
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发表时间：
2006-01-01
影响因子：
15.9
通讯作者：
Tempst, P
中科院分区：
文献类型：
--
作者：
Villanueva, J;Shaffer, DR;Tempst, P
最近的研究通过质谱 (MS) 建立了独特的血清多肽模式，据报道与临床相关结果相关。更广泛地接受这些特征作为疾病的有效生物标志物可能遵循这些成分的序列特征和它们生成机制的阐明。使用高度优化的肽提取和基于基质辅助激光解吸/电离飞行时间 (MALDI-TOF) MS 的方法，我们现在表明，有限的血清肽子集（特征）可以在 3 种类型的实体瘤患者和非癌症对照患者之间提供准确的类别区分。 61 个特征肽的靶向序列鉴定表明，它们分为几个紧密的簇，并且大多数是由肽链外切酶活性产生的，这些肽链赋予癌症类型特异性差异，叠加在离体凝血和补体降解途径的蛋白水解事件上。这套小而强大的标记肽可以对前列腺癌样本的外部验证集进行高度准确的类别预测。总之，这项研究提供了疾病的肽标记谱与差异蛋白酶活性之间的直接联系，并且我们描述的模式可能具有作为癌症检测和分类的替代标记的临床实用性。我们的研究结果对未来肽生物标志物的发现工作也具有重要意义。
Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.