Taylor Barry S, Pal Manoj, Yu Jianjun, Laxman Bharathi, Kalyana-Sundaram Shanker, Zhao Rong, Menon Anjana, Wei John T, Nesvizhskii Alexey I, Ghosh Debashis, Omenn Gilbert S, Lubman David M, Chinnaiyan Arul M, Sreekumar Arun
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Mol Cell Proteomics. 2008 Mar;7(3):600-11. doi: 10.1074/mcp.M700263-MCP200. Epub 2007 Dec 11.
There is considerable evidence for an association between prostate cancer development and inflammation, which results in autoantibody generation against tumor proteins. This immune system-driven amplification of the autoantibody response to intracellular antigens can serve as a sensitive tool to detect low abundance serum proteomic tumor markers for prostate cancer as well as provide insight into biological processes perturbed during cancer development. Here we examine serum humoral responses in a cohort of 34 patients with either benign prostatic hyperplasia or clinically localized prostate cancer (PCa). The experimental strategy couples multidimensional liquid-phase protein fractionation of localized and metastatic prostate cancer tissue lysates to protein microarrays and subsequent mass spectrometry. A supervised learning analysis of the humoral response arrays generated a parsimonious predictor having 78% sensitivity and 75% specificity in distinguishing PCa from benign prostatic hyperplasia in a cohort of American males with elevated prostate-specific antigen. Enrichment analysis of the PCa-specific humoral signature revealed large scale immune reprogramming mediated by STAT transcription factors and the generation of autoantibodies to enzymes involved in nitrogen metabolism. Meta-analysis of independent prostate cancer gene expression data validated the presence of STAT-induced immunomodulation. Concomitant validation of elevated levels of the nitrogen metabolism pathway was obtained by direct measurement of metabolic levels of glutamate and aspartate in prostate cancer tissues. Thus, in addition to functioning as markers in prostate cancer detection, humoral response profiles can serve as powerful tools revealing pathway dysregulation that might otherwise be suppressed by the complexity of the cancer proteome.
有大量证据表明前列腺癌的发生与炎症之间存在关联，炎症会导致针对肿瘤蛋白产生自身抗体。这种由免疫系统驱动的针对细胞内抗原的自身抗体反应放大，可作为一种灵敏工具，用于检测前列腺癌低丰度血清蛋白质组肿瘤标志物，还能深入了解癌症发生过程中受到干扰的生物学过程。在此，我们检测了34例患有良性前列腺增生或临床局限性前列腺癌（PCa）患者的血清体液反应。实验策略将局限性和转移性前列腺癌组织裂解物的多维液相蛋白质分级分离与蛋白质微阵列及后续质谱分析相结合。对体液反应阵列进行的监督学习分析生成了一个简约预测指标，在一组前列腺特异性抗原升高的美国男性中，区分PCa与良性前列腺增生时，其灵敏度为78%，特异性为75%。对PCa特异性体液特征的富集分析揭示了由STAT转录因子介导的大规模免疫重编程以及针对参与氮代谢的酶产生自身抗体。对独立前列腺癌基因表达数据的荟萃分析验证了STAT诱导的免疫调节的存在。通过直接测量前列腺癌组织中谷氨酸和天冬氨酸的代谢水平，同时验证了氮代谢途径水平的升高。因此，体液反应谱除了可作为前列腺癌检测的标志物外，还能作为强大工具揭示通路失调，而这在其他情况下可能会被癌症蛋白质组的复杂性所掩盖。
