Identification of Colon Cancer Protein Biomarkers in the Blood

血液中结肠癌蛋白生物标志物的鉴定

基本信息

项目摘要

DESCRIPTION (provided by applicant): Detection of colorectal cancer (CRC) by examination of peripheral blood samples could enhance screening efforts of the general population and lead to better survival rates in those patients with this type of cancer. Patients have a much higher survival rate when CRC is detected at an early stage. Furthermore, even within the population of patients diagnosed with a specific stage of CRC, there can be dramatic differences in prognosis for reasons that are understood poorly. Rapid developments in proteomic analytical approaches suggest the potential to identify candidate CRC-selective biomarker proteins, akin to Prostate Specific Antigen (PSA) for prostate cancer or CA125 for ovarian cancer. A rational approach to identifying an appropriate CRC biomarker panel would be to first determine what proteins are uniquely present or elevated in colon cancer cells, compared to normal colon cells, or shed into the interstitial fluid around the tumor cells. Having identified CRC-selective proteins, one could then investigate which may be elevated in the peripheral blood. This strategy for comprehensive and detailed comparative analysis of CRC vs. normal intestinal epithelial cells could overcome key hindrances that beset many blood-screening approaches, which are often confounded by the fact that just a handful of high-abundance proteins represent more than 90% of the blood protein content. For most analytical approaches, these high abundance proteins provide a fog that obscures CRC-selective proteins or peptides. Here we propose a strategy and workflow that incorporate several interrelated analytical advances in proteomic sample processing, nano-scale liquid chromatography (nano-LC), and mass spectrometry (MS) that enhance the suitability of nano-LC/MS approaches for the analysis of tissues. These advances provide (i) highly quantitative recovery of tissue proteins (ii) highly reproducible and sensitive protein expression profiling, (iii) quantification of a significantly greater number of proteins than otherwise feasible, and (iv) highly sensitive quantification of specific proteins of interest. Employing this analytical strategy, we will (1) perform comparative proteomic analysis of cells derived from CRC vs. adjacent normal colon epithelium, in order to identify CRC-selective proteins, (2) investigate the complement of proteins or peptides that CRC cells may secrete into the extracellular environment, as these may have higher likelihood of making their way to peripheral blood, and (3) evaluating strategies to quantify CRC-selective proteins in the peripheral blood, using patient-matched blood samples collected prior to cancer surgery. Establishing the potential of this workflow and strategy would be essential for the logical follow-on to the proposed project, which would be to seek CRC-selective proteins in peripheral blood in a comprehensive clinical study. The overall outcomes of the proposed study include a blood based screening tool for the early detection of CRC, as well as a more comprehensive understanding of CRC-selective markers that could improve assessment of patient prognosis, or stratification of disease for more effective therapy.
描述(由申请人提供): 通过检查外周血样本检测结直肠癌(CRC)可以加强一般人群的筛查工作,并提高此类癌症患者的生存率。当CRC在早期被发现时,患者的生存率要高得多。此外,即使在被诊断患有CRC的特定阶段的患者人群中,由于了解不多的原因,预后也可能存在显着差异。蛋白质组学分析方法的快速发展表明,有可能识别候选的CRC选择性生物标志物蛋白,类似于前列腺癌的前列腺特异性抗原(PSA)或卵巢癌的CA 125。鉴定适当的CRC生物标志物组的合理方法是首先确定与正常结肠细胞相比,结肠癌细胞中独特存在或升高的蛋白质,或脱落到肿瘤细胞周围的间质液中。在确定了CRC选择性蛋白质之后,人们可以研究哪些蛋白质可能在外周血中升高。这种对CRC与正常肠上皮细胞进行全面详细比较分析的策略可以克服困扰许多血液筛查方法的关键障碍,这些方法通常被少数高丰度蛋白质占血液蛋白质含量的90%以上这一事实所混淆。对于大多数分析方法来说,这些高丰度蛋白质提供了一层雾,掩盖了CRC选择性蛋白质或肽。在这里,我们提出了一个战略和工作流程,将几个相互关联的分析进展,蛋白质组学样品处理,纳米级液相色谱(nano-LC),和质谱(MS),提高nano-LC/MS方法分析组织的适用性。这些进展提供了(i)组织蛋白的高度定量回收(ii)高度可重复和灵敏的蛋白表达谱分析(profiling),(iii)比其他可行方法显著更多数量的蛋白的定量,和(iv)感兴趣的特定蛋白的高度灵敏的定量。采用这种分析策略,我们将(1)对源自CRC与邻近正常结肠上皮的细胞进行比较蛋白质组学分析,以鉴定CRC选择性蛋白,(2)研究CRC细胞可能分泌到细胞外环境中的蛋白质或肽的补体,因为这些蛋白质或肽可能具有更高的可能性进入外周血,和(3)使用在癌症手术前收集的患者匹配的血液样品,评估定量外周血中CRC选择性蛋白的策略。建立这种工作流程和策略的潜力对于拟议项目的逻辑后续工作至关重要,该项目将在全面的临床研究中寻找外周血中的CRC选择性蛋白。拟议研究的总体结果包括用于早期检测CRC的基于血液的筛查工具,以及对CRC选择性标志物的更全面理解,这些标志物可以改善患者预后的评估,或疾病分层以获得更有效的治疗。

项目成果

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WILFRIDO DIOKNO MOJICA其他文献

WILFRIDO DIOKNO MOJICA的其他文献

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{{ truncateString('WILFRIDO DIOKNO MOJICA', 18)}}的其他基金

Identification of Colon Cancer Protein Biomarkers in the Blood
血液中结肠癌蛋白生物标志物的鉴定
  • 批准号:
    7883588
  • 财政年份:
    2009
  • 资助金额:
    $ 7.93万
  • 项目类别:

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