A mouse to human search for plasma proteome changes associated with pancreatic tumor development.
A mouse to human search for plasma proteome changes associated with pancreatic tumor development.
复制标题
DOI：
10.1371/journal.pmed.0050123
复制
发表时间：
2008-06-10
期刊：
影响因子：
15.8
通讯作者：
Hanash SM
中科院分区：
文献类型：
--
作者：
Faca VM;Song KS;Wang H;Zhang Q;Krasnoselsky AL;Newcomb LF;Plentz RR;Gurumurthy S;Redston MS;Pitteri SJ;Pereira-Faca SR;Ireton RC;Katayama H;Glukhova V;Phanstiel D;Brenner DE;Anderson MA;Misek D;Scholler N;Urban ND;Barnett MJ;Edelstein C;Goodman GE;Thornquist MD;McIntosh MW;DePinho RA;Bardeesy N;Hanash SM
人类血浆蛋白质组的复杂性和异质性在鉴定与肿瘤发展相关的蛋白质变化方面提出了重大挑战。人类癌症的改良基因工程小鼠（GEM）模型已被证明忠实地概括了人类疾病的分子、生物学和临床特征。在这里，我们试图利用一个特征良好的胰腺癌GEM模型的优点来确定蛋白质组学技术是否允许鉴定与肿瘤发展相关的蛋白质变化，以及这些变化是否与人类胰腺癌相关。从肿瘤发展的早期和晚期小鼠以及匹配的对照中抽取血浆。利用基于广泛蛋白质分离的蛋白质组学方法，我们确定了1442种蛋白质，这些蛋白质在血浆中分布在7个数量级的丰度。根据荷瘤小鼠血浆中增加的水平和组织中确证的蛋白质或RNA表达，对选择的蛋白质进行分析，证实了30名新诊断的胰腺癌患者的血液与30名对照标本的一致性。在CARET（胡萝卜素和视黄醇功效试验）队列的26个人中进行了一项盲法研究，测试了根据小鼠肿瘤发展早期水平增加而选择的五种蛋白质。该小组在胰腺癌症状出现和临床诊断前7至13个月获得的血液标本中，将胰腺癌病例与匹配的对照组区分开来。我们的研究结果表明，GEM癌症模型与深入的蛋白质组学分析相结合，为识别适用于人类癌症的候选标记提供了一种有用的策略，具有早期检测的潜在效用。Samir Hanash及其同事在小鼠模型中发现了胰腺肿瘤发展早期阶段增加的蛋白质，这可能是检测人类早期肿瘤的有用工具。癌症是危及生命的、杂乱无章的细胞群，可以发生在人体的任何地方。当细胞获得基因变化，使其不受控制地生长并在全身扩散（转移）时，它们就会发展。如果癌症在很小的时候就被发现了，而且还没有转移，手术通常可以治愈。不幸的是，许多癌症只有当它们大到足以压迫周围组织并引起疼痛或其他症状时才会被发现。到这个时候，手术切除原发肿瘤可能是不可能的，可能有继发性癌症分散在身体周围。在这种情况下，放疗和化疗有时会有所帮助，但对于那些癌症发现较晚的患者来说，前景往往很糟糕。胰腺腺癌是一种晚期发现特别困难的癌症类型。这种癌症在早期很少引起任何症状。此外，它最终导致的症状——黄疸、腹部和背部疼痛以及体重减轻——在许多其他疾病中都可以看到。因此，胰腺癌通常在确诊前就已经扩散，大多数患者在确诊后一年内死亡。如果能够开发出一种检测早期胰腺癌的方法，许多患者的生命可能会得到延长。肿瘤通常会释放特定的蛋白质——“癌症生物标志物”——进入血液中，而血液是一种很容易取样的体液。如果一种由胰腺癌细胞释放到血液中的蛋白质能够被识别出来，就有可能开发出一种针对这种致命癌症的非侵入性筛查试验。在这项研究中，研究人员使用“蛋白质组学”方法来识别早期胰腺癌的潜在生物标志物。蛋白质组学是研究由生物体、组织或细胞产生的蛋白质的模式，以及与各种疾病相关的这些模式的变化。研究人员通过研究小鼠的血浆蛋白质组（血液液体部分的蛋白质）开始寻找胰腺癌的生物标志物，这些小鼠的基因工程使其发展成与人类胰腺肿瘤非常相似的癌症。通过使用高分辨率质谱法和丙烯酰胺同位素标记两种技术，研究人员确定了165种蛋白质，这些蛋白质在早期和/或晚期胰腺癌小鼠的血浆中比在对照小鼠的血浆中含量更高。然后，为了测试这些蛋白质变化是否与人类胰腺癌有关，研究人员分析了从胰腺癌患者收集的血液样本。他们报告说，这些样本比从慢性胰腺炎患者身上采集的血液中含有更多的这些蛋白质，慢性胰腺炎的症状与胰腺癌相似。最后，研究人员使用在临床试验中收集的血液样本，胡萝卜素和视黄醇功效试验（一项癌症预防研究），研究人员表明，在肿瘤发展的早期阶段，对小鼠模型中五种数量增加的蛋白质进行测量，可以在癌症诊断前13个月区分胰腺癌患者和匹配的对照组。这些发现表明，对人类癌症基因工程小鼠模型进行深入的蛋白质组学分析可能是识别适合早期检测人类癌症的生物标志物的有效方法。先前使用人类样本识别此类生物标志物的尝试受到阻碍，原因是个体之间存在许多与癌症无关的血浆蛋白差异，以及从早期癌症患者获取样本存在问题。这些发现表明，使用人类癌症的小鼠模型可以规避这两个问题。更具体地说，这些发现确定了一组蛋白质，这些蛋白质可能有助于早期发现胰腺癌，因此可能延长一些患胰腺癌的患者的生命。然而，在常规筛查试验可用之前，还需要确定更多的标记物，并在更大的患者群体中完成广泛的验证研究。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0050123访问这些网站。MedlinePlus百科全书有一个关于胰腺癌的页面（英语和西班牙语）。MedlinePlus提供了更多信息的链接，美国国家癌症研究所为患者和卫生专业人员提供了关于胰腺癌的信息（英语和西班牙语），英国慈善机构Cancerbackup也为患者提供了关于胰腺癌的信息，癌症临床蛋白质组学技术倡议（美国国家癌症研究所倡议）提供了关于蛋白质组学和癌症的教程以及小鼠蛋白质组学技术倡议的信息
The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological, and clinical features of human disease. Here, we sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer. Plasma was sampled from mice at early and advanced stages of tumor development and from matched controls. Using a proteomic approach based on extensive protein fractionation, we confidently identified 1,442 proteins that were distributed across seven orders of magnitude of abundance in plasma. Analysis of proteins chosen on the basis of increased levels in plasma from tumor-bearing mice and corroborating protein or RNA expression in tissue documented concordance in the blood from 30 newly diagnosed patients with pancreatic cancer relative to 30 control specimens. A panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse was tested in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 mo prior to the development of symptoms and clinical diagnosis of pancreatic cancer. Our findings indicate that GEM models of cancer, in combination with in-depth proteomic analysis, provide a useful strategy to identify candidate markers applicable to human cancer with potential utility for early detection. Samir Hanash and colleagues identify proteins that are increased at an early stage of pancreatic tumor development in a mouse model and may be a useful tool in detecting early tumors in humans. Cancers are life-threatening, disorganized masses of cells that can occur anywhere in the human body. They develop when cells acquire genetic changes that allow them to grow uncontrollably and to spread around the body (metastasize). If a cancer is detected when it is still small and has not metastasized, surgery can often provide a cure. Unfortunately, many cancers are detected only when they are large enough to press against surrounding tissues and cause pain or other symptoms. By this time, surgical removal of the original (primary) tumor may be impossible and there may be secondary cancers scattered around the body. In such cases, radiotherapy and chemotherapy can sometimes help, but the outlook for patients whose cancers are detected late is often poor. One cancer type for which late detection is a particular problem is pancreatic adenocarcinoma. This cancer rarely causes any symptoms in its early stages. Furthermore, the symptoms it eventually causes—jaundice, abdominal and back pain, and weight loss—are seen in many other illnesses. Consequently, pancreatic cancer has usually spread before it is diagnosed, and most patients die within a year of their diagnosis. If a test could be developed to detect pancreatic cancer in its early stages, the lives of many patients might be extended. Tumors often release specific proteins—“cancer biomarkers”—into the blood, a bodily fluid that can be easily sampled. If a protein released into the blood by pancreatic cancer cells could be identified, it might be possible to develop a noninvasive screening test for this deadly cancer. In this study, the researchers use a “proteomic” approach to identify potential biomarkers for early pancreatic cancer. Proteomics is the study of the patterns of proteins made by an organism, tissue, or cell and of the changes in these patterns that are associated with various diseases. The researchers started their search for pancreatic cancer biomarkers by studying the plasma proteome (the proteins in the fluid portion of blood) of mice genetically engineered to develop cancers that closely resemble human pancreatic tumors. Through the use of two techniques called high-resolution mass spectrometry and acrylamide isotopic labeling, the researchers identified 165 proteins that were present in larger amounts in plasma collected from mice with early and/or advanced pancreatic cancer than in plasma from control mice. Then, to test whether any of these protein changes were relevant to human pancreatic cancer, the researchers analyzed blood samples collected from patients with pancreatic cancer. These samples, they report, contained larger amounts of some of these proteins than blood collected from patients with chronic pancreatitis, a condition that has similar symptoms to pancreatic cancer. Finally, using blood samples collected during a clinical trial, the Carotene and Retinol Efficacy Trial (a cancer-prevention study), the researchers showed that the measurement of five of the proteins present in increased amounts at an early stage of tumor development in the mouse model discriminated between people with pancreatic cancer and matched controls up to 13 months before cancer diagnosis. These findings suggest that in-depth proteomic analysis of genetically engineered mouse models of human cancer might be an effective way to identify biomarkers suitable for the early detection of human cancers. Previous attempts to identify such biomarkers using human samples have been hampered by the many noncancer-related differences in plasma proteins that exist between individuals and by problems in obtaining samples from patients with early cancer. The use of a mouse model of human cancer, these findings indicate, can circumvent both of these problems. More specifically, these findings identify a panel of proteins that might allow earlier detection of pancreatic cancer and that might, therefore, extend the life of some patients who develop this cancer. However, before a routine screening test becomes available, additional markers will need to be identified and extensive validation studies in larger groups of patients will have to be completed. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050123. The MedlinePlus Encyclopedia has a page on pancreatic cancer (in English and Spanish). Links to further information are provided by MedlinePlus The US National Cancer Institute has information about pancreatic cancer for patients and health professionals (in English and Spanish) The UK charity Cancerbackup also provides information for patients about pancreatic cancer The Clinical Proteomic Technologies for Cancer Initiative (a US National Cancer Institute initiative) provides a tutorial about proteomics and cancer and information on the Mouse Proteomic Technologies Initiative
登录
查看更多内容
影响因子：
2.2
作者：
Bloomston, M;Shafii, S;Rosemurgy, AS
通讯作者：
Rosemurgy, AS
影响因子：
7
作者：
Chen, Ru;Brentnall, Teresa A.;Bronner, Mary P.
通讯作者：
Bronner, Mary P.
影响因子：
2.9
作者：
Chen, Ru;Pan, Sheng;Brentnall, Teresa A.
通讯作者：
Brentnall, Teresa A.
影响因子：
64.5
作者：
Foster, LJ;de Hoog, CL;Mann, M
通讯作者：
Mann, M
影响因子：
7
作者：
Gronborg, M;Kristiansen, TZ;Pandey, A
通讯作者：
Pandey, A