Biomarkers of Opisthorchis viverrini-induced cholangiocarcinoma

Opisthorchis viverrini 诱导的胆管癌的生物标志物

• 批准号: 8025569
• 负责人: Jeffrey Michael Bethony
• 金额: $ 57.11万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025569
• 关键词: Address; Archives; Asians; Bile duct carcinoma; Biliary; Biological Markers; Carcinogens; Case-Control Studies; Cell Culture Techniques; Cell Line; Cholangiocarcinoma; Chronic; Clinical; Cohort Studies; Communicable Diseases; Complement; Complex; Country; Culture Media; Development; Diagnosis; Diet; Disease; Disease Progression; Disorder by Site; Dissection; Duct (organ) structure; Early Diagnosis; Epithelial Cells; Epithelium; Event; Excision; Extrahepatic; Far East; Fasciola hepatica; Feeds; Fibrosis; Fishes; Freezing; Frozen Sections; Helminths; Human; Incidence; Individual; Infection; Inflammation; International Agency for Research on Cancer; Intrahepatic Cholangiocarcinoma; Investigation; Label; Laos; Lasers; Lesion; Link; Liquid Chromatography; Liver; Liver neoplasms; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Membrane Proteins; Modeling; Monitor; National Institute of Allergy and Infectious Disease; Opisthorchis viverrini; Parasites; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Persons; Plasma; Population; Prevalence; Process; Proteins; Proteomics; Province; Relative (related person); Resected; Risk; Risk Factors; Sampling; Scanning; Site; Source; Southeastern Asia; Staging; Survival Rate; System; Technology; Thailand; Time; Tissue Banking; Tissue Banks; Tissue Sample; Tissues; Tumor Tissue; World Health Organization; base; bile duct; carcinogenesis; cholangiocyte; cohort; diagnostic accuracy; infection related cancer; innovation; intrahepatic; mortality; multiple reaction monitoring; outcome forecast; pathogen; programs; protein expression; success; tandem mass spectrometry; tool; tumor

DESCRIPTION (provided by applicant): Cholangiocarcinoma (CCA) - bile duct cancer - is associated with late presentation, poses challenges for diagnosis and has high mortality, features that highlight the need for biomarkers than can be measured early and in accessible samples such as plasma. However, despite extensive investigations, efforts have failed to yield biomarkers with adequate diagnostic accuracy and utility for CCA. We will address previous limitations in the discovery of CCA biomarker(s) by undertaking a biomarker program in the global epicenter of CCA, Khon Kaen province, Thailand, which has highest incidence of intrahepatic CCA in the world. A key factor in the success of this proposal is that, while the causative agent for CCA in the West remains obscure, the single most important risk factor for intrahepatic CCA in Thailand has long been established - infection with the liver fluke Opisthorchis viverrini (OV). As determined by the WHO's IARC, no stronger link between a human malignancy and a eukaryotic pathogen exists than between CCA and infection with OV. We will utilize this well-established link between a parasite infection and cancer for the discovery and verification of biomarkers for CCA in plasma. Using a quantitative proteomic approach, we propose to scan 30 frozen, resected liver tumor tissues from confirmed OV-induced CCA cases to assemble a suite of proteins (candidate biomarkers) proximal to the disease site. We will complement this analysis with a scan of CCA cell lines which, unlike the frozen liver sections, measure the expression of secreted/membrane proteins (the secretome). Potential biomarkers identified from these two sources will be verified in plasma samples paired with the 30 frozen, resected liver tissues from confirmed OV-induced CCA patients. The candidate biomarkers will then be verified in the plasma of OV- infected individuals at risk for CCA in a case control study from our NIAID-sponsored longitudinal study that traces cholangiocarcinogenesis from chronic O. viverrini infection to CCA. The use of this exceptional set of samples will enable us to address previous limitations to CCA biomarker discovery as follows. First, we can reliably measure risk for exposure by determining infection with OV. Second, the Khon Kaen study site has the highest incidence of CCA in the world, giving us access to large numbers of CCA samples. Third, using our NIAID-sponsored longitudinal study, we can trace pathogenesis along the entire continuum: from infection with OV to diagnosis with CCA. Fourth, we plan biomarker discovery in banked tissue proximal to the tumor (resected liver) followed by verification in plasma from these same CCA patients and then in "at risk" patients in our cohort study. Hence, the overarching innovation of this proposal is that we will utilize a model of human carcinogenesis in which the major risk factor, as well as many of the intermediate stages on the pathway, to CCA have been well-defined. PUBLIC HEALTH RELEVANCE: Cholangiocarcinoma (CCA) is a form of liver cancer with a devastatingly poor prognosis. In East Asia, unlike in the West, long term infection with a parasitic worm leads to CCA. Because of access to numerous cases of CCA in Thailand and nearby countries, and because it is feasible to monitor the development of CCA from the time of infection with the parasite, we propose a biomarker discovery program using CCA samples from liver fluke infected persons in Thailand. This could eventuate in tools for early diagnosis of CCA, which are not available at present, and thereby allow for treatment, not only in Asian populations but for people at risk of CCA in the US and other western countries.

描述（由申请人提供）：胆管癌（CCA） - 胆管癌 - 与晚期呈现有关，对诊断的挑战构成挑战，具有高死亡率，这些特征强调了对生物标志物的需求，而不是早期和可访问的样品（如等质者）。然而，尽管进行了广泛的调查，但努力仍未产生具有足够诊断准确性和效用的CCA的生物标志物。我们将通过在CCA的全球CCA，泰国孔肯省的全球震中进行生物标志物计划来解决CCA生物标志物的以前局限性，该计划在世界范围内的CCA发病率最高。该提案成功的关键因素是，尽管西方CCA的致病剂仍然晦涩难懂，但长期以来一直建立了泰国肝内CCA的最重要的危险因素 - 感染了肝氟live opisthorchis viverrini（OV）。由WHO的IARC确定，人类恶性肿瘤与真核病原体之间没有比CCA和OV感染之间的紧密联系。我们将利用寄生虫感染与癌症之间的这种良好的联系，以发现和验证血浆中CCA的生物标志物。使用定量蛋白质组学方法，我们建议从确认的OV诱导的CCA病例中扫描30冷冻，切除肝脏肿瘤组织，以组装靠近该疾病部位的蛋白质（候选生物标志物）。我们将通过扫描CCA细胞系的扫描来补充这种分析，与冷冻肝脏切片不同，它测量了分泌/膜蛋白的表达（分泌组）。从这两种来源中鉴定出的潜在生物标志物将在血浆样品与30个冷冻的，从确认的OV诱导的CCA患者中切除的肝组织配对。然后，将在我们的NIAID赞助的纵向研究中，将候选生物标志物在有CCA风险的OV感染个体的血浆中进行验证，这些纵向研究追溯了从慢性O. viverrini感染到CCA的胆管癌发生。使用此特殊样本集将使我们能够解决对CCA生物标志物发现的先前限制，如下所示。首先，我们可以通过确定OV感染来可靠地衡量暴露的风险。其次，Khon Kaen研究地点的CCA发病率最高，使我们可以访问大量CCA样品。第三，使用我们的NIAID赞助的纵向研究，我们可以沿整个连续体追踪发病机理：从带有OV的感染到CCA诊断。第四，我们计划在肿瘤近端（切除的肝脏）近端进行生物标志物发现，然后在这些同一CCA患者的血浆中进行验证，然后在我们的队列研究中“处于危险”患者中。因此，该提案的总体创新是，我们将利用人类致癌的模型，其中主要危险因素以及途径上的许多中间阶段都对CCA有很好的定义。 公共卫生相关性：胆管癌（CCA）是一种肝癌的一种形式，预后较差。与西亚不同，与西亚不同，长期感染带有寄生虫蠕虫会导致CCA。由于从泰国和附近的国家 /地区遇到了许多CCA病例，并且由于从寄生虫感染时监测CCA的发展是可行的，因此我们建议使用来自泰国肝氟化物感染者的CCA样品进行生物标志物发现计划。这可能会在目前尚不可用的CCA的早期诊断工具中发生，因此不仅可以在亚洲人口中，而且在美国和其他西方国家有CCA风险的人进行治疗。