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 - 与晚期发病相关，给诊断带来挑战并且死亡率高，这些特征突出表明需要早期可在血浆等可获取样本中测量的生物标志物。然而，尽管进行了广泛的研究，但仍未能产生对 CCA 具有足够诊断准确性和实用性的生物标志物。我们将通过在 CCA 全球震中——泰国孔敬省（全球肝内 CCA 发病率最高）开展生物标志物项目，解决以前发现 CCA 生物标志物的局限性。该提案成功的一个关键因素是，虽然西方 CCA 的病原体仍不清楚，但泰国肝内 CCA 的一个最重要的危险因素早已确定 - 肝吸虫 Opisthorchis viverrini (OV) 感染。根据 WHO IARC 的确定，人类恶性肿瘤与真核病原体之间的联系并不比 CCA 与 OV 感染之间的联系更紧密。我们将利用寄生虫感染与癌症之间这一已确立的联系来发现和验证血浆中 CCA 的生物标志物。我们建议使用定量蛋白质组学方法扫描 30 个来自已确诊的 OV 诱导的 CCA 病例的冷冻切除肝肿瘤组织，以组装靠近疾病部位的一套蛋白质（候选生物标志物）。我们将通过 CCA 细胞系扫描来补充这一分析，与冰冻肝脏切片不同，CCA 细胞系扫描分泌/膜蛋白（分泌组）的表达。从这两个来源鉴定出的潜在生物标志物将在血浆样本中进行验证，该血浆样本与来自确诊的 OV 诱发 CCA 患者的 30 个冷冻切除肝组织配对。然后，候选生物标志物将在 NIAID 赞助的纵向研究中的病例对照研究中在有 CCA 风险的 OV 感染个体的血浆中得到验证，该纵向研究追踪从慢性 O. viverrini 感染到 CCA 的胆管癌发生。使用这组特殊的样本将使我们能够解决之前 CCA 生物标志物发现的局限性，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风险。其次，孔敬研究中心的 CCA 发病率是世界上最高的，使我们能够获得大量的 CCA 样本。第三，利用 NIAID 赞助的纵向研究，我们可以追踪整个连续体的发病机制：从 OV 感染到 CCA 诊断。第四，我们计划在靠近肿瘤（切除的肝脏）的储存组织中发现生物标志物，然后在这些相同的 CCA 患者的血浆中进行验证，然后在我们的队列研究中的“高危”患者中进行验证。因此，该提案的首要创新之处在于，我们将利用人类致癌模型，其中主要风险因素以及 CCA 途径的许多中间阶段已得到明确定义。 公共卫生相关性：胆管癌 (CCA) 是肝癌的一种形式，预后极差。在东亚，与西方不同，长期感染寄生虫会导致 CCA。由于在泰国和附近国家获得了大量 CCA 病例，并且从感染寄生虫时起监测 CCA 的发展是可行的，因此我们提出了一项使用来自泰国肝吸虫感染者的 CCA 样本的生物标志物发现计划。这最终可能会产生目前尚无的早期诊断 CCA 的工具，从而不仅可以为亚洲人群提供治疗，还可以为美国和其他西方国家有 CCA 风险的人群提供治疗。