Bacterial and Chemical Carcinogens in Gastric Oncogenesis

胃肿瘤发生中的细菌和化学致癌物

• 批准号: 8271317
• 负责人: D. SCOTT MERRELL
• 金额: $ 32.3万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271317
• 关键词: Acidity; Adherence; Africa South of the Sahara; Angiodysplasia; Animals; Antioxidants; Apoptosis; Attention; Biopsy; Cancer Etiology; Carcinogens; Cessation of life; Chemopreventive Agent; Clinical Research; Complex; Country; DNA Repair Gene; Diet; Dietary Component; Dietary Factors; Dietary Nitrosamine; Disease; Early Diagnosis; Employee Strikes; Epidemiologic Studies; Epithelial; Epithelial Cells; Equilibrium; Gastric mucosa; Gastritis; Gene Expression; Genes; Genome; Genotype; Goals; Grant; Harvest; Health; Helicobacter Infections; Helicobacter pylori; Histology; Histopathology; Human; IL8 gene; Immune response; In Situ Hybridization; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intake; Intraepithelial Neoplasia; Isoflavones; Japan; Lesion; Life; Macaca mulatta; Microscopic; Modeling; Molecular; Molecular Profiling; Monkeys; Morbidity - disease rate; Neoplasms; Neoplastic Cell Transformation; Nutrient; Oral; Oral Administration; Output; Pathogenesis; Patients; Peptic Ulcer; Peripheral; Peristalsis; Persons; Phenotype; Phytoestrogens; Placebos; Play; Population; Premalignant; Primates; Principal Investigator; Production; Prospective Studies; Regulatory T-Lymphocyte; Relative (related person); Research; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Staging; Stomach; Stomach Carcinoma; Subgroup; Survival Rate; T-Lymphocyte; Testing; Time; Tumor Suppressor Genes; Virulence; Virulent; base; carcinogenesis; chemical carcinogen; cytokine; dietary antioxidant; in vivo; mortality; neoplastic; novel; prevent; programs; prospective; repaired; response; stomach endoscopy; tumorigenesis

DESCRIPTION (provided by applicant): Gastric Carcinoma (GC) is the second leading cause of cancer death worldwide, but its incidence is highly variable among different countries and populations. Whether GC occurs or not depends on a complex equilibrium between inflammation resulting from gastric bacterial flora (especially Helicobacter pylori), and intake of carcinogenic and protective nutrients. H. pylori persists in the gastric mucosa of >50% of humans worldwide for the life of the host, despite intense immune and inflammatory responses, gastric acidity, peristalsis, and epithelial turnover. We receltly demonstrated that H. pylori infection alone caused only a persistent inflammatory response and that a dietary carcinogen alone caused only angiodysplasia. In contrast, the association of the carcinogen and H. pylori infection for three years induced precancerous lesions that were replaced at 5-year by intraepithelial neoplasia in half of the animals. Array, real- time RT-PCR, and in situ hybridization analysis of gastric biopsies demonstrated molecular signatures that were specific to each of the monkey subgroups, including the three animals with intraepithelial neoplasia. Progress to date illustrates the complexity of the co-carcinogenenic effects of bacterial and dietary factors and the following hypotheses:: (1) H. pylori up-regulates pro-inflammatory genes and down-regulates DNA repair genes and tumor suppressor genes (TSG); the resulting weakening of normal repair mechanisms of epithelial cells may potentiate the effects of dietary carcinogens and be counteracted by protective dietary phytoestrogens; (2) an imbalance between the functions of effector and regulatory T cells may promote carcinogenesis; and (3) The gastric milieu promotes alterations of the H. pylori genome and modifies its virulence. The rhesus monkey model is particularly well adapted to test these hypotheses and to fulfill the following specific aims: (1) to characterize the effect of the bacterial carcinogen H. pylori, of a dietary procarcinogen and of protective nutrients on gastric mucosa at the macroscopic, microscopic and molecular level; (2) to study the gastric mucosal cellular immune response in response to long term H. pylori infection and dietary factors; and (3) to explore the effect of diet and of the host's responses on H. pylori genome. Monkeys with and without H. pylori infection and/or administration of a dietary carcinogen will be exposed to an isoflavones-depleted diet and the gastric mucosa will be studied for precancerous and neoplasitc transformation This prospective study of histological and molecular effects of diet and bacterial carcinogens will provide novel and useful information regarding the early and late stages of carcinogenesis. PUBLIC HEALTH RELEVANCE: Gastric Carcinoma (GC) is the second leading cause of cancer death worldwide. Because survival at 5-year is very low, there is a need for a better understanding of the pathogenesis of the disease The proposed studies will permit a prospective analysis of the histological and molecular effects of dietary components and bacterial carcinogens during the early and late stages of carcinogenesis in a primate model.

描述（由申请人提供）：胃癌（GC）是全球第二大癌症死亡原因，但其发病率在不同国家和人群之间差异很大。 GC是否发生取决于胃细菌菌群（尤其是幽门螺杆菌）引起的炎症与致癌和保护性营养素摄入之间的复杂平衡。尽管存在强烈的免疫和炎症反应、胃酸度、蠕动和上皮更新，但幽门螺杆菌在全球超过 50% 的人的胃粘膜中持续存在。我们最近证明，单独的幽门螺杆菌感染仅引起持续的炎症反应，单独的饮食致癌物仅引起血管发育不良。相比之下，致癌物和幽门螺杆菌感染持续三年的关联会诱发癌前病变，并在五年后在一半的动物中被上皮内瘤变所取代。胃活检的阵列、实时 RT-PCR 和原位杂交分析证明了每个猴子亚群特有的分子特征，包括三只患有上皮内瘤变的动物。迄今为止的进展说明了细菌和饮食因素共同致癌作用的复杂性以及以下假设：（1）幽门螺杆菌上调促炎基因并下调DNA修复基因和肿瘤抑制基因（TSG） ;由此导致的上皮细胞正常修复机制的减弱可能会增强膳食致癌物的作用，并被保护性膳食植物雌激素所抵消； (2)效应T细胞和调节性T细胞功能失衡可能促进癌变； (3)胃环境促进幽门螺杆菌基因组的改变并改变其毒力。恒河猴模型特别适合测试这些假设并实现以下具体目标：（1）从宏观上表征细菌致癌物幽门螺杆菌、膳食致癌物和保护性营养素对胃粘膜的影响，微观和分子水平； （2）研究长期幽门螺杆菌感染和饮食因素对胃粘膜细胞免疫反应的影响； (3) 探索饮食和宿主反应对幽门螺杆菌基因组的影响。感染或未感染幽门螺杆菌和/或摄入膳食致癌物的猴子将接触不含异黄酮的饮食，并研究胃粘膜的癌前病变和肿瘤转化。这项关于饮食和细菌致癌物的组织学和分子效应的前瞻性研究将提供有关癌症发生的早期和晚期阶段的新颖且有用的信息。公众健康相关性：胃癌 (GC) 是全球第二大癌症死亡原因。由于 5 年生存率非常低，因此需要更好地了解该疾病的发病机制。拟议的研究将允许对早期和晚期饮食成分和细菌致癌物的组织学和分子影响进行前瞻性分析灵长类动物模型中的致癌作用。

项目成果

SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans.

• DOI: 10.1371/journal.ppat.0020110
• 发表时间: 2006-10
• 期刊: PLOS PATHOGENS
• 影响因子: 6.7
• 作者: Aspholm, Marina;Olfat, Farzad O.;Norden, Jenny;Sonden, Berit;Lundberg, Carina;Sjostrom, Rolf;Altraja, Siiri;Odenbreit, Stefan;Haas, Rainer;Wadstrom, Torkel;Engstrand, Lars;Semino-Mora, Cristina;Liu, Hui;Dubois, Andre;Teneberg, Susann;Arnqvist, Anna;Boren, Thomas
• 通讯作者: Boren, Thomas

Mechanism of H. pylori intracellular entry: an in vitro study.

• DOI: 10.3389/fcimb.2012.00013
• 发表时间: 2012
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Liu H;Semino-Mora C;Dubois A
• 通讯作者: Dubois A

Development of a noninvasive method for detecting and monitoring the time course of Helicobacter pylori infection.

开发一种非侵入性方法来检测和监测幽门螺杆菌感染的时间过程。

• DOI: 10.1128/iai.72.9.5358-5364.2004
• 发表时间: 2004
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Nyan,DougbehC;Welch,AnthonyR;Dubois,Andre;ColemanJr,WilliamG
• 通讯作者: ColemanJr,WilliamG

In situ expression of cagA and risk of gastroduodenal disease in Helicobacter pylori-infected children.

幽门螺杆菌感染儿童中 cagA 的原位表达与胃十二指肠疾病的风险。

• DOI: 10.1097/mpg.0b013e3181bab326
• 发表时间: 2010
• 期刊: Journal of pediatric gastroenterology and nutrition
• 影响因子: 2.9
• 作者: Rick,JamesR;Goldman,Matthew;Semino-Mora,Cristina;Liu,Hui;Olsen,Cara;Rueda-Pedraza,Eugenia;Sullivan,Carolyn;Dubois,Andre
• 通讯作者: Dubois,Andre

Role of mucin Lewis status in resistance to Helicobacter pylori infection in pediatric patients.

• DOI: 10.1111/j.1523-5378.2010.00765.x
• 发表时间: 2010-08
• 期刊: Helicobacter
• 影响因子: 4.4
• 作者: Lindén S;Semino-Mora C;Liu H;Rick J;Dubois A
• 通讯作者: Dubois A