Inhibition of Rat Oral Carcinogenesis by Dietary Black Raspberries

食用黑树莓对大鼠口腔癌的抑制作用

基本信息

批准号：
8492247
负责人：
CHRISTOPHER M WEGHORST
金额：
$ 19.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492247
关键词：
4-Nitroquinoline-1-oxide Accounting Acute Address Animal Model Animals Anthracenes Biological Biological Markers Biological Models Cancer Patient Cells Cessation of life Cheek structure Chemicals Chemoprevention Chemopreventive Agent Chronic Clinical Clinical Data Clinical Trials Colon Complement Consumption Data Defect Development Diagnosis Diet Disease Dissection Ellagic Acid Employment Environment Environmental Exposure Epidemiology Epithelial Esophagus Etiology Evaluation Event Food Foundations Future Genes Genome Genomics Hamsters Human Immune response Inbred F344 Rats Incidence Inflammation Inflammatory Inflammatory Response Intervention Investigation Lesion Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Molecular Profiling Mouth Neoplasms Mucous Membrane Mus Oral Oral cavity Oral mucous membrane structure Participant Pathologic Phase I Clinical Trials Pre-Clinical Model Prevention Prevention strategy Primary Neoplasm Prostaglandins Raspberries Rattus Reagent Recording of previous events Recurrence Research Infrastructure Resources Risk Risk Reduction Rodent Model Role Signal Transduction Solid Neoplasm Study models Survival Rate System Systems Biology Testing Time Tissues Tongue Translating Tumor Tissue Validation base cancer chemoprevention cancer prevention cancer risk carcinogenesis clinically relevant comparative dimethylbenzanthracene drinking water evidence base fruits and vegetables in vivo malignant mouth neoplasm novel nutrition oral cancer prevention oral carcinogenesis pre-clinical pre-clinical research preclinical study prevent public health relevance response tool tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Epidemiological data demonstrate a strong correlation between frequent consumption of fresh fruits and vegetables and a decreased risk of oral cancer. In support of these data, preclinical studies have demonstrated the remarkable ability of black raspberries (BRBs) to prevent the development of aerodigestive tract tumors in animals, including oral (hamsters), esophagus (rat), and colon (rats). Furthermore, our ongoing Phase I clinical trials have demonstrated the ability of BRBs to modulate inflammatory biomarkers of molecular efficacy in a manner that supports a chemopreventive strategy for oral cancer. From these human clinical trials, we have established a novel molecular signature of clinically relevant, oral mucosa-derived, BRB-responsive biomarkers. Efforts to elucidate the underlying basis of BRB-mediated oral chemoprevention and predictive efficacy to prevent human oral cancer development will require further employment of a suitable animal model with sufficient molecular reagents. While the hamster cheek pouch model has a history of successfully identifying chemicals and foods with cancer preventing activity (including BRBs), exploratory and comparative molecular studies are hampered by the lack of hamster genome information and subsequent lack of reagents and tools for in depth systems biology investigations. Therefore, another suitable animal model of oral cancer must be employed. The rat tongue/4NQO system of oral carcinogenesis represents such an established and well-studied model for the investigation of black raspberry-mediated oral chemoprevention. The present proposal will explore the ability of BRBs to inhibit oral cancer using the rat tongue model and compare the molecular efficacy of BRBs in the rat tongue to that which has been established in human oral tumors and "high-at-risk" mucosa. We hypothesize that the bioactive components in BRBs will inhibit tumorigenesis and decrease the expression of clinically relevant, pro-inflammatory molecular biomarkers associated with oral carcinogenesis. The following Specific Aims uniquely combines aspects of nutrition, molecular efficacy, and cancer prevention to address the proposed hypothesis. Studies proposed in Specific Aim 1 will establish the ability of dietary BRBs or a single BRB bioactive component (ellagic acid; EA) to inhibit tongue lesion formation during 4NQO-induced oral carcinogenesis in F344 rats. Studies proposed in Specific Aim 2 will determine the comparative molecular efficacy of BRBs and EA on rat tongue carcinogenesis using a clinically-relevant transcriptional profile of genes previous shown to be modulated by BRBs in tumor and "high at-risk" oral mucosal cells of oral cancer patients. Following the successful completion of the above Specific Aims, our novel studies will (i) define the chemopreventive potential of dietary BRBs in a rat tongue model of oral cancer, (ii) validate a signature of BRB molecular efficacy in rat oral mucosa that is directly relevant to human oral cancer and (iii) provide a foundation for future mechanistic investigation of oral cancer chemoprevention.

描述（由申请人提供）：流行病学数据表明，经常食用新鲜水果和蔬菜与降低口腔癌风险之间存在很强的相关性。为了支持这些数据，临床前研究表明黑树莓 (BRB) 具有预防动物呼吸消化道肿瘤发展的显着能力，包括口腔（仓鼠）、食道（大鼠）和结肠（大鼠）。此外，我们正在进行的一期临床试验已经证明，BRB 能够以支持口腔癌化学预防策略的方式调节分子功效的炎症生物标志物。从这些人体临床试验中，我们建立了临床相关的口腔粘膜衍生的 BRB 反应性生物标志物的新分子特征。阐明 BRB 介导的口腔化学预防的根本基础和预防人类口腔癌发展的预测功效的努力将需要进一步采用具有足够分子试剂的合适动物模型。虽然仓鼠颊囊模型具有成功识别具有癌症预防活性的化学物质和食物（包括 BRB）的历史，但由于缺乏仓鼠基因组信息以及随后缺乏用于深入系统生物学的试剂和工具，探索性和比较分子研究受到阻碍调查。因此，必须采用另一种合适的口腔癌动物模型。口腔癌发生的大鼠舌头/4NQO系统代表了用于研究黑树莓介导的口腔化学预防的已建立且经过充分研究的模型。目前的提案将利用大鼠舌头模型探索 BRB 抑制口腔癌的能力并将大鼠舌头中 BRB 的分子功效与人类口腔肿瘤和“高危”粘膜中已确定的分子功效进行比较。我们假设 BRB 中的生物活性成分将抑制肿瘤发生并降低与口腔癌发生相关的临床相关促炎分子生物标志物的表达。以下具体目标独特地结合了营养、分子功效和癌症预防等方面来解决所提出的假设。具体目标 1 中提出的研究将确定膳食 BRB 或单一 BRB 生物活性成分（鞣花酸；EA）在 4NQO 诱导的 F344 大鼠口腔癌发生过程中抑制舌头病变形成的能力。具体目标 2 中提出的研究将使用先前显示在肿瘤和口腔“高危”口腔粘膜细胞中受 BRB 调节的基因的临床相关转录谱来确定 BRB 和 EA 对大鼠舌癌发生的比较分子功效。癌症患者。在成功完成上述具体目标后，我们的新研究将 (i) 确定饮食 BRB 在口腔癌大鼠舌模型中的化学预防潜力，(ii) 验证与人类口腔癌直接相关的大鼠口腔粘膜中 BRB 分子功效的特征，并 (iii) 为未来口腔癌化学预防的机制研究奠定基础。