Inhibition of Rat Oral Carcinogenesis by Dietary Black Raspberries

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，临床前研究已经证明黑覆盆子（BRBs）在动物中具有显著的预防空气消化道肿瘤发展的能力，包括口腔（仓鼠）、食道（大鼠）和结肠（大鼠）。此外，我们正在进行的I期临床试验已经证明brb能够以一种支持口腔癌化学预防策略的方式调节炎症生物标志物的分子功效。从这些人体临床试验中，我们已经建立了一种临床相关的、口腔粘膜来源的、brb反应性生物标志物的新分子特征。为了阐明brb介导的口服化学预防的潜在基础和预防人类口腔癌发展的预测功效，需要进一步采用合适的动物模型和足够的分子试剂。虽然仓鼠颊袋模型具有成功识别具有抗癌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研究的试剂和工具，探索性和比较分子研究受到阻碍。因此，必须采用另一种合适的口腔癌动物模型。大鼠舌/4NQO口腔癌变系统为研究黑莓介导的口腔化学预防提供了一个成熟且研究充分的模型。本课题将利用大鼠舌模型探讨BRBs抑制口腔癌的能力

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.