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口腔癌风险降低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了黑树莓（BRB）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I期临床试验已经证明了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，我们已经建立了一种新的临床相关的，口腔粘膜来源的，BRB反应性生物标志物的分子特征。为了阐明BRB介导的口腔化学预防和预防人类口腔癌发展的预测功效的潜在基础，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鉴定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研究的试剂和工具，探索性和比较性分子研究受到阻碍。因此，必须采用另一种合适的口腔癌动物模型。大鼠舌/4 NQO系统的口腔癌代表了这样一个建立和充分研究的模型，调查黑树莓介导的口腔化学预防。本研究将利用大鼠舌体模型探讨BRBs抑制口腔癌的能力 并将BRB在大鼠舌中的分子功效与在人类口腔肿瘤和“高危”粘膜中建立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的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方面，以解决所提出的假设。具体目标1中提出的研究将确定饮食BRB或单一BRB生物活性成分（鞣花酸; EA）在F344大鼠中4 NQO诱导的口腔癌发生过程中抑制舌损伤形成的能力。具体目标2中提出的研究将使用先前显示由BRB在肿瘤和口腔癌患者的“高危”口腔粘膜细胞中调节的基因的临床相关转录谱，确定BRB和EA对大鼠舌癌发生的比较分子疗效。在成功完成上述特定目标后，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） 验证大鼠口腔粘膜中BRB分子功效的特征，其与人类口腔癌直接相关，以及（iii）为口腔癌化学预防的未来机制研究提供基础。

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.