Mechanisms linking hypoxia, inflammation and chemosensitivity in feline oral squamous cell carcinoma

该项目的长期目标是帮助改善一种重要的伴侣动物疾病——猫口腔鳞状细胞癌（FOSCC）的预后。FOSCC通常对化疗和放疗有耐药性，由于肿瘤的大小和位置，许多患者不能选择完全的手术切除。FOSCC细胞显示炎症环氧化酶（COX）途径的活性。它们还表达炎症、侵袭和治疗抵抗的介质，称为CD147簇分化因子（CD147）。肿瘤缺氧（低氧）是许多类型癌症的常见事件，并与治疗耐药性和疾病进展有关。这一阶段的研究计划将测试环加氧酶和CD147以缺氧依赖的方式促进猫OSCC进展和化疗耐药的总体假设。第一个目的是确定缺氧是否激活COX通路，刺激CD147表达，降低对化疗的敏感性。将采用CD147和PGE2合成途径的遗传操作。在体外实验中发现的关键介质将在小鼠模型中进行检查，使用来自遗传实验的细胞系，有或没有化疗。在第二个目标中，细胞内信号通路作为缺氧，炎症和肿瘤进展之间的机制联系将被确定。该目标还将包括评估PGE2受体对FOSCC行为的意义。我们的假设是，已知由PGE2受体EP-4激活的Pi3K/AKT信号通路，以及在缺氧和氧化应激期间，将是猫OSCC细胞缺氧诱导反应所必需的。受体和信号通路对体外和体内化学耐药的贡献也将被确定。第三个目的是确定抗炎药物和从枸杞（低灌木蓝莓和蔓越莓）中提取的生物活性植物化学物质是否能增加猫OSCC细胞的化学敏感性。据推测，浆果提取物的抗炎和抗氧化特性将改善FOSCC对化疗的反应。最终，长期目标是在猫身上进行临床试验。虽然这个项目的重点是猫OSCC，但揭示的基本机制将与各种与炎症相关的癌症（如胃肠道和膀胱癌）相关。发现新的炎症相关靶点也将与长期使用抗炎药物治疗的非癌性疾病（如退行性关节疾病）相关。最后，这项研究计划将提供持续的机会，以培养未来的科学家在动物健康领域。

The long term goal of this program is to help improve the prognosis of an important companion animal disease, feline oral squamous cell carcinoma (FOSCC). FOSCC is often resistant to chemotherapy and radiation, and complete surgical resection is not an option for many patients due to tumour size and location. FOSCC cells show activity of the inflammatory cyclooxygenase (COX) pathway. They also express a mediator of inflammation, invasion and treatment resistance called cluster of differentiation factor 147 (CD147). Tumour hypoxia (low oxygen) is a common event in many types of cancer and has been associated with treatment resistance and disease progression. This phase of the research program will test the overall hypothesis that cyclooxygenases and CD147 contribute to feline OSCC progression and chemotherapy resistance in a hypoxia-dependant manner. The first objective is to determine if hypoxia activates the COX pathway, stimulates CD147 expression, and reduces sensitivity to chemotherapy. Genetic manipulation of CD147 and the PGE2 synthesis pathway will be employed. Key mediators identified in the in vitro experiments will be examined in the mouse model using cell lines from the genetic experiments, with and without chemotherapy. In the second objective, intracellular signalling pathways serving as a mechanistic link between hypoxia, inflammation and tumour progression will be identified. This objective will also include evaluating the significance of PGE2 receptors to FOSCC behaviour. The hypothesis is that the Pi3K/AKT signalling pathway, known to be activated by PGE2 receptor EP-4, as well as during periods of hypoxia and oxidative stress, will be required for hypoxia-induced responses in feline OSCC cells. Contributions of the receptors and signalling pathways to in vitro and in vivo chemoresistance will also be determined. The third objective is to determine if anti-inflammatory drugs and bioactive phytochemical extracts from Vaccinium berries (lowbush blueberry and cranberry) can increase chemosensitivity in feline OSCC cells. It is hypothesized that the anti-inflammatory and anti-oxidant properties of the berry extracts will improve FOSCC response to chemotherapy. Eventually, the long term goal is to develop clinical trials in cats. Although this program focuses on feline OSCC, the fundamental mechanisms that are revealed will have relevance to a variety of cancers associated with inflammation (such as cancer of the gastrointestinal tract and urinary bladder). Discovering novel inflammation-associated targets will also have relevance to non-cancerous conditions that are treated with long-term anti-inflammatory drugs, such as degenerative joint disease. Finally, this research program will provide ongoing opportunities to train future scientists in the field of animal health.