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

猫口腔鳞状细胞癌缺氧、炎症和化疗敏感性的相关机制

• 批准号: RGPIN-2019-06898
• 负责人: Martin, Chelsea
• 金额: $ 2.33万
• 依托单位: University of Prince Edward Island
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761967
• 关键词: Mechanisms; linking; hypoxia; inflammation; chemosensitivity

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.

该计划的长期目标是帮助改善一种重要的伴发动物疾病-猫口腔鳞状细胞癌(FOSCC)的预后。FOSCC通常对化疗和放疗耐药，由于肿瘤的大小和位置，许多患者不能选择完全手术切除。FOSCC细胞具有炎症环氧合酶(COX)途径的活性。它们还表达一种炎症、侵袭和治疗耐药的介质，称为分化因子147簇(CD147)。肿瘤缺氧(低氧)在许多类型的癌症中是一种常见的事件，并与治疗抵抗和疾病进展有关。这一阶段的研究计划将检验环氧合酶和CD147以低氧依赖的方式促进猫科口腔鳞癌进展和化疗耐药的总体假设。第一个目标是确定缺氧是否激活了COX途径，刺激了CD147的表达，并降低了对化疗的敏感性。将采用CD147和PGE2合成途径的基因操作。在体外实验中确定的关键介质将在小鼠模型中使用来自基因实验的细胞株进行检查，无论是否进行化疗。在第二个目标中，将确定作为缺氧、炎症和肿瘤进展之间的机械联系的细胞内信号通路。这一目标还将包括评估PGE2受体对FOSCC行为的意义。该假说认为，PI3K/AKT信号通路在猫口腔鳞状细胞癌细胞的缺氧诱导反应中是必需的，该信号通路已知由PGE2受体EP-4激活，以及在缺氧和氧化应激期间激活。受体和信号通路在体外和体内化疗耐药中的作用也将被确定。第三个目标是确定从越橘(低灌木蓝莓和蔓越莓)中提取的抗炎药物和生物活性植物化学提取物是否可以增加猫口腔鳞状细胞癌细胞的化疗敏感性。据推测，浆果提取物的抗炎和抗氧化性能将改善FOSCC对化疗的反应。最终，长期目标是开发猫的临床试验。虽然这个项目主要关注猫科OSCC，但所揭示的基本机制将与各种与炎症相关的癌症(如胃肠道癌症和膀胱癌)相关。发现新的炎症相关靶点也将与长期使用抗炎药治疗的非癌症疾病相关，例如退行性关节疾病。最后，这项研究计划将提供持续的机会，培训未来的动物健康领域的科学家。