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通常对化学疗法和放射线有抵抗力，并且由于肿瘤的大小和位置，完全手术切除是许多患者的选择。 FOSCC细胞显示炎性环氧合酶（COX）途径的活性。他们还表达了炎症，侵袭和治疗耐药性的介体，称为分化因子147的簇（CD147）。在许多类型的癌症中，肿瘤缺氧（低氧）是一个常见事件，与治疗性和疾病进展有关。研究计划的这一阶段将检验总体假设，即环氧酶和CD147以缺氧依赖性方式促进猫OSCC的进展和化学疗法抗性。第一个目标是确定缺氧是否激活COX途径，刺激CD147表达并降低对化学疗法的敏感性。将采用CD147的遗传操纵和PGE2合成途径。在体外实验中确定的关键介质将在小鼠模型中使用遗传实验的细胞系进行检查，并进行化学疗法。在第二个目标中，将确定在缺氧，炎症和肿瘤进展之间作为机械联系的细胞内信号通路。该目标还将包括评估PGE2受体对FOSCC行为的重要性。假设是，PI3K/AKT信号通路（已知被PGE2受体EP-4激活，以及在缺氧和氧化应激期间，对于猫OSCC细胞中缺氧诱导的反应将需要缺氧和氧化应激。还将确定受体和体内化学耐药性的受体和信号通路的贡献。第三个目标是确定来自牛牛浆果（Lowbush蓝莓和蔓越莓）中的抗炎药和生物活性植物学提取物是否可以增加猫OSCC细胞的化学敏效率。假设浆果提取物的抗炎和抗氧化特性将改善FOSCC对化学疗法的反应。最终，长期目标是在猫中开发临床试验。尽管该计划的重点是猫OSCC，但揭示的基本机制将与与炎症相关的各种癌症（例如胃肠道癌和膀胱癌）相关。发现新型炎症相关的靶标也将与长期抗炎药（例如退化性关节疾病）治疗的非癌性疾病有关。最后，该研究计划将为培训动物健康领域的未来科学家提供持续的机会。