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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684327
• 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抵抗力，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细胞显示炎性环氧合酶（考克斯）途径的活性。它们还表达称为分化因子簇147（CD 147）的炎症、侵袭和治疗抗性的介质。肿瘤缺氧（低氧）是许多类型癌症中的常见事件，并与治疗抵抗和疾病进展相关。本阶段的研究计划将测试的总体假设，环氧合酶和CD 147有助于猫口腔鳞状细胞癌的进展和化疗耐药性的缺氧依赖性的方式。第一个目标是确定缺氧是否激活考克斯通路，刺激CD 147表达，并降低对化疗的敏感性。将采用CD 147和PGE 2合成途径的基因操作。将在小鼠模型中使用来自遗传实验的细胞系，在有和没有化疗的情况下检查体外实验中鉴定的关键介质。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制联系的细胞内信号传导途径。这一目标还将包括评估PGE 2受体对FOSCC行为的意义。假设是已知由PGE 2受体EP-4以及在缺氧和氧化应激期间激活的Pi 3 K/AKT信号通路将是猫OSCC细胞中缺氧诱导的反应所需的。还将确定受体和信号传导途径对体外和体内化学抗性的贡献。第三个目标是确定抗炎药物和越橘浆果（矮丛蓝莓和蔓越莓）的生物活性植物化学提取物是否可以增加猫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。虽然该计划的重点是猫科动物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用长期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，培养未来的科学家在动物健康领域。