Neuroimmune Mechanisms of Cancer-Related Symptoms in Oral Squamous Cell Carcinoma

口腔鳞状细胞癌癌症相关症状的神经免疫机制

• 批准号: 9408393
• 负责人: Robert Dantzer
• 金额: $ 10.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408393
• 关键词: Affect; Animals; Attenuated; Behavioral; Biological Response Modifiers; Biology; Brain; Cancer Etiology; Cancer Patient; Cell Death; Cells; Cisplatin; Communication; Cytokine Signaling; Cytotoxic Chemotherapy; DNA Damage; Deglutition Disorders; Development; Dioxygenases; Enzymes; Epidemic; Event; Fatigue; Functional disorder; Goals; Human Papillomavirus; Human papillomavirus 16; Immune; Immune response; Immune system; Impaired cognition; Implant; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intervention; Kynurenine; Left; Malignant Neoplasms; Measures; Mediating; Mental Depression; Microglia; Mixed Function Oxygenases; Modality; Molecular; Moods; Mus; Neuraxis; Neuroimmunomodulation; Neurons; Normal tissue morphology; Oncogenic Viruses; Operative Surgical Procedures; Oral cavity; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Pain; Pathway interactions; Patients; Pattern; Peripheral; Pharyngeal structure; Population; Preventive treatment; Quality of life; Radiation; Radiation therapy; Recruitment Activity; Research; Risk; Role; Running; Signal Pathway; Signal Transduction; Sleep Disorders; Societies; Symptoms; Testing; Time; Toxic effect; Treatment Efficacy; Treatment-Related Cancer; Tryptophan; United States Food and Drug Administration; behavioral response; behavioral study; cancer therapy; cell transformation; chemoradiation; chemotherapy; cost; curative treatments; daily functioning; design; experience; improved; indoleamine; innovation; male; mouse model; mouth squamous cell carcinoma; negative affect; neoplastic cell; neuronal circuitry; neurotoxic; oral mucositis; palliative; prevent; public health relevance; reduce symptoms; relating to nervous system; repaired; response; social; symptom treatment; tumor

 DESCRIPTION (provided by applicant): Patients with human papilloma virus (HPV+)-related oropharyngeal squamous cell carcinoma (OPSCC) experience severe systemic symptoms including fatigue, depression, and cognitive dysfunction during the course of cancer therapy. These symptoms negatively affect quality of life and compromise their daily social and vocational functioning, even after cessation of therapy. The long-term goal of this project is to elucidate, using a syngeneic murine model of HPV+ OPSCC exposed to chemoradiation, how the tumor and cancer therapy induce symptoms and what can be done to prevent symptom development. Because of the strong analogy between cancer-related symptoms and the behavioral signs of inflammation-induced sickness, the working hypothesis is that the inflammatory response to HPV+ OPSCC and to cytotoxic therapy propagates to the brain and activates the neuronal circuitry of sickness. This hypothesis will be tested in 3 specific aims designed to: (1) characterize the association between the development of sickness and the time course of peripheral and central inflammation, and determine the status of microglia activation in mice implanted with HPV+ positive tumor cells and exposed to chemoradiation; (2) identify the molecular factors that cause tumor- and chemoradiation-associated sickness by focusing on triggers and mediators of inflammation, including damage-associated molecular patterns (DAMPs) and cytokine signaling pathways; and (3) determine whether activation of the kynurenine pathway downstream of cytokine signaling pathways contributes to the development of chemoradiation-induced sickness. Because the immune system of the host is involved in chemoradiation-induced clearance of OPSCC especially in HPV+ tumors, we will search for druggable targets in the chain of events leading from the release of DAMPs to the recruitment of neuronal circuits of sickness that do not compromise tumor clearance and survival. There is an increasing incidence rate of HPV+ OPSCC that contrasts with steady declines in HPV-OPSCC. HPV+ OPSCC predominantly affects individuals at peak productive points in their lives, with enormous costs to affected individuals and the society. Identification of means to alleviate symptom burden and facilitate the return to normal daily functioning will have an important positive individual and societal impact.

 描述（由适用提供）：患有人乳头瘤病毒（HPV+）的患者 - 相关的口咽鳞状细胞癌（OPSCC）在癌症治疗过程中经历了严重的全身症状，包括疲劳，抑郁和认知功能障碍。这些症状也会对生活质量产生负面影响，并在停止治疗后损害​​其日常社会和职业功能。该项目的长期目标是使用暴露于化学辐射的HPV+ OPSCC的合成鼠模型阐明，肿瘤和癌症疗法如何引起症状以及可以采取什么措施来防止症状发展。由于癌症相关症状与炎症引起的疾病的行为迹象之间有很强的比喻，因此起作用的假设是对HPV+ OPSCC的炎症反应以及对细胞毒性疗法的炎症反应可以传播到大脑并激活疾病的神经元回路。该假设将在3个特定目的中进行测试，以：（1）表征疾病发展与周围和中枢感染的时间过程之间的关联，并确定在植入HPV+阳性肿瘤细胞的小鼠中的小胶质细胞活化状态，并暴露于化学疗法； （2）通过关注炎症的触发因素和介体（包括损伤相关的分子模式（DAMP）和细胞因子信号传导途径，可以确定引起肿瘤和化学放疗相关疾病的分子因素； （3）确定细胞因子信号通路下游的kynurenine途径的激活是否有助于化学放疗诱导的疾病的发展。由于宿主的免疫学系统参与化学放疗引起的OPSCC清除率，尤其是在HPV+肿瘤中，因此我们将在从潮湿释放到招募疾病神经元电路的一系列事件中寻找可吸毒的靶标，这些疾病不会损害肿瘤清除和生存。 HPV+ OPSCC的发病率越来越高，与HPV-OPPCC的稳定下降形成对比。 HPV+ OPSCC主要影响个人生活中峰值生产力的个人，对受影响的个人和社会的成本提高了。识别减轻症状的手段并促进恢复正常的日常功能，将产生重要的积极个人和社会影响。