Effect of Cyclical Intermittent Hypoxia on Lung Cancer Progression

周期性间歇性缺氧对肺癌进展的影响

• 批准号: 9886831
• 负责人: Diane C Lim
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886831
• 关键词: Affect; Air; Asbestos; Bilateral; Biological Assay; Bone Marrow; Cell physiology; Cells; Cessation of life; Chemicals; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Cytokine Gene; Diesel Exhaust; Drops; Ethics; Exposure to; Funding; Future; Gases; Gene Expression; Genes; Goals; Grant; High Prevalence; Human; Hypoxia; Immune; Immune system; Immunosuppressive Agents; Incidence; Inflammation; Knowledge; Left; Link; Longitudinal Studies; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methodology; Military Personnel; Modeling; Mus; Obstructive Sleep Apnea; Organ; Outcome; Oxygen; Pathologic; Pathology; Pathway interactions; Patients; Periodicity; Population; Production; Publications; Publishing; Regulatory T-Lymphocyte; Reporting; Research Design; Risk Factors; Sampling; Scanning; Severities; Site; Sleep Apnea Syndromes; Spleen; Survival Rate; System; Thymus Gland; Time; Transgenic Mice; Transgenic Organisms; Tumor Volume; Veterans; Virus; Wild Type Mouse; angiogenesis; cancer cell; cancer survival; chemokine; clinical practice; cytokine; improved; innovation; microCT; modifiable risk; mortality; mouse model; outcome forecast; pre-clinical; pressure; prevent; primary outcome; programs; recruit; secondary outcome; side effect; smoking prevalence; subcutaneous; transcriptome sequencing; tumor hypoxia; tumor progression

Objective: Lung cancer continues to have a very poor prognosis, with Veterans having a higher incidence of lung cancer and worse outcome compared to civilians.1 Obstructive sleep apnea (OSA) has been associated with higher cancer incidence2-5 and mortality,2, 6-8 and again, Veterans have a higher prevalence of OSA that is more severe compared to civilians.9 Our overarching objective is to determine how cyclical intermittent hypoxia (CIH), a major underlying pathology of OSA, promotes lung cancer progression. Our hypothesis is that CIH increases the differentiation of immature immune cells to suppressor immune cells which then, inadvertently, protects the cancer. We have published that CIH accelerates primary lung cancer progression in Triple Transgenic KrasG12D+; p53fl/fl; myristolated p110fl/fl ROSA-gfp (TT-Kpp) mice (funded by VA CPPF grant). This grant is the next step - to explore mechanisms of HOW CIH promotes cancer progression. Research Design: The technical innovation of this grant is that we will be the first to measure the effect of mild, moderate and severe CIH on cancer progression in TT-Kpp mice (Aim 1). The conceptual innovation of this grant is that we will be the first to use this TT-Kpp model to explore whether systemic CIH increases production, differentiation and recruitment of suppressor immune cells to primary lung cancer. Methodology: Aim 1: TT-Kpp mice injected with Ad5CC10Cre virus will be exposed to one of 4 conditions: sham (room air), mild CIH (CIH15, (drops in FiO2 0.21 to FiO2 0.15 [SaO2 nadir of 82%]) moderate CIH (CIH10, (drops in FiO2 0.21 to FiO2 0.15 [SaO2 nadir of 61%]) or severe CIH (CIH5; drops in FiO2 0.21 to FiO2 0.05 [SaO2 nadir of 37%]). Primary outcome will be quantitative tumor volumes (monthly microCT scans); secondary outcome will be survival. Aim 2: Assess the effect of CIH5 (vs Sham) on production, differentiation and recruitment of suppressor immune cells in mice with and without cancer. Primary outcome will be quantitative M-MDSC/TAM/Tregs in bone marrow, spleen, thymus, left lung and right lung at early (2 weeks) and late (4 months) time points; secondary outcome will be functional assays of suppressor immune cells. Exploratory Aim 3: Develop a clone cancer cell from lung cancer of TT-Kpp mice. Also, assess the effect of CIH5 (vs Sham) regulating (1) chemokine/cytokine genes within lung cancer cell (via PCR panel at early and late time point) and (2) other genes (via RNA-seq at one time point). Together, the PCR and RNA-seq information will be utilized in a future grant where we will use CRISPR editing of significant genes within clone cells and inject them into a wild type mouse (syngeneic orthotopic model) to further understand mechanism of effect of CIH on cancer progression. Findings: First submission. Clinical Relationships: We may provide evidence that CIH, a major pathology of obstructive sleep apnea, is a modifiable risk factor that can improve lung cancer survival. Impact/Significance: Positive airway pressure, a treatment for OSA has no side effects and may be a powerful adjunct therapy to prevent lung cancer progression.

目的：肺癌的预后较差，退伍军人的发生率更高 与平民相比，肺癌和较差的结果。1阻塞性睡眠呼吸暂停（OSA）已经相关 癌症发病率较高，2-5和死亡率，2、6-8，并且退伍军人的患病率较高 与平民相比更为严重。9我们的总体目标是确定周期性间歇性缺氧如何 （CIH）是OSA的主要潜在病理，可促进肺癌的进展。我们的假设是CIH 增加了未成熟免疫细胞以抑制免疫细胞的分化，然后无意间， 保护癌症。我们已经发表了CIH加速三倍的原发性肺癌进展 转基因krasg12d+; p53fl/fl;肉豆蔻透明的P110FL/FL ROSA-GFP（TT-KPP）小鼠（由VA CPPF拨款资助）。这 Grant是下一步 - 探索CIH如何促进癌症进展的机制。研究设计： 这笔赠款的技术创新是，我们将是第一个衡量温和，中等和中等效果的人 严重的CIH对TT-KPP小鼠的癌症进展（AIM 1）。这笔赠款的概念创新是我们 将是第一个使用此TT-KPP模型探索系统性CIH是否增加产量，分化的人 并募集抑制剂免疫细胞对原发性肺癌。方法：目标1：TT-KPP小鼠 注射AD5CC10CRE病毒将暴露于4个条件之一：假（房间空气），轻度CIH（CIH15， （在FIO2 0.21中滴至FiO2 0.15 [SAO2 NADIR，82％]）中等CIH（CIH10，（FIO2 0.21滴至FiO2 0.15 [SAO2 NADIR的61％]）或严重的CIH（CIH5； FIO2 0.21降至FIO2 0.05 [SAO2 NADIR 37％]）。基本的 结果将是定量的肿瘤体积（每月微观扫描）；次要结果将是生存。目的 2：评估CIH5（VS SHAM）对抑制器免疫的生产，分化和募集的影响 有或没有癌症的小鼠中的细胞。主要结果将是骨骼中的定量M-MDSC/TAM/Tregs 骨髓，脾脏，胸腺，在早期（2周）和晚期（4个月）的时间点左肺和右肺；次要 结果将是抑制免疫细胞的功能测定。探索目标3：开发克隆癌细胞 来自TT-KPP小鼠的肺癌。另外，评估调节CIH5（VS假）的效果（1）趋化因子/细胞因子 肺癌细胞内的基因（通过PCR面板在早期和晚期点）和（2）其他基因（通过RNA-Seq AT 一个时间点）。 PCR和RNA-seq信息一起将在未来的赠款中使用 CRISPR编辑克隆细胞中的重要基因，并将其注入野生型小鼠（合成型） 原位模型）进一步了解CIH对癌症进展的影响机制。调查结果：首先 提交。临床关系：我们可能提供证据表明CIH是阻塞性睡眠的主要病理 呼吸暂停是一种可修改的危险因素，可以改善肺癌存活。影响/意义：正气道 压力，OSA治疗没有副作用，可能是防止肺的强大辅助疗法 癌症进展。