The Emphysematous Microenvironment Promotes Lung Tumorigenesis and Progression

肺气肿微环境促进肺肿瘤的发生和进展

• 批准号: 8680330
• 负责人: STEVEN D SHAPIRO
• 金额: $ 67.01万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680330
• 关键词: Address; Animal Model; Area; Blood; Blood specimen; Cancer Etiology; Cancer Patient; Cause of Death; Cells; Cessation of life; Chest; Chronic Obstructive Airway Disease; Cohort Studies; Collagen; Development; Diagnosis; Disease; Disease Pathway; Distal; Elastin; Fostering; Gene Expression Profile; Generations; Genes; Genetic Engineering; Genomics; Geographic Distribution; Growth; Growth and Development function; Individual; Inflammation; Inflammatory; Location; Lung; Lung Inflammation; Malignant Neoplasms; Malignant neoplasm of lung; Measurable; Measures; Modeling; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Peptide Hydrolases; Play; Population; Production; Proteins; Proteomics; Public Health; Pulmonary Emphysema; Recruitment Activity; Recurrence; Research; Risk; Role; Scanning; Series; Serum; Serum Proteins; Staging; Stem cells; Structure of parenchyma of lung; Study Subject; Techniques; Testing; Time; Tissue Model; Tissues; Tumor Volume; United States; Universities; University of Pittsburgh Cancer Institute; Variant; Woman; X-Ray Computed Tomography; base; cancer diagnosis; cancer therapy; cohort; design; high risk; human tissue; lung cancer screening; lung tumorigenesis; macrophage; malignant breast neoplasm; men; mouse model; neutrophil; repaired; research study; response; screening; spatial relationship; therapy development; tool; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Lung cancer is responsible for more than 158,000 deaths and chronic obstructive pulmonary disease (COPD) is responsible for more than 125,000 deaths annually in the US, making them major public health issues. Each is responsible for more deaths in women in the US than breast cancer. Patients with COPD are at increased risk for the development of lung cancer, although the reasons for this are unclear. The research proposed in this application is designed to test the hypothesis that the development of emphysema is associated with a microenvironment in the lung that fosters the development and growth of lung cancer. This hypothesis will be tested by four approaches. Utilizing information from a large cohort of patients with early stage lung cancer already recruited at the University of Pittsburgh Cancer Institute (UPCI), rigorous quantitative analytic techniques will be applied to CT scans of the chest to determine whether the presence and extent of emphysema on the initial scan predicts long-term survival in Stage 1 lung cancer. The location of lung cancers will be correlated with the distribution of emphysema within the lungs and the rate of cancer growth to address the question of whether emphysema is a global marker for increased risk or if tumors are more likely to develop and grow faster in areas of worse emphysema. Lung tissue removed during surgical treatment of the cancer, as well as blood samples, will be analyzed using state-of-the-art genomic and proteomic techniques to test the hypothesis that there is more inflammation in the lung surrounding lung cancers that arise in individuals with emphysema and that this lung inflammation is measurable in the levels of certain proteins circulating in the blood. Lastly, a mouse model of emphysema and lung cancer will be used to define the mechanisms by which inflammation associated with emphysema promotes tumor growth and dissemination, testing the hypothesis that certain proteases released by inflammatory cells not only contribute to lung destruction but also to tumor development and growth. Taken together, these studies have the potential to provide needed information to identify patients within the COPD population who are at highest risk for lung cancer, identify those individuals who are diagnosed with early stage lung cancer who are at high or low risk for recurrence based on their COPD status, and provide information about which COPD pathways to target in developing new therapies to treat both lung cancer and COPD.

描述（由申请人提供）：肺癌造成158,000多人死亡，慢性阻塞性肺疾病（COPD）每年在美国造成超过125,000人死亡，这使他们成为主要的公共健康问题。每个人的死亡人数都比乳腺癌多。 COPD患者的肺癌发展风险增加，尽管原因尚不清楚。本应用程序中提出的研究旨在检验以下假设：肺气肿的发展与肺部的微环境有关，从而促进了肺癌的发展和生长。该假设将通过四种方法进行检验。利用来自匹兹堡大学癌症研究所（UPCI）已经招募的大量早期肺癌患者的信息，将应用严格的定量分析技术，用于胸部的CT扫描，以确定在初始扫描中的存在和程度是否可以预测最初扫描的长期生存。肺癌的位置将与肺中肺气肿的分布以及癌症生长率相关，以解决肺气肿是否是增加风险的全球标志或肿瘤在肺气肿较差的地区的可能性更快和更快的速度。在癌症的手术治疗期间切除的肺组织以及血液样本将使用最先进的基因组和蛋白质组学技术进行分析，以检验以下假说，即肺部周围肺部炎症的炎症更多，这些肺部肿瘤患有肺炎的个体和这种肺炎症在某些蛋白质水平上是可循环的，这些肺部炎症是可测量的。最后，将使用一种肺气肿和肺癌的小鼠模型来定义与肺气肿相关的炎症促进肿瘤生长和传播的机制，检验了炎性细胞释放的某些蛋白酶不仅有助于肺部破坏，而且导致肿瘤发育和生长。综上所述，这些研究有可能提供所需的信息，以识别COPD人群中患有肺癌最高风险的患者，确定那些被诊断出患有早期肺癌的人，他们根据其COPD状况患有高或低风险的复发风险，并提供有关哪种COPD途径的信息，以培养新疗法以治疗肺癌和COPD。