Common Pathogenetic Mechanisms of Lung Cancer and COPD

肺癌和慢性阻塞性肺病的常见发病机制

• 批准号: 8459981
• 负责人: CHRIS H WENDT
• 金额: $ 66.81万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459981
• 关键词: Affect; American; Biological Markers; Breathing; Cancer Etiology; Cardiopulmonary; Cardiovascular Diseases; Case-Control Studies; Cause of Death; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Chronic Airflow Obstruction; Chronic Obstructive Airway Disease; Clinic; Clinical; Communities; Data; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Epithelial Cells; Exercise; Extracellular Matrix; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genome; Germ Lines; Health; Incidence; Individual; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Lesion; Link; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Target; Mutation; Nucleotides; Oncogenic; Outcome; Oxidants; Pathway interactions; Patients; Pattern; Phase; Phenotype; Physiological; Prevention; Prevention strategy; Process; Protein p53; Proteome; Proto-Oncogenes; Publishing; Pulmonary Emphysema; RAS genes; Reporting; Resistance; Ribosomes; Risk; Risk Factors; Smoke; Smoker; Smoking; Solid Neoplasm; Specimen; Stress; Stroke; Systems Biology; TP53 gene; Technology; Testing; Thinking; Tissues; Tobacco; Tobacco-Associated Carcinogen; Tumor Biology; Tumor Suppressor Genes; Woman; Work; base; biobank; cancer risk; carcinogenesis; case control; clinical phenotype; disease phenotype; gain of function mutation; genome wide association study; genome-wide; improved; innovation; killings; loss of function mutation; lung Carcinoma; lung cancer screening; lung carcinogenesis; men; mortality; neoplastic; never smoker; novel diagnostics; novel strategies; pre-clinical; prevent; ras Oncogene; screening; therapeutic target; tumor

DESCRIPTION (provided by applicant): Together, lung cancer and chronic obstructive pulmonary disease (COPD) are the leading cause of death related to lung disease in the US. Accumulating data indicate that the presence of COPD increases the risk of lung cancer independent of smoking. COPD is highlighted by chronic inflammation initiated by inhaling oxidant species during tobacco combustion. The idea that chronic inflammation is a risk factor for malignancy is not new as several chronic inflammatory diseases are harbingers of cancer. These strong inferences about the links between chronic inflammation and cancer are further buttressed by recent studies linking inflammation to the tumor suppressor gene, p53 and proto-oncogene Ras. Until quite recently, conventional thinking about the genesis of solid tumors has been that the process begins in epithelial cells with somatic or germ line loss of function mutations in key tumor suppressor genes. There is strong experimental evidence to shift this paradigm demonstrating that tumor associated fibroblasts and the extracellular matrix profoundly influence tumor biology. It is therefore apparent that the stroma of the COPD lung is a highly inflammatory, fibrotic milieu; one that we hypothesize is a fertile ground for promoting and nurturing oncogenic mutations resulting from tobacco carcinogens or other exogenous or intrinsic oncogenic stresses. We propose to conduct a comprehensive genome-wide examination of COPD tissue specimens- at the level of the genome, transcriptome, genome-wide ribosome translational profile and proteome - to discover neoplastic gene expression patterns in the COPD lung that are harbingers of carcinogenesis. If successful, these results will identify biomarkers that predict those COPD patients at risk of developing lung cancer, identify therapeutic targets for chemoprevention and thus alter the course of these deadly diseases.

描述（由申请人提供）：在美国，肺癌和慢性阻塞性肺病（COPD）是肺部疾病相关死亡的主要原因。累积的数据表明，COPD的存在增加了肺癌的风险，而与吸烟无关。慢性阻塞性肺病是突出的慢性炎症所引发的吸入氧化剂的物质在烟草燃烧。慢性炎症是恶性肿瘤的危险因素的想法并不新鲜，因为几种慢性炎症性疾病是癌症的先兆。这些关于慢性炎症和癌症之间联系的强有力的推论得到了最近将炎症与肿瘤抑制基因p53和原癌基因Ras联系起来的研究的进一步支持。直到最近，关于实体瘤发生的传统想法一直是，该过程始于上皮细胞，关键肿瘤抑制基因的体细胞或生殖系功能缺失突变。有强有力的实验证据表明，肿瘤相关的成纤维细胞和细胞外基质深刻地影响肿瘤生物学。因此，很明显，COPD肺的间质是一个高度炎症性的纤维化环境;我们假设这是一个促进和培育致癌突变的肥沃土壤，这些突变是由烟草致癌物或其他外源性或内在致癌应激引起的。我们建议对COPD组织标本进行全面的全基因组检查-在基因组，转录组，全基因组核糖体翻译谱和蛋白质组水平上-以发现COPD肺中的肿瘤基因表达模式，这些基因表达模式是致癌的预兆。如果成功，这些结果将确定预测那些有患肺癌风险的COPD患者的生物标志物，确定化学预防的治疗靶点，从而改变这些致命疾病的病程。