Asthma is a Prognostic Indicator for Pulmonary Metastasis of Breast Cancer

哮喘是乳腺癌肺转移的预后指标

• 批准号: 7787921
• 负责人: JAMES Joseph LEE
• 金额: $ 9.32万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787921
• 关键词: Adhesions; Adrenal Cortex Hormones; Adult; Age; Allergens; Allergic; Animals; Asthma; Blood Circulation; Breathing; Cancer Patient; Cell Communication; Cells; Clinic; Control Animal; Data; Databases; Diagnosis; Disease; Disease Progression; Distant; Distant Metastasis; Environment; Epidemiologic Studies; Extravasation; Extrinsic asthma; Goals; Growth; Human; Incidence; Inflammation; Inflammatory; Injection of therapeutic agent; Institutes; Kinetics; Lead; Leukocytes; Link; Lung; Lung diseases; Mammary Neoplasms; Matched Case-Control Study; Mediating; Melanoma Cell; Metastatic Neoplasm to the Lung; Modeling; Mus; Neoplasm Metastasis; Nested Case-Control Study; Noninfiltrating Intraductal Carcinoma; Onset of illness; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pneumonia; Probability; Prospective Studies; Recurrence; Relative (related person); Research Design; Retrospective Studies; Role; Screening procedure; Site; Staging; Study Subject; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Translations; Treatment Protocols; United States; Vascular Endothelium; Woman; breast cancer diagnosis; case control; circulating cancer cell; cohort; expectation; experience; lymphatic circulation; malignant breast neoplasm; mouse model; neoplastic cell; novel; primary outcome; prognostic indicator; public health relevance; trafficking; tumor

DESCRIPTION (provided by applicant): PROJECT SUMMARY: The specific mechanisms that elicit breast cancer metastasis are still the subject of study. However, an implicit assumption is that they occur as a consequence of cells shed from breast tumors that have entered peripheral and/or lymphatic circulation; subsequent cell-cell interactions with the vascular endothelium lead to adhesion and extravasation from circulation. Our studies of mouse models of allergic pulmonary inflammation have demonstrated that the proposed pathways leading to metastasis have significant similarities with the mechanisms mediating allergen-induced tissue-specific recruitment of leukocytes. In particular, the activation of the lung vascular endothelium is an underlying mechanism required by circulating pro-inflammatory cells to mediate firm adhesion and eventual diapedesis into the pulmonary parenchyma. We have capitalized on these allergic asthma studies and have utilized a melanoma cell transfer model of metastasis to demonstrate that relative to allergen-naive control animals, the number of pulmonary metastases in allergic mice is significantly increased. In addition, these preliminary studies showed that the increase in metastasis was T cell dependent and was effectively blocked with drugs commonly used to treat asthma patients (e.g., inhaled corticosteroids). Thus, the data suggest that pulmonary allergic inflammation generates an environment favorable for adhesion and extravasation of circulating cancer cells. Moreover, the evolutionarily conserved character of these trafficking mechanisms suggests valid extrapolation of this mouse model data to human patients. The Central Hypothesis of this application is that allergen-induced activation of the pulmonary vascular endothelium associated with asthma increases the rate of metastasis to the lung. Collectively, our preliminary studies showed that allergic pulmonary inflammation results in a significant increase in the probability of metastasis to the lungs of mice as compared to non-allergic animals. More significantly, further studies also examined a breast cancer patient database and showed that a similar correlation likely exists in humans. The objectives of this application will be achieved through a nested case-control study within an underlying cohort of breast cancer patients whose disease progression has led to distant metastasis. The Specific Aim of this application is to determine if the odds of a prior diagnosis of asthma is greater among women with lung metastasis (cases) compared to women with metastasis to other distant sites (controls). Our long term goal is the eventual translation of this retrospective study into a larger more comprehensive prospective study defining specific parameters of this potential relationship. PUBLIC HEALTH RELEVANCE: RELEVANCE: The importance of establishing a link between breast cancer metastasis and asthma is difficult to overestimate given the remarkable rise in the incidence of asthma among women, which has led to nearly 1 in 10 adult women in the United States (including those with breast cancer) being diagnosed with this disease. We believe that the completion of this application has the potential of leading to therapeutic pulmonary regimes (e.g., enhanced treatment protocols) aggressively targeting the asthma of breast cancer patients with the expectation of increased survival rates among this large subset of breast cancer patients.

描述（由申请人提供）：项目摘要：引起乳腺癌转移的特定机制仍然是研究主题。但是，一个隐式的假设是，它们是由于进入周围和/或淋巴循环的乳腺肿瘤的细胞而发生的。随后与血管内皮的细胞细胞相互作用会导致循环中的粘附和渗出。我们对过敏性肺部炎症的小鼠模型的研究表明，导致转移的提出的途径与介导过敏原诱导的白细胞的组织特异性募集的机制显着相似。特别是，肺血管内皮的激活是循环促炎细胞所需的一种基本机制，以介导牢固的粘附和最终的diapedesis介导肺实质。我们已经利用了这些过敏性哮喘研究，并利用了转移的黑色素瘤细胞转移模型，以证明相对于过敏原对照动物，过敏小鼠中肺转移的数量显着增加。此外，这些初步研究表明，转移的增加是T细胞依赖性的，并且被通常用于治疗哮喘患者的药物（例如吸入的皮质类固醇）有效阻断。因此，数据表明肺部过敏性炎症会产生一个有利于循环癌细胞粘附和渗出的环境。此外，这些运输机制的进化保守特征表明，该小鼠模型数据有效地外推向人类患者。该应用的中心假设是，与哮喘相关的肺血管内皮的激活增加了转移对肺的速率。总体而言，我们的初步研究表明，与非过敏性动物相比，过敏性肺部炎症会显着增加小鼠肺的转移概率。更重要的是，进一步的研究还检查了乳腺癌患者数据库，并表明人类可能存在类似的相关性。该应用程序的目标将通过嵌套的病例对照研究实现，其疾病进展导致远处转移的乳腺癌患者队列中。本应用的具体目的是确定与其他远处部位（对照组）相比，患有肺转移（病例）的女性（病例）先前诊断哮喘的几率是否更大。我们的长期目标是将这项回顾性研究最终转化为更全面的前瞻性研究，以定义这种潜在关系的特定参数。 公共卫生相关性：相关性：建立乳腺癌转移与哮喘之间建立联系的重要性很难高估妇女哮喘发病率的显着升高，这导致了美国十分之一的成年妇女（包括患有这种疾病的乳腺癌患者（包括患有乳腺癌的妇女）。我们认为，该应用的完成有可能导致肺癌患者哮喘患者的哮喘的治疗性肺部状况（例如增强的治疗方案），并期望这一大量乳腺癌患者的存活率提高。