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）：项目总结：引发乳腺癌转移的具体机制仍是研究的主题。然而，一个隐含的假设是，它们是由于乳腺肿瘤脱落的细胞进入外周和/或淋巴循环而发生的;随后细胞与血管内皮的相互作用导致粘附和从循环中外渗。我们对小鼠过敏性肺部炎症模型的研究表明，所提出的导致转移的途径与介导过敏原诱导的组织特异性白细胞募集的机制具有显着的相似性。特别是，肺血管内皮的激活是循环促炎细胞介导牢固粘附并最终渗入肺实质所需的潜在机制。我们利用这些过敏性哮喘研究，并利用转移的黑色素瘤细胞转移模型来证明，相对于未接受过过敏原的对照动物，过敏性小鼠肺转移的数量显著增加。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有效阻断（例如，吸入的皮质类固醇）。因此，数据表明，肺部过敏性炎症产生有利于循环癌细胞粘附和外渗的环境。此外，这些贩运机制的进化保守特征表明该小鼠模型数据有效地外推到人类患者。本申请的中心假设是与哮喘相关的变应原诱导的肺血管内皮细胞活化增加了肺转移的速率。总的来说，我们的初步研究表明，与非过敏性动物相比，过敏性肺部炎症导致小鼠肺转移的可能性显著增加。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。本申请的目的将通过在疾病进展导致远处转移的乳腺癌患者的基础队列中进行巢式病例对照研究来实现。本申请的具体目的是确定与转移到其他远处部位的女性（对照）相比，肺转移女性（病例）既往诊断哮喘的几率是否更大。我们的长期目标是最终将这项回顾性研究转化为一项更大、更全面的前瞻性研究，确定这种潜在关系的具体参数。 公共卫生关系：相关性：鉴于女性哮喘发病率的显著上升，在乳腺癌转移和哮喘之间建立联系的重要性难以高估，这导致美国近十分之一的成年女性（包括乳腺癌患者）被诊断患有这种疾病。我们相信，完成这一申请有可能导致肺治疗方案（例如，增强的治疗方案）积极地靶向乳腺癌患者的哮喘，期望在这一大的乳腺癌患者亚群中增加存活率。