Asthma is a Prognostic Indicator for Pulmonary Metastasis of Breast Cancer

描述(申请人提供)：项目总结：诱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，它们的发生是由于从乳腺肿瘤脱落的细胞进入外周和/或淋巴循环；随后的细胞与血管内皮细胞相互作用导致粘连和渗出循环。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变应原诱导的组织特异性白细胞募集的机制有显著的相似之处。特别是，肺血管内皮细胞的激活是循环促炎细胞介导牢固黏附和最终进入肺实质所需的基本机制。我们利用了这些过敏性哮喘的研究，并利用黑色素瘤细胞转移转移模型来证明，相对于未接种过敏原的对照动物，过敏性小鼠的肺转移数量显著增加。此外，这些初步研究表明，转移的增加是T细胞依赖的，并可被治疗哮喘患者的常用药物(例如吸入皮质类固醇)有效地阻断。因此，这些数据表明，肺变态反应性炎症产生了有利于循环癌细胞黏附和外渗的环境。此外，这些转运机制在进化上的保守性表明，这种小鼠模型数据对人类患者的推断是有效的。这一应用的中心假设是，与哮喘相关的过敏原诱导的肺血管内皮细胞激活增加了肺转移的比率。总而言之，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部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，并显示类似的相关性可能存在于人类中。这项应用的目标将通过在疾病进展导致远处转移的乳腺癌患者的潜在队列中进行嵌套病例对照研究来实现。这项应用的具体目的是确定在有肺转移的妇女(病例)中，与转移到其他远处部位的妇女(对照)相比，先前诊断为哮喘的几率是否更大。我们的长期目标是最终将这项回溯性研究转化为一项更大、更全面的前瞻性研究，定义这种潜在关系的具体参数。 公共卫生相关性：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很难被高估，这导致美国近十分之一的成年女性(包括乳腺癌患者)被诊断出患有这种疾病。我们相信，这一应用的完成有可能导致针对乳腺癌患者哮喘的肺治疗方案(例如，强化治疗方案)，并期望在这一大群乳腺癌患者中提高存活率。

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.