Role of CHI3L1 in accelerating breast cancer metastasis: a mechanistic approach

描述(申请人提供)：转移是乳腺癌死亡的主要原因。最近的研究估计，患有哮喘的患者的乳腺癌复发转移率是非哮喘患者的两倍。在哮喘和乳腺癌中发现高水平的CHI3L1，当这些疾病同时存在时，CHI3L1的水平甚至更高。我们假设CHI3L1诱导的肺部炎症为招募循环中的乳腺癌细胞创造了适当的环境，从而增加了肺转移率。因此，抑制CHI3L1有望减少转移。我们最近发现，几丁质微粒，CHI3L1的生物结合伙伴，减少了乳腺肿瘤小鼠的肺转移，并提高了存活率。我们提出了以下两个特定目标：1)确定与CHI3L1相关的炎症是否改变了肺环境，以吸引循环中的乳腺肿瘤细胞并加速转移生长；2)确定几丁质微粒、抗CHI3L1中和抗体或两者联合抑制CHI3L1是否会减少肿瘤转移。这些目标将通过豚草变应原致敏或使用AAV-CHI3L1载体在肺内局部表达CHI3L1来诱导肺部炎症来实现。然后我们将确定肺组织的变化，以及它是否为循环中的乳腺肿瘤细胞提供了必要的“土壤”。为了实现这一目标，将确定肿瘤生长和转移的体内成像以及相关的炎症反应。我们还将确定抑制CHI3L1是否显著减少肿瘤的生长和转移。意义：哮喘和肺部疾病的特征是CHI3L1表达增加。由污染、过敏和吸烟引起的肺部炎症的比率一直在稳步上升。本文提出的研究将提供对CHI3L1在促进转移中的作用以及在慢性炎症条件下加剧转移的组织特异性分子信号的更多了解。此外，通过在体内使用阻断CHI3L1活性的分子来限制炎症，对于许多同样患有炎症性疾病的癌症患者来说，有可能减少转移。将免疫疗法(抗CHI3L1抗体)与天然生物产物甲壳素颗粒相结合，可以为抑制转移疾病提供新的治疗模式选择。 公共卫生相关性：肺部转移是乳腺癌患者死亡的主要原因之一。有慢性肺部炎症性疾病的乳腺癌患者转移发生率较高。哮喘相关炎症在肿瘤转移中起关键作用，表达CHI3L1等介质。利用豚草变应原致敏的小鼠并转导过表达CHI3L1，我们将描绘涉及肺转移的机制。我们将确定抑制CHI3L1是否会减少转移。

DESCRIPTION (provided by applicant): Metastasis is responsible for a majority of breast cancer deaths. Recent studies estimate that rate of recurrent metastasis of breast cancer is twice as high in patients with asthma compared to those without asthma. High levels of CHI3L1 are found in asthma and breast cancer with even higher levels when these diseases are present together. We hypothesize that CHI3L1- induced pulmonary inflammation generates the proper environment for recruiting circulating breast cancer cells, thus increasing the rate of metastasis to the lung. Thus, inhibiting CHI3L1 is expected to reduce metastasis. We have recently shown that chitin microparticles, the biological binding partner for CHI3L1 decrease pulmonary metastasis and increase survival in mammary tumor-bearing mice. We propose the following two specific Aims: 1) To determine if inflammation associated with CHI3L1 in the lung alters the pulmonary environment to attract circulating breast tumor cells and accelerate metastatic growth and 2) To determine if inhibition of CHI3L1 by either chitin microparticles, anti-CHI3L1 neutralizing antibody or combination of the two decreases tumor metastasis. These Aims will be addressed by inducing pulmonary inflammation by either ragweed allergen sensitization or by locally expressing CHI3L1 in the lung using AAV-CHI3L1 vector. We will then determine the changes in pulmonary tissue and if it provides the necessary "soil" for the circulating breast tumor cells. Towards this goal, in vivo imaging for tumor growth and metastasis and related inflammatory response will be determined. We will also determine if inhibition of CHI3L1 significantly reduces tumor growth and metastasis. Significance: Asthma and pulmonary diseases are characterized by increased expression of CHI3L1. Rates of pulmonary inflammation due to pollution, allergies and smoking have been steadily increasing. The studies proposed here will provide a greater understanding of the role of CHI3L1 in enhancing metastasis and the tissue-specific molecular signals that act to exacerbate metastasis under conditions of chronic inflammation. Moreover limiting inflammation by use of molecules that block the activity of CHI3L1 in vivo has the potential to decrease metastasis for many cancer patients also suffering from inflammatory diseases. Combining immunotherapy (anti-CHI3L1 antibody) with the natural bio-product chitin particles could provide novel modes of treatment options for inhibiting metastatic diseases. PUBLIC HEALTH RELEVANCE: Metastasis to the lung is one of the major causes of death in breast cancer patients. Incidence of metastasis is higher in breast cancer patients with chronic pulmonary inflammatory illnesses. Asthma-associated Inflammation plays a key role in the metastasis with expression of mediators such as CHI3L1. Using mice sensitized with ragweed allergen and transduced to overexpress CHI3L1, we will delineate the mechanisms involved in metastasis to the lung. We will determine if inhibition of CHI3L1 decreases metastasis.