Role of CHI3L1 in accelerating breast cancer metastasis

转移是大多数乳腺癌死亡的原因。最近的研究估计，乳腺癌复发转移率在哮喘患者中是没有哮喘的患者的两倍。在哮喘和乳腺癌中发现了高水平的CHI 3L 1，当这些疾病同时存在时，其水平甚至更高。我们假设CHI 3L 1诱导的肺部炎症产生了合适的环境来招募循环中的乳腺癌细胞，从而增加了转移到肺部的速度。因此，预期抑制CHI 3L 1可减少转移。我们最近发现，几丁质微粒，CHI 3L 1的生物结合伴侣，减少肺转移，增加乳腺肿瘤荷瘤小鼠的生存。我们提出以下两个具体目的：1）确定肺中与CHI 3L 1相关的炎症是否改变肺环境以吸引循环乳腺肿瘤细胞并加速转移性生长，以及2）确定通过几丁质微粒、抗CHI 3L 1中和抗体或两者的组合抑制CHI 3L 1是否降低肿瘤转移。这些目的将通过通过豚草变应原致敏或通过使用AAV-CHI 3L 1载体在肺中局部表达CHI 3L 1来诱导肺部炎症来解决。然后，我们将确定肺组织的变化，以及它是否为循环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以及相关炎症反应的体内成像。我们还将确定CHI 3L 1的抑制是否显著降低肿瘤生长和转移。意义：哮喘和肺部疾病的特征是CHI 3L 1表达增加。由于污染、过敏和吸烟导致的肺部炎症率一直在稳步上升。本文提出的研究将提供对CHI 3L 1在增强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好理解。此外，通过使用体内阻断CHI 3L 1活性的分子来限制炎症具有减少许多也患有炎性疾病的癌症患者的转移的潜力。将免疫疗法（抗CHI 3L 1抗体）与天然生物产物几丁质颗粒相结合可以提供用于抑制转移性疾病的治疗选择的新模式。

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.