Role of CHI3L1 in accelerating breast cancer metastasis

CHI3L1在加速乳腺癌转移中的作用

• 批准号: 8657277
• 负责人: VIJAYA L IRAGAVARAPU-CHARYULU
• 金额: $ 9.68万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657277
• 关键词: Address; Affinity; Allergens; Ambrosia; Antibodies; Asthma; Binding; Biological; Breast Cancer Cell; Cancer Patient; Cause of Death; Cells; Cessation of life; Chitin; Chitinase; Chronic; Clara cell; Disease; Distant; Early Intervention; Environment; Epithelial Cells; Exhibits; Female; Glycoproteins; Goals; Growth; Hypersensitivity; Image; Immunotherapy; Implant; Incidence; Inflammation; Inflammatory; Inflammatory Response; Internal Ribosome Entry Site; Intervention; Laboratories; Lung; Lung diseases; Mammary Neoplasms; Mediator of activation protein; Metastatic Neoplasm to the Lung; Molecular; Mus; Neoplasm Metastasis; Organ; Patients; Play; Pneumonia; Pollution; Predisposition; Prevalence; Production; Proteins; Publishing; Recruitment Activity; Recurrence; Role; Signal Transduction; Smoking; Soil; Structure of parenchyma of lung; Survival Rate; Testing; Tissues; Translating; adeno-associated viral vector; asthmatic patient; design; in vivo; malignant breast neoplasm; metastatic process; neoplastic cell; neutralizing antibody; novel; overexpression; particle; promoter; small hairpin RNA; tumor; tumor growth; tumorigenesis; vector

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.

转移是导致大多数乳腺癌死亡的原因。最近的研究估计，哮喘患者的乳腺癌复发转移率是无哮喘患者的两倍。在哮喘和乳腺癌中发现高水平的CHI3L1，当这些疾病同时出现时，其水平甚至更高。我们假设CHI3L1诱导的肺部炎症为招募循环乳腺癌细胞提供了适当的环境，从而增加了转移到肺部的率。因此，抑制CHI3L1有望减少转移。我们最近的研究表明，CHI3L1的生物结合伙伴几丁质微粒可以减少乳腺荷瘤小鼠的肺转移并提高生存率。我们提出以下两个具体目的：1)确定肺中与CHI3L1相关的炎症是否改变肺部环境以吸引循环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。这些目的将通过豚草过敏原致敏诱导肺部炎症或使用AAV-CHI3L1载体在肺中局部表达CHI3L1来解决。然后我们将确定肺组织的变化，以及它是否为循环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是否能显著减少肿瘤的生长和转移。意义：哮喘和肺部疾病以CHI3L1表达增高为特征。由污染、过敏和吸烟引起的肺部炎症的发病率一直在稳步上升。本文提出的研究将进一步了解CHI3L1在促进转移中的作用，以及慢性炎症条件下加剧转移的组织特异性分子信号。此外，通过在体内使用阻断CHI3L1活性的分子来限制炎症有可能减少许多患有炎症性疾病的癌症患者的转移。将免疫疗法（抗chi3l1抗体）与天然生物制品甲壳素颗粒相结合，可以为抑制转移性疾病提供新的治疗选择。

项目成果

Semaphorin7A: branching beyond axonal guidance and into immunity.

• DOI: 10.1007/s12026-013-8460-5
• 发表时间: 2013-12
• 期刊: IMMUNOLOGIC RESEARCH
• 影响因子: 4.4
• 作者: Garcia-Areas, Ramon;Libreros, Stephania;Iragavarapu-Charyulu, Vijaya
• 通讯作者: Iragavarapu-Charyulu, Vijaya

Exploring the role of CHI3L1 in "pre-metastatic" lungs of mammary tumor-bearing mice.

• DOI: 10.3389/fphys.2013.00392
• 发表时间: 2013
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Libreros S;Garcia-Areas R;Keating P;Carrio R;Iragavarapu-Charyulu VL
• 通讯作者: Iragavarapu-Charyulu VL

Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice.

• DOI: 10.3389/fphys.2014.00017
• 发表时间: 2014
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Garcia-Areas R;Libreros S;Amat S;Keating P;Carrio R;Robinson P;Blieden C;Iragavarapu-Charyulu V
• 通讯作者: Iragavarapu-Charyulu V

CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors.

• DOI: 10.1007/s12026-013-8459-y
• 发表时间: 2013-12
• 期刊: IMMUNOLOGIC RESEARCH
• 影响因子: 4.4
• 作者: Libreros, Stephania;Garcia-Areas, Ramon;Iragavarapu-Charyulu, Vijaya
• 通讯作者: Iragavarapu-Charyulu, Vijaya

Induction of proinflammatory mediators by CHI3L1 is reduced by chitin treatment: decreased tumor metastasis in a breast cancer model.

• DOI: 10.1002/ijc.26379
• 发表时间: 2012-07-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Libreros, Stephania;Garcia-Areas, Ramon;Shibata, Yoshimi;Carrio, Roberto;Torroella-Kouri, Marta;Iragavarapu-Charyulu, Vijaya
• 通讯作者: Iragavarapu-Charyulu, Vijaya