(PQ1) HIV-infected T-cell exosomes in lung cancer progression

(PQ1) HIV 感染的 T 细胞外泌体在肺癌进展中的作用

基本信息

批准号：
10202519
负责人：
Ge Jin
金额：
$ 75.69万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10202519
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adjuvant Age Aging Allografting Automobile Driving Benign Blood Blood Circulation Body Fluids Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Cancer Model Cancer Patient Cancer cell line Cell Nucleus Cell Proliferation Cells Cessation of life Data Development Diagnosis Distant Endocytic Vesicle Endosomes Epidermal Growth Factor Receptor Epithelial Cells FVB Mouse Foundations General Population Genetically Engineered Mouse Growth HIV HIV Infections HIV Seropositivity HIV-1 Human Immune Immunologics In Vitro Individual KRASG12D Lead Light Liposomes Longevity Lung MAPK3 gene MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Maps Mediating Membrane Proteins Methods Mitogen-Activated Protein Kinases Modeling Molecular Mus Neoplasm Metastasis Patients Persons Phosphorylation Plasma Population Prevention Production Prognosis Proteome Proto-Oncogenes Publishing RNA Ras/Raf Relative Risks Research Response Elements Risk Risk Factors Role Signal Transduction Site Son of Sevenless Proteins Specimen T-Lymphocyte TLR3 gene Testing Therapeutic Intervention Transactivation Transgenic Mice Tumor Tissue Tumor stage Urethane antiretroviral therapy aptamer cancer cell cancer specimen resource cell motility chemical carcinogen exosome extracellular vesicles in vivo inhibitor/antagonist intercellular communication lung allograft lung cancer cell lung tumorigenesis migration mouse model novel novel strategies patient derived xenograft model reconstitution response success transplant model trend tumor progression tumorigenesis

项目摘要

Project Summary/Abstract Lung cancer (LCa) is the second most common malignancy in the US with about 222,500 new cases and 155,900 deaths each year. HIV-infected individuals and AIDS patients have increased relative risk of LCa by 250% after controlling for other potential risk factors. LCa in HIV+ people under antiretroviral therapy (ART) is diagnosed at younger ages than those in the general population. This trend in the ART era is implicitly attributed to prolonged life span and aging of the population. The success of new approaches to control lung tumorigenesis in the population is contingent to identify HIV-specific mechanisms that facilitate the tumor progression and metastasis. HIV-infected T cells release a variety of immunologically active exosomes, small vesicles of endocytic origin, to influence intercellular communication and material transfer at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. Our preliminary studies have found that exosomes secreted by HIV-infected T cells and purified from the blood of lung cancer patients of people living with HIV (PLWH) significantly stimulated lung cancer cell proliferation. HIV-associated exosomes induced MAP kinase ERK1/2 activation via interaction with epidermal growth factor receptor (EGFR) and the toll like receptor 3 (TLR3). Mechanistically, the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosome from HIV-infected T cells, is responsible for enhanced cancer cell proliferation and proto-oncogene expression. We have established a bone marrow transplant (BMT) mouse model in which lethally-irradiated FVB mice were grafted with syngeneic bone marrow cells of Tg26 HIV- transgenic mice. Growth and metastasis of allografts LCa cells were significantly enhanced in grafted mice containing HIV+ bone marrow cells compared with that in non-grafted control mice. However, reconstitution of circulating immune cells and bone marrow remained the same between two groups of mice, suggesting that TAR RNA-bearing exosomes from reconstituted HIV+ immune cells may promote LCa progression in the BMT model. Taken together, these data lead us to hypothesize that TAR RNA-bearing exosomes from HIV-infected immune cells promote lung cancer growth and progression and that controlling release of the exosomes or directly targeting the TAR RNA may serve as an adjuvant for prevention and treatment of lung cancer in HIV- infected individuals. To test this hypothesis, we will first delineate the mechanism by which HIV-1-infected T- cell exosomes stimulate LCa growth and progression in vivo using the BMT model. The potentials for therapeutic intervention of LCa promotion by HIV will be examined through inhibition of exosome production and neutralization of TAR RNA. Finally, we will comprehensively examine the HIV-positive exosomal membrane proteins for interaction with EGFR and HIV-specific cargo components in the circulation using our novel EV-omics approach. Completion of the proposed studies will shed light on the mechanisms underlying HIV-mediated promotion of LCa and lay a foundation for therapeutic intervention of non-AIDS-defining cancers.

项目摘要/摘要肺癌（LCA）是美国第二常见的恶性肿瘤，大约222,500例新病例，每年155,900人死亡。感染HIV的个体和艾滋病患者的LCA相对风险增加控制其他潜在危险因素后250％。抗逆转录病毒疗法（ART）下的HIV+人的LCA是诊断出年龄的年龄比普通人群中的年龄。艺术时代的这种趋势是隐含的归因于长期的寿命和人口衰老。新方法控制肺的成功人群中的肿瘤发生有可能确定促进肿瘤的HIV特异性机制进展和转移。 HIV感染的T细胞释放了多种免疫学活性外泌体，小内吞作用的囊泡，以影响局部和因此，远处的部位有可能导致肿瘤发生的风险增加。我们的初步研究发现由HIV感染的T细胞分泌的外泌体并从人的肺癌患者的血液中纯化患有艾滋病毒（PLWH）的生活显着刺激了肺癌细胞的增殖。 HIV相关的外泌体诱导 MAP激酶ERK1/2通过与表皮生长因子受体（EGFR）的相互作用和TOLL相互作用激活受体3（TLR3）。从机械上讲，HIV反式激活响应（TAR）元素RNA存在于来自HIV感染的T细胞中外泌体中其他HIV RNA过多，负责增强的癌细胞增殖和原始癌基因表达。我们已经建立了骨髓移植（BMT）小鼠将致命辐照的FVB小鼠与TG26 HIV-的同性骨髓细胞接枝的模型转基因小鼠。同种异体移植物的生长和转移LCA细胞在移植小鼠中显着增强与非移植对照小鼠相比，含有HIV+骨髓细胞。但是，重组两组小鼠之间循环的免疫细胞和骨髓保持不变，表明来自重建的HIV+免疫细胞的焦油RNA外泌体可能会促进BMT的LCA进展模型。综上免疫细胞促进肺癌的生长和进展，并控制外泌体的释放或直接靶向焦油RNA可以作为预防和治疗HIV-肺癌的辅助药物 - 受感染的人。为了检验这一假设，我们将首先描述HIV-1感染T-的机制细胞外泌体使用BMT模型在体内刺激LCA的生长和进展。潜力通过抑制外泌体产生，将检查LCA促进LCA的治疗干预措施和焦油RNA的中和。最后，我们将全面检查HIV阳性外泌体膜蛋白与EGFR相互作用，并使用我们新颖的Ev-omics方法。拟议研究的完成将阐明基础机制 HIV介导的LCA促进，并为非辅助癌症的治疗干预奠定了基础。