Exosomal TRAF2-CSN5 complex mediated inflammation promotes tumor growth
外泌体TRAF2-CSN5复合物介导的炎症促进肿瘤生长
基本信息
- 批准号:8212755
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant):
The overall goal of this proposal is to elucidate the mechanisms by which lung tumor exosomes promote an inflammatory response, namely the activation of macrophages, and promote the progression and growth of lung tumors. Our preliminary data indicate that pretreatment of A/J mice with exosomes produced by TC-1 lung tumor cells or exosomes isolated from the lung tissue of A/J mice that have been pretreated with the carcinogen urethane results in more rapid tumor growth and earlier progression of lung carcinomas. Urethane treatment results in the recruitment of the activated form of TRAF2 to the exosomes, and the exosomes with activated TRAF2 are taken up by the bone marrow-derived precursors of macrophages, leading to their maturation and subsequent migration to the lung. The recruitment of the activated TRAF2 to the exosomes requires degradation of the inflammation suppressor protein, CYLD, in the tumor cells; moreover, TRAF2 can mediate ubiquination of CYLD thereby promoting its degradation. The results of siRNA TRAF2 knockout indicated, however, that TRAF2 is required but is not sufficient for ubiquitination of CYLD. We have now identified two exosomal proteins that interact with TRAF2, Itch and CSN5, which have the potential to enhance the ubiquitination of CYLD in lung tumor cells. Our recent data indicating that CYLD is not packed in exosomes isolated from the peripheral blood of lung cancer patients although it is present in exosomes from healthy volunteers indicate the potential clinical relevance of this model that directly links the effects of a carcinogen with an inflammatory response and promotion of tumor development. We propose to: (1) Confirm the role of lung tumor exosomal TRAF2 in the promotion of urethane-induced lung carcinomas by determining whether knockout of TRAF2 in TC-1 lung tumor cells is sufficient for (i) inhibition of macrophage differentiation and (ii) prevention of lung tumor exosome-mediated enhancement of urethane induced lung cancer. (2) Determine if other exosomal proteins that interact with CYLD participate in the ubiquitination of CYLD in TC-1 tumor cells and determine if the elimination of these proteins stabilizes exosomal CYLD and suppresses exosomal TRAF2 activation resulting in the inhibition of macrophage activation and prevention of tumor growth. (3) Determine if macrophages pulsed with lung tumor exosomes isolated from lung cancer patients promote lung tumor growth in a NOD-SCID mouse model. The data generated should permit the development of a highly innovative model of the cellular and molecular basis for exosome-mediated chronic inflammation and promotion of tumor growth and indicate novel preventive and therapeutic strategies.
PUBLIC HEALTH RELEVANCE:
The proposed research is highly relevant to characterizing the association of lung tumor exosomes mediated inflammatory responses and lung tumor growth in that it is focused on characterizing the molecular mechanisms underlying the ability of tumor exosomes to both activate macrophages and promote tumor growth. The central hypothesis is that exosomes produced by lung tumor cells, or lung tumor tissue are taken up by bone marrow myeloid precursor cells. These cells further differentiate into macrophages and migrate into the lung, promote the progression of urethane- induced lung cancer.
描述(由申请人提供):
该提案的总体目标是阐明肺肿瘤外泌体促进炎症反应的机制,即巨噬细胞的激活,并促进肺肿瘤的进展和生长。我们的初步数据表明,从A/J小鼠的TC-1肺肿瘤细胞或外泌体中对A/J小鼠进行了预处理,这些外泌体是从A/J小鼠的肺组织中分离出来的,这些外泌体已被致癌尿烷预处理,从而导致更快的肿瘤生长和更早的肺癌进展。氨基甲酸酯治疗导致TRAF2的活化形式募集到外泌体,而具有活化TRAF2的外泌体被巨噬细胞的骨髓衍生的前体所吸收,从而导致其成熟并随后迁移到肺部。将活化的TRAF2募集到外泌体需要降解肿瘤细胞中的炎症抑制蛋白CYLD。此外,TRAF2可以介导CYLD的泛素化,从而促进其降解。但是,siRNA TRAF2敲除的结果表明,需要TRAF2,但不足以泛素化CYLD。现在,我们已经确定了两种与TRAF2,Itch和CSN5相互作用的外泌体蛋白,它们具有增强CYLD在肺部肿瘤细胞中的泛素化的潜力。我们最近的数据表明,CYLD并未包含从肺癌患者外周血分离的外泌体中,尽管它存在于健康志愿者的外泌体中,这表明该模型的潜在临床相关性直接将致癌物的影响与炎症反应反应和肿瘤发育的促进联系起来。我们提出:(1)通过确定TC-1肺肿瘤细胞中TRAF2的敲除是否足以(I)抑制巨噬细胞分化和(II)预防肺肿瘤介导的癌症癌症的癌症癌症癌症癌症癌症的癌症的抑制是否足以抑制肺肺肿瘤细胞,从而证实了肺肿瘤外泌体TRAF2在促进氨基甲酸酯诱导的肺癌中的作用。 (2)确定与CYLD相互作用的其他外泌体蛋白是否参与TC-1肿瘤细胞中CYLD的泛素化,并确定消除这些蛋白的消除是否稳定外泌体CYLD并抑制外泌体TRAF2激活导致巨噬细胞激活和预防肿瘤生长的抑制作用。 (3)确定从肺癌患者中分离出的肺部肿瘤外泌体脉冲的巨噬细胞是否在点头scid小鼠模型中促进肺部肿瘤的生长。生成的数据应允许开发外泌体介导的慢性炎症和促进肿瘤生长的高度创新模型,并表明新颖的预防和治疗策略。
公共卫生相关性:
拟议的研究与表征肺肿瘤外泌体的关联介导的炎症反应和肺部肿瘤生长高度相关,因为它的重点是表征肿瘤外泌体能力激活巨噬细胞和促进肿瘤生长的能力的分子机制。中心假设是由肺部肿瘤细胞或肺肿瘤组织产生的外泌体被骨髓髓样前体细胞吸收。这些细胞进一步分化为巨噬细胞并迁移到肺中,促进氨基甲酸酯诱导的肺癌的进展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
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Exosomal TRAF2-CSN5 complex mediated inflammation promotes tumor growth
外泌体TRAF2-CSN5复合物介导的炎症促进肿瘤生长
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Exosomal TRAF2-CSN5 complex mediated inflammation promotes tumor growth
外泌体TRAF2-CSN5复合物介导的炎症促进肿瘤生长
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Exosomal TRAF2-CSN5 complex mediated inflammation promotes tumor growth
外泌体TRAF2-CSN5复合物介导的炎症促进肿瘤生长
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