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:
    8044373
  • 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

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): 这项建议的总体目标是阐明肺肿瘤外切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,用TC-1肺癌细胞产生的外切体或从A/J小鼠肺组织中分离的外切体经致癌剂乌拉坦预处理后,A/J小鼠的肿瘤生长更快,肺癌进展更早。乌拉坦治疗导致激活形式的TRAF2重新聚集到外切体,具有激活TRAF2的外切体被巨噬细胞的骨髓源前体摄取,导致它们成熟并随后迁移到肺。激活的TRAF2募集到外体需要肿瘤细胞中炎症抑制蛋白CyLD的降解,而且TRAF2可以介导CyLD的泛化,从而促进其降解。然而,siRNA TRAF2基因敲除的结果表明,TRAF2是CyLD泛素化所必需的,但不足以实现泛素化。我们现在已经确定了两种与TRAF2相互作用的外体蛋白,Itch和CSN5,它们有可能增强肺癌细胞中CyLD的泛素化。我们最近的数据表明,尽管从健康志愿者的外切体中存在,但从肺癌患者的外周血中分离出来的外切体中并没有包装CyLD,这表明这一模型具有潜在的临床相关性,该模型直接将致癌物的影响与炎症反应和促进肿瘤发展联系起来。我们建议:(1)通过确定TRAF2在TC-1肺癌细胞中的敲除是否足以(I)抑制巨噬细胞分化和(Ii)防止肺癌外体介导的促进乌拉坦诱导的肺癌,来证实肺癌外体TRAF2在乌拉坦诱导的肺癌中的促进作用。(2)确定其他与CyLD相互作用的外体蛋白是否参与了TC-1肿瘤细胞中CyLD的泛素化,并确定这些蛋白的消除是否稳定了外体CyLD,抑制了外体TRAF2的激活,从而抑制了巨噬细胞的激活,防止了肿瘤的生长。(3)在NOD-SCID小鼠模型中,确定肺癌患者肺肿瘤外切体冲击的巨噬细胞是否促进了肺癌的生长。产生的数据应该允许开发高度创新的细胞和分子基础模型,用于外切体介导的慢性炎症和促进肿瘤生长,并指示新的预防和治疗策略。 公共卫生相关性: 这项研究与表征肺肿瘤外切体介导的炎症反应和肺肿瘤生长之间的关系密切相关,因为它侧重于表征肿瘤外切体激活巨噬细胞和促进肿瘤生长能力的分子机制。中心假设是由肺肿瘤细胞或肺肿瘤组织产生的外切体被骨髓髓系前体细胞摄取。这些细胞进一步分化为巨噬细胞并迁移到肺部,促进乌拉坦诱导的肺癌的进展。

项目成果

期刊论文数量(0)
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HUANG-GE ZHANG其他文献

HUANG-GE ZHANG的其他文献

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{{ truncateString('HUANG-GE ZHANG', 18)}}的其他基金

RA synovial fibroblast exosomes(RA-EXo) mediated bone erosion via AhR/TRAF2pathway
RA滑膜成纤维细胞外泌体(RA-EXo)通过AhR/TRAF2通路介导骨侵蚀
  • 批准号:
    10622327
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award application
BLR
  • 批准号:
    9899084
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award application
BLR
  • 批准号:
    10454206
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award application
BLR
  • 批准号:
    10265394
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation
可食用外泌体样纳米颗粒预防脑部炎症的机制
  • 批准号:
    10668525
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation
可食用外泌体样纳米颗粒预防脑部炎症的机制
  • 批准号:
    10517568
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms
植物外泌体非编码RNA介导的抗炎机制
  • 批准号:
    9036506
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
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
  • 批准号:
    8212755
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
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
  • 批准号:
    8696800
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
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
  • 批准号:
    8398935
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

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