Inflammation and immunity in the crucible of premalignancy

癌前考验中的炎症和免疫

• 批准号: 9270511
• 负责人: Adrian Erlebacher
• 金额: $ 45.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270511
• 关键词: Acute; Age; Age-Months; Animal Model; Automobile Driving; Behavior; Biological Models; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Model; Carcinoma; Cell Polarity; Cell Proliferation; Cells; Cellular Immunity; Characteristics; Collaborations; Complex; DNA Damage; Data; Dendritic Cells; Development; Dinoprostone; Endometrial Carcinoma; Evaluation; Fostering; Genetic; Goals; Human; Hyperplasia; Immune; Immune response; Immunity; Immunologic Monitoring; Immunologics; Immunology; In Situ; Incidence; Inflammation; Interleukin-1 beta; Interleukin-17; Lesion; Leukocytes; Lymphoid Cell; Malignant - descriptor; Modality; Modeling; Mus; Organ; Pathogenesis; Pathway interactions; Play; Population; Premalignant; Prostaglandins; Regulation; Regulatory Pathway; Role; Source; T cell response; T-Lymphocyte; Time; Tumor Initiators; Tumor Suppressor Genes; Tumor stage; Uterus; Work; angiogenesis; base; body system; cancer immunotherapy; carcinogenesis; cell behavior; cell type; density; experimental study; host neoplasm interaction; insight; intraepithelial; mouse model; neoplastic cell; neutrophil; novel; prevent; public health relevance; response; tumor; tumor eradication; tumor immunology; tumor microenvironment; tumor progression; virtual

DESCRIPTION (provided by applicant): Inflammation and cellular immunity likely have their greatest influence over multistep carcinogenesis during the premalignant stage of tumor development. Inflammation and immunity are also expected to engage in extensive cross-regulation during premalignancy, but the key interactions that will influence tumor progression and incidence remain largely undefined due to the lack of tractable model systems. This proposal will characterize the cross-regulatory immune circuitry operative during premalignancy in the recently established Ptenlox/lox PRcre/+ (P10/PR-cre) mouse model of type I endometrial carcinoma (EC). This model involves constitutive uterine deletion of the Pten tumor suppressor gene, and has the key features that tumor formation is rapid, completely penetrant, and synchronous throughout the uterus, with hyperplasia at 4 wks of age unfailingly progressing to invasive carcinoma by 3 months of age. Moreover, the hyperplastic lesions of P10/PR-cre mice, while premalignant, are associated with massive accumulations of intraepithelial polymorphonuclear neutrophils (PMNs), elevated densities of NK, γδ, CD8, and CD4 T cells, and a mixed Th1/Th17 cellular immune response. Since the uterus is a relatively large but non-essential organ amenable to detailed analyses of indwelling immune cell behavior, this model offers an unprecedented opportunity to mechanistically dissect regulatory pathways during premalignancy. Aim I is based upon preliminary data showing that the acute uterine inflammation apparent at 4 wks of age is preceded by a state of relative immunological quiescence, and will characterize what appears to be a discrete trigger that initiates full-blown inflammation, potentially driven by a collaboration between dendritic cells (DCs) and innate lymphoid cells. Aim II is based upon preliminary data showing that premalignant uteri are under close DC immunosurveillance, and will determine how PMNs and their secreted products PGE2 and IL-1ß regulate tumor-associated DCs to ultimately control the magnitude and polarity of the premalignancy-associated cellular immune response. Lastly, Aim III will determine the contributions of IL-17-dependent and -independent pathways to uterine inflammation and tumor progression in P10/PR-cre mice. Together, this work will establish P10/PR-cre mice as a new and powerful animal model to mechanistically probe the premalignant tumor microenvironment, with the landscape-defining experiments proposed here likely to reveal features of host-tumor interactions relevant to the development of many kinds of epithelial cancers.

描述（由应用提供）：在肿瘤发育的临时阶段，炎症和细胞免疫学可能对多步癌的影响最大。预计炎症和免疫学还将在预审前进行广泛的交叉调节，但是由于缺乏可拖动的模型系统，会影响肿瘤进展和入射的主要相互作用在很大程度上仍然不确定。该建议将表征在最近建立的Ptenlox/Lox prcre/+（P10/PR-CRE）I型子宫内膜癌（EC）的小鼠模型中，在预先命名期间运行的交叉调节免疫电路（EC）。该模型涉及PTEN肿瘤抑制基因的组成型子宫缺失，并具有关键特征：肿瘤形成是快速，完全渗透的，并且在整个子宫中同步，在4周龄的4周中，增生始终持续到3个月的入侵性癌。 Moreover, the hyperplastic lesions of P10/PR-cre mice, while premalignant, are associated with massive accumulations of intraepithelial polymorphonuclear neutrophils (PMNs), elevated densities of NK, γδ, CD8, and CD4 T cells, and a mixed Th1/Th17 cellular immunoresponse.由于子宫是一个相对较大但不必要的器官，因此可以详细地分析留置免疫细胞行为，因此该模型为在预示例期间机械剖析调节途径提供了前所未有的机会。 AIM II基于初步数据，表明急性子宫感染出现在4周的年龄之前，先于相对免疫静止的状态，并将表征似乎是一个离散的触发触发，该触发触发会引发全面的感染，这可能是由树突状细胞（DCS）（DCS）和先天性淋巴机细胞之间的协作驱动的。 AIM II基于初步数据，表明前子宫在DC免疫监视之下，并将确定PMN及其分泌产品PGE2和IL-1ß如何调节与肿瘤相关的DC最终控制与预先相关性的细胞免疫膜的幅度和极性。最后，AIM III将确定IL-17依赖性和非依赖性途径对P10/PR-CRE小鼠的子宫注射和肿瘤进展的贡献。总之，这项工作将建立P10/PR-CRE小鼠作为一种新的强大动物模型，以机械探测前肿瘤微环境，这里提出的景观定义的实验可能揭示了与许多上皮癌的发展相关的宿主相互作用的特征。