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（由申请人提供）：炎症和细胞免疫可能对肿瘤发展的癌前阶段的多步致癌作用产生最大影响。炎症和免疫也被认为在癌前病变期间参与广泛的交叉调节，但由于缺乏易处理的模型系统，影响肿瘤进展和发病率的关键相互作用在很大程度上仍不确定。该建议将描述在最近建立的Ptenlox/lox PRcre/+（P10/PR-cre）小鼠模型I型子宫内膜癌（EC）的癌前病变期间的交叉调节免疫回路。该模型涉及Pten肿瘤抑制基因的组成性子宫缺失，并且具有以下关键特征：肿瘤形成是快速的、完全渗透的并且在整个子宫中是同步的，其中4周龄时的增生在3月龄时必然进展为浸润性癌。此外，P10/PR-cre小鼠的增生性病变，而癌前病变，与上皮内多形核中性粒细胞（PMN）的大量积累，NK，γδ，CD 8和CD 4 T细胞的密度升高，以及混合的Th 1/Th 17细胞免疫应答。由于子宫是一个相对较大但非必需的器官，适合于对留置免疫细胞行为进行详细分析，因此该模型提供了一个前所未有的机会来机械地剖析癌前病变期间的调节途径。目的I是基于初步数据，显示在4周龄时明显的急性子宫炎症之前是相对免疫静止的状态，并且将表征似乎是启动全面炎症的离散触发，可能由树突状细胞（DC）和先天淋巴细胞之间的协作驱动。目的II是基于初步的数据显示，癌前子宫下密切的DC免疫监视，并将确定如何中性粒细胞及其分泌的产物PGE 2和IL-1 β调节肿瘤相关的DC，最终控制的规模和极性的癌前相关的细胞免疫反应。最后，目的III将确定IL-17依赖性和非依赖性途径对P10/PR-cre小鼠子宫炎症和肿瘤进展的贡献。总之，这项工作将建立P10/PR-cre小鼠作为一种新的和强大的动物模型，以机械地探测癌前肿瘤微环境，这里提出的肿瘤定义实验可能揭示与多种上皮癌发展相关的宿主-肿瘤相互作用的特征。