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具有最大的影响。预计炎症和免疫也会在癌前阶段参与广泛的交叉调节，但影响的关键相互作用。由于缺乏可处理的模型系统，肿瘤的进展和发病率在很大程度上仍不清楚。该提案将描述最近建立的癌前病变期间交叉调节免疫回路的特征。 I 型子宫内膜癌 (EC) Ptenlox/lox PRcre/+ (P10/PR-cre) 小鼠模型 该模型涉及 Pten 抑癌基因的组成性子宫缺失，其关键特征是肿瘤形成快速、完全渗透。 ，并且在整个子宫中同步发生，4周龄时的增生必然会在3个月龄时发展为浸润性癌，此外， P10/PR-cre 小鼠虽然处于癌前状态，但与上皮内多形核中性粒细胞 (PMN) 的大量积累、NK、γδ、CD8 和 CD4 T 细胞密度升高以及自子宫以来的混合 Th1/Th17 细胞免疫反应有关。是一个相对较大但非必需的器官，适合对留置免疫细胞行为进行详细分析，该模型提供了前所未有的机会目标 I 基于初步数据，从机械角度剖析癌前病变期间的调节途径，该数据表明，在 4 周龄时出现的急性子宫炎症之前是相对免疫静止状态，并且将表征似乎是启动全面免疫的离散触发因素。 Aim II 的初步数据表明，癌前子宫处于紧密的 DC 状态，可能是由树突状细胞 (DC) 和先天性淋巴细胞之间的协作驱动的炎症。免疫监视，并将确定 PMN 及其分泌产物 PGE2 和 IL-1ß 如何调节肿瘤相关 DC，以最终控制癌前相关细胞免疫反应的强度和极性。最后，Aim III 将确定 IL-17- 的贡献。 P10/PR-cre 小鼠子宫炎症和肿瘤进展的依赖和独立途径共同，这项工作将建立 P10/PR-cre 小鼠作为一种新的强大的动物模型。机械地探索癌前肿瘤微环境，这里提出的景观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。