C/EBPb Modulates Macrophages and Tumor-Initiating Cells During Preneoplastic Prog

C/EBPb 在肿瘤前期调节巨噬细胞和肿瘤起始细胞

• 批准号: 8639865
• 负责人: Heather L Machado
• 金额: $ 23.41万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-12 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639865
• 关键词: 3-Dimensional; Biological Models; Breast Cancer Cell; CCL2 gene; Cells; Classification; Coculture Techniques; Complex; Data; Development; Disease; Environment; Event; Genes; Goals; Hormones; Human; Hyperplasia; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-6; Lesion; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Oncogenic; Outcome; Patients; Population; Premalignant; Protein Isoforms; Radio; Recruitment Activity; Recurrence; Research; Resistance; Role; Signal Transduction; Stem cells; Structure of thyroid parafollicular cell; Subfamily lentivirinae; System; Target Populations; Testing; Transcription Coactivator; Transgenic Mice; Transplantation; Tumor Cell Invasion; Xenograft Model; cancer cell; cancer stem cell; chemokine; cytokine; hormone therapy; in vivo; macrophage; malignant breast neoplasm; mammary gland development; migration; mouse model; neoplastic cell; novel; outcome forecast; overexpression; self-renewal; stem cell population; success; therapy resistant; transcription factor; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT Inflammation has emerged as a critical component of the tumor microenvironment that is required for tumor progression. Infiltrating inflammatory cells, including tumor-associated macrophages (TAMs), have been shown to promote breast cancer cell invasion and have been correlated with metastasis and poor prognosis. However, very little is known about the mechanisms regulating macrophage recruitment to the tumor microenvironment, and their role in tumor initiation due to a lack of suitable models to study preneoplastic progression. Gene profiling studies of both pre-malignant DCIS (ductal carcinoma in situ) and invasive breast cancer have resulted in the classification of various subtypes, which largely dictate patient outcome. It has been proposed that different breast cancer subtypes contain distinct cancer stem cell populations (tumor- initiating cells, TICs), which interact within a niche environment to enhance malignant progression. These TICs have been shown to be radio- and chemo-resistant, and are postulated to contribute to disease recurrence. The long-term research goal of the proposed studies is to elucidate the initiating oncogenic events that induce a pro-inflammatory environment, which is conducive for preneoplastic progression to invasive cancer. The immediate objective of this proposal is to delineate the interactions between TICs and TAMs that promote tumor initiation and progression, and how C/EBP¿ mediates these interactions. The specific hypothesis tested herein is that C/EBP¿ induces key inflammatory cytokines and chemokines that mediate TICs and are critical for the recruitment of TAMs during preneoplastic progression. The proposed studies will utilize two different novel preneoplastic mouse models to dissect these complex interactions. Accordingly, the following aims are proposed: Specific Aim 1: To determine whether C/EBP¿-LIP is required for preneoplastic progression and tumorigenesis. Specific Aim 2: To determine whether C/EBP¿-LIP is essential for TAM recruitment to preneoplastic lesions through the induction of CCL2. Specific Aim 3: To determine whether C/EBP¿-LIP regulates TIC self-renewal through IL-6 signaling, and whether TAMs are required for TIC activity. The proposed studies will utilize both mouse and human inducible preneoplastic models to study the role of C/EBP¿-LIP in TAM recruitment during preneoplastic progression, and to characterize the interactions between TAMs and TICs in the premalignant microenvironment. Completing these goals will enhance our understanding of the molecular mechanisms that regulate TICs in the niche microenvironment during preneoplastic progression, which will be critical for devising new treatments that selectively target therapy-resistant TICs.

项目总结/摘要 炎症已经成为肿瘤微环境的关键组成部分， 肿瘤进展。浸润的炎性细胞，包括肿瘤相关巨噬细胞（TAM），已经被证实是一种恶性肿瘤。 显示促进乳腺癌细胞侵袭，并与转移和不良预后相关。 然而，对于调节巨噬细胞向肿瘤募集的机制知之甚少 由于缺乏合适的模型来研究癌前病变， 进展癌前病变导管原位癌和浸润性乳腺癌的基因表达谱研究 癌症导致了各种亚型的分类，这在很大程度上决定了患者的结果。它有 已经提出不同的乳腺癌亚型含有不同的癌症干细胞群体（肿瘤- 起始细胞，TIC），其在小生境环境内相互作用以增强恶性进展。这些TIC 已经显示出放射和化学抗性，并且被假定有助于疾病复发。 拟议研究的长期研究目标是阐明启动致癌事件， 诱导促炎环境，这有助于肿瘤前进展为浸润性癌症。 这项建议的直接目标是阐明贸易信息中心和技术援助机制之间的相互作用， 促进肿瘤的发生和发展，以及C/EBP如何介导这些相互作用。具体 本文测试的假设是C/EBP诱导关键的炎性细胞因子和趋化因子， 介导TIC，并且对于肿瘤前进展期间TAM的募集至关重要。的 提出的研究将利用两种不同的新的癌前小鼠模型来解剖这些复杂的 交互.因此，提出了以下目标： 具体目标1：确定癌前进展是否需要C/EBP <$-LIP， 肿瘤发生 具体目标2：确定C/EBP <$-LIP是否对TAM招募至关重要， 通过诱导CCL 2的癌前病变。 具体目标3：确定C/EBP <$-LIP是否通过IL-6调节TIC自我更新 信号传导，以及TAM是否为TIC活性所需。 拟议的研究将利用小鼠和人诱导的癌前模型来研究 C/EBP <$-LIP在肿瘤前进展期间TAM募集中的作用，并描述 癌前微环境中的TAM和TIC。完成这些目标将增强我们的理解 肿瘤前病变过程中，在微环境中调节TIC的分子机制 这对于设计选择性靶向治疗耐药性TIC的新治疗至关重要。