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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

基本信息

批准号：
8331545
负责人：
Heather L Machado
金额：
$ 15.86万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2011-09-12 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8331545
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 progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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/EBP2 mediates these interactions. The specific hypothesis tested herein is that C/EBP2 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/EBP2-LIP is required for preneoplastic progression and tumorigenesis. Specific Aim 2: To determine whether C/EBP2-LIP is essential for TAM recruitment to preneoplastic lesions through the induction of CCL2. Specific Aim 3: To determine whether C/EBP2-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/EBP2-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.

描述（由申请人提供）：炎症已成为肿瘤进展所需的肿瘤微环境的关键组成部分。浸润性炎性细胞，包括肿瘤相关巨噬细胞（TAM），已被证明可促进乳腺癌细胞侵袭，并与转移和预后不良相关。然而，由于缺乏合适的模型来研究肿瘤前进展，对调节巨噬细胞募集到肿瘤微环境的机制及其在肿瘤起始中的作用知之甚少。癌前DCIS（导管原位癌）和浸润性乳腺癌的基因分析研究导致了各种亚型的分类，这在很大程度上决定了患者的预后。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已被证明是放射和化学抗性的，并被假定有助于疾病复发。拟议研究的长期研究目标是阐明诱导促炎环境的起始致癌事件，这有助于肿瘤前进展为浸润性癌症。该提案的直接目标是描述TIC和TAM之间促进肿瘤发生和进展的相互作用，以及C/EBP 2如何介导这些相互作用。本文测试的具体假设是C/EBP 2诱导介导TIC的关键炎性细胞因子和趋化因子，并且对于肿瘤前进展期间TAM的募集至关重要。拟议的研究将利用两种不同的新的癌前小鼠模型来剖析这些复杂的相互作用。因此，提出了以下目标：具体目标1：确定C/EBP 2-LIP是否是肿瘤前进展和肿瘤发生所必需的。具体目标2：确定C/EBP 2-LIP是否是通过诱导CCL 2将TAM募集至癌前病变所必需的。具体目标3：确定C/EBP 2-LIP是否通过IL-6信号传导调节TIC自我更新，以及TAM是否是TIC活性所需的。拟议的研究将利用小鼠和人诱导的癌前模型来研究癌前进展期间C/EBP 2-LIP在TAM募集中的作用，并表征癌前微环境中TAM和TIC之间的相互作用。完成这些目标将增强我们对肿瘤前进展过程中在生态位微环境中调节TIC的分子机制的理解，这对于设计选择性靶向治疗耐药TIC的新治疗至关重要。