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

项目概要/摘要 炎症已成为肿瘤微环境的关键组成部分，这是肿瘤发生所需的 肿瘤进展。浸润性炎症细胞，包括肿瘤相关巨噬细胞（TAM） 显示可促进乳腺癌细胞侵袭，并与转移和不良预后相关。 然而，人们对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肿瘤前期，微环境及其在肿瘤发生中的作用 进展。癌前 DCIS（导管原位癌）和浸润性乳腺的基因谱研究 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治疗结果。它有 有人提出，不同的乳腺癌亚型包含不同的癌症干细胞群（肿瘤干细胞） 起始细胞（TIC），它们在利基环境中相互作用以增强恶性进展。这些 TIC 已被证明具有放射和化学抗性，并被认为会导致疾病复发。 拟议研究的长期研究目标是阐明引发致癌事件 诱导促炎环境，有利于癌前进展为侵袭性癌症。 该提案的直接目标是描述 TIC 和 TAM 之间的相互作用， 促进肿瘤发生和进展，以及 C/EBP 如何介导这些相互作用。具体的 本文测试的假设是 C/EBP 诱导关键的炎症细胞因子和趋化因子， 介导 TIC，对于肿瘤前期进展期间 TAM 的募集至关重要。的 拟议的研究将利用两种不同的新型肿瘤前小鼠模型来剖析这些复杂的 互动。因此，提出以下目标： 具体目标 1：确定 C/EBP¿-LIP 是否是癌前进展所必需的 肿瘤发生。 具体目标 2：确定 C/EBP¿-LIP 是否对于 TAM 招募至关重要 通过诱导 CCL2 产生癌前病变。 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 TIC 活动是否需要 TAM。 拟议的研究将利用小鼠和人类诱导的肿瘤前模型来研究 C/EBP¿-LIP 在肿瘤前期进展期间 TAM 募集中的作用，并表征之间的相互作用 癌前微环境中的 TAM 和 TIC。完成这些目标将增强我们的理解 肿瘤前期微环境中调节 TIC 的分子机制 进展，这对于设计选择性针对耐药 TIC 的新疗法至关重要。

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.