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

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。浸润性炎症细胞，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，并与转移和不良预后相关。然而，由于缺乏合适的模型来研究肿瘤前进展，人们对巨噬细胞向肿瘤微环境募集的调节机制以及巨噬细胞在肿瘤起始中的作用知之甚少。对癌前DCIS（导管原位癌）和浸润性乳腺癌的基因谱研究已经得出了不同亚型的分类，这在很大程度上决定了患者的预后。有研究表明，不同的乳腺癌亚型含有不同的癌症干细胞群（肿瘤启动细胞，TICs），它们在生态位环境中相互作用以促进恶性进展。这些tic已被证明具有放射和化疗耐药性，并被认为有助于疾病复发。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，这有利于肿瘤前发展为侵袭性癌症。本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/EBP2如何介导这些相互作用。本文验证的具体假设是，C/EBP2诱导了介导tic的关键炎症细胞因子和趋化因子，这些因子对肿瘤前进展过程中tam的募集至关重要。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相互作用。因此，提出了下列目标：

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.