PQ2 Obesity-induced fibrocytes promote breast cancer progression

PQ2 肥胖诱导的纤维细胞促进乳腺癌进展

基本信息

批准号：
10394275
负责人：
LISA M ARENDT
金额：
$ 34.3万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-14 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394275
关键词：
Address Adipocytes Adipose tissue Adjuvant Affect Bone Marrow Cells Breast Breast Cancer Model Breast Cancer Risk Factor Breast Cancer Treatment Breast Epithelial Cells CCL2 gene Cell Lineage Cells Chemoresistance Chemotherapy-Oncologic Procedure Chronic Clinical Collagen Data Deposition Desmoplastic Development Epidemic Extracellular Matrix Proteins Fatty acid glycerol esters Fibroblasts Fibrosis Gene Expression Gene Expression Profiling Genetic Transcription Gleevec Goals High Fat Diet Human ITGAM gene Imatinib mesylate Immunocompromised Host In Vitro Incidence Inflammation Inflammatory Label Lead Link Malignant Neoplasms Mammaplasty Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Mission Modeling Mus Myelogenous Myofibroblast Neoplasm Metastasis Obese Mice Obesity Obesity Epidemic Obesity associated cancer PDGFRB gene Patient-Focused Outcomes Patients Platelet-Derived Growth Factor alpha Receptor Population Postmenopause Prevention Public Health Recurrence Relapse Research Resistance Risk Factors Role Signal Transduction Stromal Cells Testing Thinness Tissue Microarray Tissues Transgenic Mice Transplantation Tumor Subtype Tumor stage Variant Woman aggressive breast cancer base breast cancer progression cancer therapy chemotherapy comorbidity efficacy testing genetic signature immune function improved in vivo infiltrating duct carcinoma inflammatory milieu inhibitor innovation macrophage malignant breast neoplasm mammary mortality mouse model new therapeutic target novel patient population prevent recruit response stem-like cell systemic inflammatory response therapeutic target therapy development therapy resistant tool treatment response treatment strategy tumor tumor growth tumor progression

项目摘要

Obesity has been identified as an important risk factor for postmenopausal breast cancer and is significantly correlated with diminished treatment response. It is currently not understood how inflammation within obese breast fat contributes to adipose tissue fibrosis and tumor desmoplasia. These conditions have been associated with both increased breast cancer risk and chemotherapy resistance. The long-term goal is to understand how obesity increases local and systemic inflammation leading to progression of treatment-resistant breast tumors. Preliminary studies have shown that transplant of CCL2+ breast stromal cells with transformed breast epithelial cells promoted rapid breast cancer development, with increased numbers of cancer stem-like cells (CSCs). Transient depletion of CD11b+ cells early in tumor development resulted in dramatic reductions in cancer associated fibroblasts (CAFs) and tumor growth rates. Transcriptional analysis of CD11b+ cells from both tumors and mammary glands of obese mice revealed a fibrotic gene signature and expression of platelet-derived growth factor receptor alpha (PDGFRα). This fibrotic gene signature is consistent with fibrocytes, which have attributes of both inflammatory macrophages and myofibroblasts. Based on these preliminary data, the central hypothesis is that fibrocytes are increased by obesity where they promote aggressive tumor growth and chemotherapy resistance through the expansion of CSCs via PDGFRα. This hypothesis will be tested with three specific aims: 1) Examine how fibrocytes are recruited to obese mammary fat and promote fibrosis via PDGFRα; 2) Determine how fibrocytes differentiate into CAFs and promote chemotherapeutic resistance through cancer stem-like cell (CSC) expansion; 3) Identify how obesity enhances fibrocytes in human breast tissue leading to adipose tissue fibrosis and desmoplasic, treatment-resistant breast tumors. A high fat diet model of obesity and GFP-labeled myeloid lineage cells will be used to examine differentiation of obesity-induced fibrocyte populations within the mammary gland. Gleevec, a clinical PDGFR inhibitor, will be used to target fibrocytes and reduce obesity- induced fibrosis. Using the inflammatory model of breast tumor progression, the mechanism of fibrocyte-induced tumor desmoplasia and CSCs expansion will be examined. The efficacy of Gleevec will be tested to reduce CSCs and enhance chemotherapy response. Reduction mammoplasty tissue from obese and lean women and well-annotated breast tumor tissue microarrays will be used to understand how obesity alters treatment response and tumor desmoplasia, and potentially identify patients that might benefit from adjuvant use of Gleevec for treatment of breast cancer. These studies are innovative because fibrocytes have not been investigated in the context of obesity. The impact of these studies is that targeted Gleevec therapy to treat desmoplastic tumors in obese women may significantly improve chemotherapeutic response, leading to reduced mortality. Obesity has been linked to tumor desmoplasia and treatment resistance in other cancers, and understanding the role of fibrocytes in therapy resistance may lead to broad-reaching advances for other obesity-associated cancers.

肥胖已被确定为绝经后乳腺癌的重要危险因素，并且与绝经后乳腺癌的发生密切相关。目前尚不清楚肥胖者体内的炎症如何与治疗反应减弱相关。乳房脂肪会导致脂肪组织纤维化和肿瘤结缔组织形成。乳腺癌风险和化疗耐药性均增加，长期目标是了解其中的机制。肥胖会增加局部和全身炎症，导致治疗耐药性乳腺肿瘤的进展。初步研究表明，CCL2+乳腺基质细胞与转化乳腺上皮细胞移植细胞促进乳腺癌快速发展，癌症干细胞样细胞（CSC）数量增加。肿瘤发展早期 CD11b+ 细胞的瞬时耗竭导致癌症的急剧减少两种肿瘤的 CD11b+ 细胞的相关成纤维细胞 (CAF) 和肿瘤生长率的转录分析。肥胖小鼠的乳腺显示出纤维化基因特征和血小板衍生生长的表达这种纤维化基因特征与纤维细胞一致，具有属性。基于这些初步数据，中心假设是炎症巨噬细胞和肌成纤维细胞的。纤维细胞因肥胖而增加，从而促进侵袭性肿瘤生长和化疗通过 PDGFRα 扩展 CSC 产生耐药性该假设将通过三个具体目标进行检验： 1) 检查纤维细胞如何募集到肥胖乳腺脂肪并通过 PDGFRα 促进纤维化 2) 确定纤维细胞如何分化为 CAF 并通过癌症干细胞样细胞促进化疗耐药 (CSC) 扩展；3) 确定肥胖如何增强人类乳腺组织中的纤维细胞，从而形成脂肪组织纤维化和结缔组织增生、难治性乳腺肿瘤和 GFP 标记的肥胖高脂肪饮食模型。骨髓谱系细胞将用于检查肥胖诱导的纤维细胞群的分化格列卫（Gleevec）是一种临床PDGFR抑制剂，将用于靶向纤维细胞并减少肥胖—— 利用乳腺肿瘤进展的炎症模型，研究纤维细胞诱导的纤维化机制。将检查格列卫减少肿瘤结缔组织增生和 CSC 扩张的功效。 CSCs 并增强化疗反应，减少肥胖和瘦女性的乳房成形术组织。注释良好的乳腺肿瘤组织微阵列将用于了解肥胖如何改变治疗反应和肿瘤结缔组织增生，并有可能确定可能受益于格列卫辅助治疗的患者这些研究具有创新性，因为尚未对纤维细胞进行研究。这些研究的影响是靶向格列卫疗法可治疗促纤维增生性肿瘤。肥胖女性可能会显着改善化疗反应，从而降低肥胖死亡率。已与肿瘤结缔组织增生和其他癌症的治疗耐药性相关，并了解其作用治疗抵抗中的纤维细胞可能会为其他与肥胖相关的癌症带来广泛的进展。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Factors associated with obesity alter matrix remodeling in breast cancer tissues.

与肥胖相关的因素改变乳腺癌组织中的基质重塑。

DOI：
发表时间：
2020-01
期刊：
影响因子：
3.5
作者：
Zhang, Yang;Baloglu, Fatma Kucuk;Ziemer, Lauren E Hillers;Liu, Zhiyi;Lyu, Boyang;Arendt, Lisa M;Georgakoudi, Irene
通讯作者：
Georgakoudi, Irene

Interaction between Macrophages and Adipose Stromal Cells Increases the Angiogenic and Proliferative Potential of Pregnancy-Associated Breast Cancers.

巨噬细胞和脂肪基质细胞之间的相互作用增加了妊娠相关乳腺癌的血管生成和增殖潜力。