Breast cancer health disparity:mammary fat tissue and tumor macrophages interpla

乳腺癌健康差异：乳腺脂肪组织与肿瘤巨噬细胞间质

• 批准号: 8251123
• 负责人: MARTA TORROELLA-KOURI
• 金额: $ 16.24万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-04 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251123
• 关键词: A Mouse; Address; Adipocytes; Adipose tissue; Affect; African American; Animals; Aromatase; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Treatment; CCAAT-Enhancer-Binding Proteins; CCL2 gene; Cancer Biology; Cancer Patient; Cancer and Nutrition; Caucasians; Caucasoid Race; Cell Differentiation process; Cell Line; Cell physiology; Cells; Chemotaxis; Coculture Techniques; Collaborations; Data; Development; Diet; Dinoprostone; Estrogens; Ethnic Origin; Ethnic group; Exhibits; Fatty Acids; Fatty acid glycerol esters; Foundations; Future; Genetic; Goals; High Prevalence; Historically Black Colleges and Universities; Hormones; Human; Immune; Implant; In Vitro; Individual; Inflammatory; Institution; Investigation; Latina; Lauric Acids; Lead; Leptin; Life Style; Ligands; Macrophage Activation; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Methods; Minority; Modeling; Molecular; Mouse Cell Line; Mus; Neoplasm Metastasis; Obese Mice; Obesity; Outcome; Overweight; Paracrine Communication; Pathogenesis; Patients; Peptides; Peritoneal; Physical activity; Play; Preparation; Primary Neoplasm; Proteomics; Reagent; Recruitment Activity; Research; Research Personnel; Role; STAT1 gene; STAT3 gene; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Time; Tissues; Tumor Biology; Tumor Tissue; Tumorigenicity; Woman; Work; Xenograft procedure; adipokines; anticancer research; base; cancer cell; cancer health disparity; cancer initiation; cancer risk; cell type; chemokine; design; in vitro testing; in vivo; inhibitor/antagonist; innovation; macrophage; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; novel strategies; outcome forecast; paracrine; public health relevance; receptor; research study; socioeconomics; tool; transcription factor; treatment strategy; tumor; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): The purpose of the present application is to generate the initial preliminary data using diet-induced obesity mouse models of breast cancer on the plausible roles of adipocytes, mammary tumor cells and macrophages in breast cancer pathogenesis. Our hypothesis that adipocytes and mammary tumor cells may play a role in the recruitment of macrophages to the mammary gland contributing to its tumorigenicity is novel, since there is no information regarding the crosstalk between these three cell types in the mammary tumor microenvironment. We will examine the impact of this cellular interplay on macrophage chemotaxis, M1/M2 activation profiles and cell differentiation in vitro, using co-cultures of mouse macrophage, mammary tumor and adipocyte cell lines. Specific signaling inhibitors of paracrine factors produced by adipose or tumor cells will be used to reverse these actions, and proteomics analyses will be undertaken to identify novel molecules secreted by adipocytes and mammary tumor cells with actions on macrophages. Moreover, the impact of blocking the functions of these paracrine factors on mf 's NFkB and STAT3 activation will be studied.. We will also focus on one of these paracrine factors, the adipokine leptin, produced by adipocytes and mammary tumor cells, which has a central role in breast cancer pathogenesis and in macrophage chemotaxis. A novel leptin-signaling inhibitor peptide designed by one of us will be used in in vivo experiments with diet-induced obese mice to reverse primary tumor and metastasis progression and macrophage recruitment in these animals implanted with syngeneic C57BL6 mammary tumors. We envision that results from the present proposal will ultimately provide original information that will lay the foundation to initiate similar studies in breast cancer in African American (AA) and Latina (LA) women in the future. A high-fat diet, overweight and reduced physical activity are common lifestyle aspects among AA and LA that increase cancer risk; these women also exhibit more aggressive breast cancers with less favorable outcomes. The experiments proposed in this application address for the first time the interaction between these three cell types within breast tumors. There is an urgent need to build up studies to better understand the biology of cancers across ethnicities, and to develop tools to more accurately predict their prognosis and design their customized treatment strategies. PUBLIC HEALTH RELEVANCE: The proposed studies will increase our understanding on how the actions of adipose tissue on the mammary gland may promote breast cancer through macrophage recruitment and expression of important ligands/receptors. This could lead to new ways of breast cancer prevention and/or therapeutic alternatives for overweight/obese women, especially African American and Latinas, characterized by high prevalence of obesity/overweight and more aggressive breast cancers with worst prognoses.

描述（由申请人提供）：本申请的目的是使用乳腺癌的饮食诱导肥胖小鼠模型生成关于脂肪细胞、乳腺肿瘤细胞和巨噬细胞在乳腺癌发病机制中的合理作用的初始初步数据。我们的假设是，脂肪细胞和乳腺肿瘤细胞可能在巨噬细胞募集到乳腺中促进其致瘤性方面发挥作用，这是新的，因为没有关于乳腺肿瘤微环境中这三种细胞类型之间串扰的信息。我们将使用小鼠巨噬细胞、乳腺肿瘤和脂肪细胞系的共培养物，研究这种细胞相互作用对巨噬细胞趋化性、M1/M2活化特征和体外细胞分化的影响。将使用脂肪或肿瘤细胞产生的旁分泌因子的特异性信号传导抑制剂来逆转这些作用，并将进行蛋白质组学分析以鉴定脂肪细胞和乳腺肿瘤细胞分泌的对巨噬细胞具有作用的新分子。此外，将研究阻断这些旁分泌因子的功能对mf的NFkB和STAT 3激活的影响。我们也将集中在这些旁分泌因子之一，脂肪细胞和乳腺肿瘤细胞产生的脂肪因子瘦素，它在乳腺癌的发病机制和巨噬细胞趋化性中具有核心作用。我们设计的一种新型瘦素信号传导抑制肽将用于饮食诱导的肥胖小鼠的体内实验，以逆转植入同基因C57 BL 6乳腺肿瘤的这些动物中的原发性肿瘤和转移进展以及巨噬细胞募集。我们设想，本提案的结果最终将提供原始信息，为将来在非洲裔美国人（AA）和拉丁裔（LA）妇女中开展类似的乳腺癌研究奠定基础。高脂肪饮食，超重和减少体力活动是AA和LA中常见的生活方式方面，增加了癌症风险;这些女性还表现出更具侵袭性的乳腺癌，结果不太理想。本申请中提出的实验首次解决了乳腺肿瘤中这三种细胞类型之间的相互作用。迫切需要建立研究，以更好地了解不同种族癌症的生物学，并开发工具来更准确地预测其预后并设计定制的治疗策略。 公共卫生关系： 拟议的研究将增加我们对脂肪组织对乳腺的作用如何通过巨噬细胞募集和重要配体/受体的表达促进乳腺癌的理解。这可能会为超重/肥胖妇女，特别是非裔美国人和拉丁美洲人，带来乳腺癌预防和/或治疗替代方案的新方法，其特征是肥胖/超重和更具侵袭性的乳腺癌的高患病率，最严重的乳腺癌。

项目成果

Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue.

• DOI: 10.3390/cancers7010143
• 发表时间: 2015-01-15
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Santander AM;Lopez-Ocejo O;Casas O;Agostini T;Sanchez L;Lamas-Basulto E;Carrio R;Cleary MP;Gonzalez-Perez RR;Torroella-Kouri M
• 通讯作者: Torroella-Kouri M