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

• 批准号: 9917573
• 负责人: LISA M ARENDT
• 金额: $ 35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-14 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917573
• 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; 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; base; breast cancer progression; cancer therapy; chemotherapy; comorbidity; efficacy testing; genetic signature; immune function; improved; in vivo; infiltrating duct carcinoma; inflammatory milieu; inhibitor/antagonist; innovation; macrophage; malignant breast neoplasm; mortality; mouse model; new therapeutic target; novel; patient population; prevent; recruit; response; stem-like cell; therapeutic target; therapy development; therapy resistant; tool; treatment response; treatment strategy; tumor; tumor growth; tumor progression

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.

肥胖症已被确定为绝经后乳腺癌的重要危险因素，并且显着 与治疗反应减少相关。目前尚不了解肥胖中的炎症 乳腺脂肪有助于脂肪组织纤维化和肿瘤脱发。这些条件已关联 随着乳腺癌风险增加和抗化疗的抗性。长期目标是了解如何 肥胖会增加局部和全身感染，从而导致耐药性乳腺肿瘤的进展。 初步研究表明，CCL2+乳腺基质细胞的移植具有转化的乳腺上皮 细胞促进乳腺癌快速发展，随着癌症干细胞的数量增加（CSC）。 肿瘤发育早期CD11b+细胞的短暂部署导致癌症的急剧减少 相关的成纤维细胞（CAF）和肿瘤生长速率。来自两个肿瘤的CD11b+细胞的转录分析 肥胖小鼠的乳腺揭示了纤维化基因的特征和血小板衍生的生长的表达 因子受体α（PDGFRα）。这种纤维化基因特征与具有属性的纤维细胞一致 炎症性巨噬细胞和肌纤维细胞。基于这些初步数据，中央假设 是肥胖会增加纤维细胞，从而促进侵袭性肿瘤生长和化学疗法 通过PDGFRα扩展CSC的电阻。该假设将以三个特定的目的进行检验： 1）检查如何将纤维细胞募集到肥胖的乳腺脂肪并通过PDGFRα促进纤维化； 2）确定 纤维细胞如何分化为CAF并通过癌变茎样细胞促进化学治疗性抗性 （CSC）扩展； 3）确定肥胖如何增强人类乳腺组织中导致脂肪组织的纤维细胞 纤维化和脱木质，耐药性乳腺肿瘤。肥胖和GFP标记的高脂饮食模型 髓样谱系细胞将用于检查肥胖引起的纤维细胞种群的分化 乳腺。 Gleevec是一种临床PDGFR抑制剂，将用于靶向纤维细胞并降低肥胖症 - 诱导纤维化。使用乳腺肿瘤进展的炎症模型，纤维细胞诱导的机制 将检查肿瘤脱粒质和CSC膨胀。 Gleevec的效率将进行测试以降低 CSC并增强化疗反应。减少肥胖女性和瘦女性的乳腺成形术组织 被宣布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desmoplasia，并有可能识别可能受益于调整Gleevec的患者 治疗乳腺癌。这些研究具有创新性，因为尚未在 肥胖的背景。这些研究的影响是针对性的Gleevec治疗以治疗脱与肿瘤的肿瘤 肥胖女性可能会显着改善化学治疗反应，从而导致死亡率降低。肥胖有 与其他癌症中的肿瘤脱发和治疗耐药性有关，并了解 治疗耐药性中的纤维细胞可能会导致其他肥胖相关癌症的广泛进步。