PQ2 Obesity-induced fibrocytes promote breast cancer progression

肥胖已被确定为绝经后乳腺癌的一个重要危险因素， 与治疗反应减弱有关。目前尚不清楚肥胖患者体内的炎症是如何发生的。 乳房脂肪有助于脂肪组织纤维化和肿瘤纤维组织增生。这些情况与 乳腺癌风险和化疗耐药性都增加了。长期目标是了解 肥胖增加局部和全身炎症，导致治疗抵抗性乳腺肿瘤的进展。 初步研究表明，移植CCL2+乳腺基质细胞与转化的乳腺上皮细胞， 细胞促进了乳腺癌的快速发展，增加了癌症干细胞（CSC）的数量。 肿瘤发展早期CD11b+细胞的瞬时消耗导致癌症的显著减少 相关的成纤维细胞（CAF）和肿瘤生长速率。来自两种肿瘤的CD11b+细胞的转录分析 和乳腺揭示了纤维化的基因特征和血小板衍生生长的表达， 因子受体α（PDGFR α）。这种纤维化基因特征与纤维细胞一致， 炎性巨噬细胞和肌成纤维细胞的细胞。根据这些初步数据，中心假设 肥胖增加了纤维细胞，它们促进了肿瘤的侵袭性生长和化疗 通过PDGFR α扩增CSC产生耐药性。将以三个具体目标检验这一假设： 1)检查纤维细胞如何被招募到肥胖的乳腺脂肪中并通过PDGFR α促进纤维化; 2）确定 纤维细胞如何分化为CAFs并通过癌干细胞样细胞促进化疗抗性 (CSC)3）确定肥胖如何增强人类乳腺组织中的纤维细胞，从而导致脂肪组织 纤维化和促结缔组织增生的难治性乳腺肿瘤。高脂饮食肥胖模型的建立及GFP标记 骨髓谱系细胞将被用于检查肥胖诱导的纤维细胞群在骨髓中的分化。 乳腺格列卫是一种临床PDGFR抑制剂，将用于靶向纤维细胞和减少肥胖- 诱导纤维化。使用乳腺肿瘤进展的炎症模型，研究了纤维细胞诱导的乳腺癌细胞凋亡的机制。 检查肿瘤纤维组织增生和CSC扩增。将测试格列卫的疗效， CSC和增强化疗反应。从肥胖和瘦女性中减少乳房成形术组织， 一个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，并有可能确定患者可能受益于辅助使用格列卫， 乳腺癌的治疗这些研究是创新性的，因为纤维细胞尚未在 肥胖的背景。这些研究的影响是，靶向格列卫治疗促结缔组织增生性肿瘤， 肥胖妇女可显著改善化疗反应，导致死亡率降低。肥胖已 与肿瘤结缔组织增生和其他癌症的治疗耐药性有关， 纤维细胞的治疗抗性可能导致其他肥胖相关癌症的广泛进展。

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.