PQ2 Obesity-induced fibrocytes promote breast cancer progression

肥胖已被确定为绝经后乳腺癌的重要危险因素，并显著 与治疗反应减弱相关。目前尚不清楚肥胖症中的炎症是如何 乳房脂肪会导致脂肪组织纤维化和肿瘤结缔组织增生。这些条件已被关联 乳腺癌风险和化疗耐药性的增加。长期目标是了解如何 肥胖会增加局部和全身炎症，导致难治性乳腺肿瘤的进展。 初步研究表明，将CCL2乳腺基质细胞与转化的乳腺上皮细胞一起移植 细胞促进了乳腺癌的快速发展，癌症干细胞(CSCs)数量增加。 在肿瘤发展的早期，CD11b细胞的短暂耗尽导致癌症的显著减少 相关成纤维细胞(CAF)和肿瘤生长率。两种肿瘤中CD11b细胞的转录分析 肥胖小鼠的乳腺表现出纤维化的基因特征和血小板源性生长的表达 因子受体α(PDGFRα)。这种纤维化基因特征与纤维细胞是一致的，纤维细胞具有 炎性巨噬细胞和肌成纤维细胞。根据这些初步数据，中心假设 肥胖会增加纤维细胞，从而促进肿瘤的侵袭性生长和化疗 通过PDGFRα扩增CSCs产生抗性。这一假设将以三个具体目标进行检验： 1)研究纤维细胞如何被招募到肥胖的乳房脂肪中，并通过PDGFRα促进纤维化；2)确定 成纤维细胞如何通过肿瘤干细胞分化为CAF并促进化疗耐药 (CSC)扩张；3)确定肥胖如何促进人类乳房组织中的纤维细胞导致脂肪组织 纤维化和结缔组织增生症，难治性乳腺肿瘤。一种高脂饮食肥胖模型及GFP标记 髓系细胞将用于检测肥胖诱导的纤维细胞群在 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。利用乳腺肿瘤进展的炎症模型，探讨纤维细胞诱导乳腺肿瘤进展的机制 将检查肿瘤间质增生和CSCs扩张情况。格列卫的疗效将接受测试，以降低 CSCs和增强化疗反应。减少肥胖和瘦女性的乳房整形组织 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 和肿瘤促结缔组织增生症，并有可能确定可能受益于格列卫辅助治疗的患者 乳腺癌的治疗。这些研究是创新的，因为纤维细胞还没有在 肥胖的背景。这些研究的影响是，有针对性的格列卫疗法治疗结缔组织增生性肿瘤 肥胖女性可能会显著提高化疗反应，从而降低死亡率。肥胖症有 在其他癌症中与肿瘤结缔组织增生和治疗耐药有关，并了解 纤维细胞在治疗抵抗中可能会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.