In vivo monitoring of tumor microenvironment regulation for macrophages

巨噬细胞肿瘤微环境调节的体内监测

• 批准号: 10391205
• 负责人: Timothy D Eubank
• 金额: $ 36.1万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391205
• 关键词: Acidity; Acidosis; Acute; Address; Angiogenic Factor; Animal Cancer Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Area; Award; Blood Vessels; Bone Marrow; Breast Cancer Model; Breast Cancer Patient; Chronic; Development; Dichloromethylene Diphosphonate; Effectiveness; Electron Spin Resonance Spectroscopy; Elements; Endothelium; Event; Fibrinogen; Functional disorder; Homeostasis; Hypoxia; Image; Image Guided Biopsy; Imaging technology; Immunologics; Knockout Mice; Label; Liposomes; Location; Magnetic Resonance; Magnetic Resonance Imaging; Mammary Neoplasms; Methodology; Modality; Mus; Occupations; Oxygen; Particulate; Perfusion; Play; Population; Prognosis; Progress Reports; Protein Tyrosine Kinase; Radiation therapy; Regulation; Reporting; Role; Sampling; Scanning; Shapes; Site; Solid Neoplasm; TEK gene; TIE-2 Receptor; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Treatment outcome; Tumor Tissue; Tumor-associated macrophages; United States National Institutes of Health; Vascular Endothelial Growth Factors; Work; acute infection; angiogenesis; base; cancer therapy; chemokine receptor; chemotherapy; clinical efficacy; clinically relevant; cohort; docetaxel; extracellular; imaging modality; improved; in vivo; in vivo monitoring; innovation; insight; macrophage; monocyte; mouse model; normoxia; parent grant; recruit; repaired; residence; response; transcription factor; tumor; tumor hypoxia; tumor microenvironment; tumor progression; wound healing

Hypoxia and macrophages drive tumor aggressiveness and treatment outcome leading to worse prognosis for breast cancer patients. Contrary to acute hypoxia where tissue homeostasis is vital for development and repair, chronic hypoxia observed in solid tumors stimulate unproductive angiogenesis by excessive vascular endothelial growth factor expression leading to dysfunctional vessels that perpetuate hypoxia and acidic extracellular pH; factors that limit effective perfusion of treatment modalities like chemotherapies and radiotherapies and promote tumor aggressiveness. Macrophages are intimately involved in regulating unproductive angiogenesis thru secretion of soluble factors that support this activity. In the parent grant, we advanced electron paramagnetic resonance (EPR)-based techniques towards in vivo real-time tumor microenvironment (TME) profiling in animal cancer models. Using these approaches, we showed macrophage hypoxia-inducible transcription factors (HIF)- 1α and HIF-2α had disparate roles in regulating TME parameters like oxygen and pHe through structural and functional alterations in vessels that dictated docetaxel efficacy. We showed that HIF-1α augments expression of endothelial tyrosine kinase (TIE2) receptor on macrophages called TIE2-expressing macrophages (TEMs) previously-reported to be “pro-angiogenic”, but now better defined as “pro-hypoxic” by dysregulating vessels leading to poor perfusion. The overall objective of the renewal is to investigate macrophage location and function that perpetuates a hypoxic TME detrimental to perfusion of therapeutic modalities. To achieve this central objective, we propose these specific aims: (SA1): To optimize magnetic resonance imaging modalities for in vivo multifunctional mapping of local tumor tissue parameters. Advances in paramagnetic probes and imaging technologies such as rapid scan EPR imaging and Overhauser-enhanced MRI allow for mapping specific areas of hypoxia and acidosis and characterizing their relationship to tumor macrophage locoregional populations. (SA2): Elucidate tumor macrophage location-specific functions in regulating hypoxia and acidosis in a mouse model of breast cancer. We will sample tumor origin and regions of hypoxia in PyMT breast cancer models using image-guided biopsy to understand the bi-directional shaping of TME and macrophages that contribute to poor vessel perfusion and hypoxia. (SA3): Investigate recruited and tissue- resident macrophage populations and their respective roles in contributing to tumor hypoxia and acidosis that dictate chemotherapy effectiveness. We will track fluorescent bone marrow monocytes to tumor origin, and generate conditional macrophage-deficient breast tumor mice to systematically determine a causal role of specific macrophage populations. Summarizing, in vivo mapping of tumor hypoxia and acidosis using innovative magnetic resonance technology in mice deficient in specific macrophage populations or lacking hypoxia-regulated macrophage functions in a mouse model of breast cancer may provide new insight into a macrophage/TME axis that suppresses the efficacy of clinically-relevant anti-cancer therapies.

缺氧和巨噬细胞驱动肿瘤的侵略性和治疗结果，导致预后较差 乳腺癌患者。与组织稳态对发育和修复至关重要的急性缺氧相反， 在实体瘤中观察到的慢性低氧刺激过量血管内皮刺激非生产性的血管生成 生长因子表达导致功能失调的视频，使缺氧和细胞外酸性持续 ph;限制有效灌注治疗方式等因素，例如化学疗法和放射疗法 促进肿瘤的侵略性。巨噬细胞密切参与调节非生产性血管生成 通过支持该活动的固体因素的分泌。在父母赠款中，我们提出了电子顺磁性 共振（EPR）基于动物体内实时肿瘤微环境（TME）分析的技术 癌症模型。使用这些方法，我们显示了巨噬细胞缺氧诱导的转录因子（HIF） - 1α和HIF-2α通过结构和 决定多西他赛效率的血管的功能改变。我们表明HIF-1α增强表达 巨噬细胞上的内皮酪氨酸激酶（TIE2）受体的表达2表达巨噬细胞（TEMS） 以前被报告为“促血管生成”，但现在通过失调的血管更好地定义为“促催化性” 导致灌注不良。更新的总体目标是研究巨噬细胞的位置和功能 这会使缺氧的TME持续不利于治疗方式的灌注。实现这一中心 目的，我们提出了这些特定目标：（SA1）：优化磁共振成像方式 局部肿瘤组织参数的体内多功能映射。顺磁问题的进步和 成像技术，例如快速扫描EPR成像和大胰岛素增强的MRI允许映射 缺氧和酸中毒的特定区域，并表征它们与肿瘤巨噬细胞的关系 人群。 （SA2）：阐明肿瘤巨噬细胞在调节缺氧和 乳腺癌小鼠模型中的酸中毒。我们将采样肿瘤起源和PYMT中缺氧的区域 使用图像引导的活检来了解TME和 导致血管灌注和缺氧不良的巨噬细胞。 （SA3）：调查招募和组织 居民巨噬细胞种群及其在肿瘤缺氧和 决定化疗有效性的酸中毒。我们将跟踪荧光骨髓单核细胞到肿瘤 起源，并产生有条件的巨噬细胞缺陷乳腺肿瘤小鼠，以系统地确定因果关系 特定巨噬细胞种群的作用。总结使用肿瘤缺氧和酸中毒的体内图 特定于特定巨噬细胞种群的小鼠的创新磁共振技术或缺乏 低氧调节的巨噬细胞功能在乳腺癌的小鼠模型中可能提供新的见解 巨噬细胞/TME轴可抑制临床上与抗癌疗法的有效性。