In vivo monitoring of tumor microenvironment regulation by macrophages

巨噬细胞调节肿瘤微环境的体内监测

• 批准号: 9039554
• 负责人: Timothy D Eubank
• 金额: $ 34.51万
• 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: 2015-11-05 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039554
• 关键词: Ablation; Acidosis; Affect; Area; Breast Cancer Model; CD3 Antigens; Cell physiology; Cells; Chemicals; Data; Dependence; Development; Education; Effectiveness; Electron Spin Resonance Spectroscopy; Electrons; Glutathione; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hypoxia; Image; Imaging Techniques; Literature; Magnetic Resonance; Magnetic Resonance Imaging; Malignant - descriptor; Mammary Neoplasms; Matrix Metalloproteinases; Measurement; Medicine; Metabolic Pathway; Modality; Monitor; Mus; Normal Cell; Oxidation-Reduction; Oxygen; Phenotype; Physiologic pulse; Physiological; Play; Proteins; Protons; Publishing; Regulation; Relaxation; Reporting; Resistance; Role; Sampling; Signal Transduction; T-Lymphocyte; Techniques; Testing; Time; Tissues; Transgenic Mice; Treatment Efficacy; Tumor Tissue; Vascular Endothelial Growth Factors; analog; angiogenesis; anti-cancer therapeutic; base; cancer therapy; cell type; chemotherapy; clinical efficacy; clinically relevant; docetaxel; experimental study; extracellular; fighting; in vivo; innovation; insight; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; novel; outcome forecast; public health relevance; sensor; success; treatment strategy; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): The overall goal of this project is to prove the hypothesis that bi-directional interaction between tumor microenvironment and macrophages plays significant role in tumor progression and therapy efficacy. This hypothesis is specifically formulated at the level of living tissue and therefore will be tested in vivo using innovative electron paramagnetic resonance (EPR)-based multifunctional approaches. These approaches will be used to correlate, in vivo, the role of macrophages and macrophage-specific HIF-1a and HIF-2a in the regulation of tumor hypoxia, extracellular pH (pHe), redox and glutathione (GSH); and how deletion of these factors affects clinically-relevant anti-cancer treatment strategies in the PyMT mouse model of breast cancer. The specific aims are: (SA1) To optimize magnetic resonance modalities for in vivo multifunctional monitoring of tumor tissue parameters: pH, oxygen, redox and GSH. Novel paramagnetic probes and techniques will be optimized for multi-functional application in tumor tissue with the focus on application to the PyMT mammary tumors in mice. (SA2) To investigate the role of macrophages in regulating the tumor microenvironment in breast cancer. We hypothesize that macrophages significantly affect oxygen tension, acidosis, redox and intracellular GSH (EPR signature of tumor microenvironment) in breast cancer, and that despite both being hypoxia-inducible proteins, macrophage HIF-1a and HIF-2a have disparate and opposing roles in the regulation of the these parameters in the tumor microenvironment, and that we can detect changes in corresponding EPR signature between transgenic mice containing the macrophage ablation or HIF-1a or HIF- 2a deletions. (SA3) To investigate macrophage-regulated tumor microenvironment and their role in chemotherapy efficacy in breast cancer. We will test the hypothesis that tumor pO2, pHe, redox and GSH all combine to form a tumor microenvironment profile that can predict levels of success for standard chemotherapies, and macrophages are a lynchpin in tumor microenvironment regulation. Specifically, we will test whether predominance in tumor macrophage polarity (M1/M2) will regulate a tumor microenvironment and the efficacy of standard chemotherapies, such as docetaxel, and whether macrophage HIF-1a deletion will increase docetaxel effectiveness. In summary, the results may provide new insight into the tumor microenvironment and macrophage regulation of efficacy of clinically-relevant anti-cancer therapies.

 描述（由适用提供）：该项目的总体目标是证明肿瘤微环境与巨噬细胞之间双向相互作用的假设在肿瘤进展和治疗有效性中起着重要作用。该假设是在活组织水平上专门提出的，因此将使用创新的电子顺磁共振（EPR）基于基于多功能的多功能方法在体内进行测试。这些方法将用于在体内将巨噬细胞和巨噬细胞特异性HIF-1A和HIF-2A的作用相关联在调节肿瘤缺氧，细胞外pH（PHE），氧化还原和谷胱甘肽（GSH）中的作用；这些因素的缺失如何影响乳腺癌PYMT小鼠模型中与临床相关的抗癌治疗策略。具体目的是：（SA1）优化用于体内多功能监测肿瘤组织参数的磁共振方式：pH，氧气，氧化还原和GSH。新型的顺磁问题和技术将用于在肿瘤组织中多功能应用，重点是应用小鼠PYMT乳腺肿瘤。 （SA2）研究巨噬细胞在调节肿瘤微环境中的作用。我们假设巨噬细胞显着影响乳腺癌中氧气张力，酸中毒，氧化还原和细胞内GSH（肿瘤微环境的EPR信号（EPR签名），尽管这两者都是低氧蛋白，但巨噬细胞HIF-1A和HIF-1A和HIF-2A的低氧蛋白质均具有这些参数，我们可以在这些参数中进行探索和反对的角色。包含巨噬细胞消融或HIF-1A或HIF-2A缺失的转基因小鼠之间的相应EPR签名。 （SA3）研究巨噬细胞调节的肿瘤微环境及其在乳腺癌中化学疗法效率中的作用。我们具体而言，我们将检验以下假设：肿瘤PO2，PHE，氧化还原和GSH均组合以形成肿瘤微环境谱，可以预测标准化学疗法的成功水平，而巨噬细胞是肿瘤微环境调节中的lynchpin。具体而言，我们将测试肿瘤巨噬细胞极性（M1/M2）中的优势是否会调节肿瘤微环境和标准化学疗法的效率，例如多西他赛，以及巨噬细胞HIF-1A的缺失是否会增加。多西他赛的有效性。总而言之，结果可能会提供有关肿瘤微环境和巨噬细胞调节临床相关的抗癌疗法有效性的新见解。