Radiation Therapy: Dissecting the Role of Stromal Cells in Tumor Control

放射治疗：剖析基质细胞在肿瘤控制中的作用

基本信息

批准号：
8578172
负责人：
David Guy Kirsch
金额：
$ 41.51万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578172
关键词：
Animals Binding Biological Bone Marrow CXCR4 gene Cancer Control Cancer Patient Cell Hypoxia Cell Line Cell Surface Receptors Cells Clinical Trials Complex DNA Damage Foundations Future Gene Targeting Gene-Modified Genetically Engineered Mouse Goals Hypoxia Hypoxia Inducible Factor In Vitro Knowledge Lead Ligands Malignant Neoplasms Measures Mediating Mission Modality Modeling Molecular Mus Myeloid Cells National Cancer Institute Oxygen Pathway interactions Patients Primary Neoplasm Public Health Radiation Radiation Tolerance Radiation therapy Radiobiology Recruitment Activity Recurrence Reporting Research Research Support Resistance Role Signal Transduction Pathway Stromal Cells System Technology Testing bHLH-PAS factor HLF cancer radiation therapy cancer therapy cell type hypoxia inducible factor 1 improved in vivo innovation insight irradiation killings macrophage migration monocyte mouse model neoplastic cell novel novel strategies public health relevance radiation resistance recombinase response sarcoma soft tissue transcription factor tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Radiation therapy is utilized to treat approximately 50% of all patients with cancer. However, a fundamental gap in improving the efficacy of radiation therapy exists because the mechanisms by which radiotherapy controls tumors remain poorly understood. For example, although hypoxia is a well-established cause of resistance to radiation therapy, the signal transduction pathways by which hypoxia regulates tumor response to radiation therapy remains to be fully elucidated. The overall goal of this research is to better understand how the efficacy of radiation therapy is influenced by the tumor stroma and microenvironment. We hypothesize that radiation therapy cures cancer by killing tumor parenchymal cells, but the tumor stroma influences the response of tumor parenchymal cells to radiation by regulating the tumor microenvironment. To study the complex interactions of tumor stroma and parenchymal cells during radiation therapy, we have generated novel genetically engineered mice. Previously, we used Cre recombinase to develop genetically engineered mouse models of soft tissue sarcoma to study radiation biology. We have now generated novel strains of genetically engineered mice in which primary cancers can be generated with Flp recombinase. In this system, Cre recombinase can still be utilized to modify genes specifically in the tumor stroma. Utilizing Flp and Cre recombinases (i.e. dual recombinase technology) to study the tumor microenvironment's impact on radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify tumor stromal cells. The proposed research is significant, because we will dissect the mechanisms by which myeloid cells are recruited to tumors during radiation therapy to regulate tumor response. Ultimately, such knowledge has the potential to lay the foundation for novel approaches to improve the efficacy of radiation therapy.

描述（由申请人提供）：用于治疗大约50％的所有癌症患者。然而，由于放射疗法控制肿瘤的机制仍然鲜为人知，因此存在提高放射治疗疗效的基本差距。例如，尽管缺氧是对放射治疗抗药性的良好原因，但缺氧调节肿瘤对放射治疗的反应的信号转导途径仍有待完全阐明。这项研究的总体目标是改善了解放射治疗的疗效如何受肿瘤基质和微环境的影响。我们假设放射治疗通过杀死肿瘤实质细胞来治愈癌症，但是肿瘤基质通过调节肿瘤微环境来影响肿瘤实质细胞对辐射的反应。为了研究放射治疗期间肿瘤基质和实质细胞的复杂相互作用，我们产生了新型的基因工程小鼠。以前，我们使用CRE重组酶开发了软组织肉瘤的基因工程小鼠模型来研究辐射生物学。现在，我们已经产生了新型的基因工程小鼠菌株，其中可以用FLP重组酶产生主要的癌症。在该系统中，CRE重组酶仍然可以用于在肿瘤基质中专门修饰基因。利用FLP和CRE重组酶（即双重重组酶技术）来研究肿瘤微环境对放射治疗的影响具有很高的创新性，因为可以用一种重组酶启动原发性癌症，而另一种重组酶则可以利用来特异性地修饰肿瘤肿瘤细胞。拟议的研究很重要，因为我们将在放射治疗期间剖析髓样细胞募集到肿瘤以调节肿瘤反应的机制。最终，这种知识有可能为提高放射治疗的疗效的新方法奠定基础。