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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：
8843808
负责人：
David Guy Kirsch
金额：
$ 43.24万
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 2016-01-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843808
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 Health 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 radiation resistance radiation response 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）：放射疗法用于治疗大约 50% 的癌症患者。然而，由于放疗控制肿瘤的机制仍知之甚少，因此在提高放疗疗效方面存在根本性差距。例如，尽管缺氧是放射治疗抵抗的一个公认原因，但缺氧调节肿瘤对放射治疗反应的信号转导途径仍有待充分阐明。本研究的总体目标是更好地了解肿瘤基质和微环境如何影响放射治疗的疗效。我们假设放射治疗通过杀死肿瘤实质细胞来治愈癌症，但肿瘤基质通过调节肿瘤微环境来影响肿瘤实质细胞对放射的反应。为了研究放射治疗过程中肿瘤基质和实质细胞复杂的相互作用，我们培育了新型基因工程小鼠。此前，我们使用Cre重组酶开发了软组织肉瘤基因工程小鼠模型来研究放射生物学。我们现在已经培育出新的基因工程小鼠品系，其中可以通过 Flp 重组酶产生原发性癌症。在该系统中，Cre重组酶仍可用于特异性修饰肿瘤基质中的基因。利用Flp和Cre重组酶（即双重组酶技术）来研究肿瘤微环境对放射治疗的影响具有高度创新性，因为原发性癌症可以用一种重组酶引发，而另一种重组酶可以用于特异性修饰肿瘤基质细胞。拟议的研究意义重大，因为我们将剖析放射治疗过程中骨髓细胞被招募到肿瘤以调节肿瘤反应的机制。最终，这些知识有可能为提高放射治疗疗效的新方法奠定基础。