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

描述（由申请人提供）：放射治疗用于治疗约50%的癌症患者。然而，在提高放射治疗的疗效方面存在根本性的差距，因为放射治疗控制肿瘤的机制仍然知之甚少。例如，尽管缺氧是对放射治疗抵抗的公认原因，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充分阐明。这项研究的总体目标是更好地 了解肿瘤间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，但肿瘤间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间质和实质细胞的复杂相互作用，我们产生了新型基因工程小鼠。在此之前，我们使用Cre重组酶来开发软组织肉瘤的基因工程小鼠模型，以研究辐射生物学。我们现在已经产生了新的基因工程小鼠品系，其中原发性癌症可以用Flp重组酶产生。在该系统中，Cre重组酶仍然可以用于特异性修饰肿瘤间质中的基因。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是高度创新的，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。这项研究意义重大，因为我们将剖析骨髓细胞在放射治疗过程中被招募到肿瘤中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。

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.