Defining the cellular target of radiotherapy in primary mouse models of cancer

描述（由申请人提供）：人类癌症在由血管、成纤维细胞和免疫细胞组成的复杂环境中发展。肿瘤微环境有助于癌症的发生、进展和对治疗的反应。近三分之二的癌症患者在患病期间接受了放射治疗。尽管超过75%的患者接受治疗的目的是为了治愈，但目前尚不清楚放射疗法是否能治愈肿瘤

DESCRIPTION (provided by applicant): Human cancers develop in a complex environment composed of blood vessels, fibroblasts, and immune cells. The tumor microenvironment contributes to cancer development, progression, and response to therapy. Nearly two-thirds of all cancer patients receive radiation therapy during their illness. Although greater than 75% of these patients are treated with the intent to cure, it remains unclear if radiation cures tumors by killing tumor parenchymal cells or supporting stromal cells such as endothelial cells. The long-term goal of this study is to determine the mechanisms of tumor cure by radiation to enhance the efficacy of radiation therapy in the clinic. The overall objective of this application is to deine the cellular target(s) of radiation therapy in primary mouse models of cancer. Utilizing the two highly efficient site-specific recombinases, Cre and Flp, it is possible to contemporaneously mutate different genes specifically in tumor parenchymal cells and stromal cells. This dual recombinase technology enables the radiosensitivity of either the tumor parenchyma or the tumor microenvironment to be manipulated in primary tumors by mutating genes involved in DNA damage repair and apoptosis. The central hypothesis of this study is that radiation therapy cures tumors by killing tumor parenchymal cells rather than endothelial cells. Using micro-CT targeted irradiation and genetically engineered mouse models of primary lung adenocarcinoma and soft tissue sarcoma, the following specific aims will be completed: Aim 1: Determine the contribution of endothelial cells to tumor response to radiotherapy. Aim 2: Determine the contribution of tumor parenchymal cells to tumor response to radiotherapy. By selectively sensitizing or protecting either tumor parenchymal cells or endothelial cells, the critical target() of radiation therapy in primary cancers will be defined. Evaluating the contribution of the tumor microenvironment to tumor response to radiation therapy will help determine the viability of targeting stromal cells to improve the efficacy of radiation therapy in the clinic.