Radiation response within the tumor microenvironment

描述（由申请人提供）：放疗仍然是癌症治疗的主要手段，但许多患者在无病生存期没有获益。微环境，特别是通过肿瘤血管的微环境，对放疗后癌细胞的存活有重要影响。我们小组最近的工作利用了DNA双链断裂（DSB）的活细胞报告者的荧光成像来跟踪照射后DSB的形成以及损伤修复或持续的动力学。在这里，我们将检查小鼠异种移植肿瘤的辐射反应，并解剖癌细胞和基质之间的串扰。我们计划利用我们实验室开发的互补方法来检查肿瘤微环境中的辐射反应，然后检查局部事件的异质性与肿瘤总体反应之间的关系。具体来说，我们小组的成员率先使用了1)荧光DSB报告来跟踪肿瘤内癌细胞的DNA损伤和修复，2)带有荧光基质或血管细胞的转基因裸鼠来跟踪肿瘤中的血管生成，3)微阵列分析可以区分癌症和基质细胞中的基因表达模式，4)PET/MRI/CT和图像集成的先进方法来跟踪肿瘤对靶向辐射的反应。5)肿瘤细胞氧合和代谢决定因素的体外和计算建模。通过整合这些工具，我们期望对细胞增殖与停滞进行多尺度分析和建模，考虑DNA损伤和修复的内在决定因素以及微环境水平上血管几何形状和血管生成的影响。我们希望随着时间的推移将这些事件投射到肿瘤大小和总体代谢水平上。

DESCRIPTION (provided by applicant): Radiotherapy remains a mainstay in cancer treatment yet many patients obtain no benefit in disease-free survival. The microenvironment, particularly via the tumor vasculature, exerts a major influence on cancer cell survival after radiotherapy. Recent work by our groups has exploited fluorescence imaging of a live-cell reporter of DNA double strand breaks (DSBs) to follow DSB formation after irradiation and the kinetics of damage repair or persistence. Here, we will examine radiation response in xenograft tumors in mice and dissect cross-talk between cancer cells and stroma. We plan to leverage complementary approaches developed in our laboratories to examine radiation response within the tumor microenvironment and then to examine the relationship between the heterogeneity of local events and overall response of tumors. Specifically, members of our group have pioneered use of 1) fluorescent DSB reporters to track DNA damage and repair in cancer cells within tumors, 2) transgenic nude mice with fluorescent stroma or vascular cells to track angiogenesis in tumors, 3) microarray analysis that can distinguish the gene expression patterns in the cancer and stromal cells, 4) advanced approaches to PET/MRI/CT and image integration to track tumor responses to targeted radiation, and 5) in vitro and computational modeling of determinants of tumor cell oxygenation and metabolism. By integrating these tools, we anticipate pursuing a multi-scale analysis and modeling of cellular proliferation vs. arrest, factoring in intrinsic determinants of DNA damage and repair and the effects of vascular geometry and angiogenesis at the level of microenvironment. We hope to project these events over time onto tumor size and metabolism on a gross level.