The "Phoenix Rising" pathway of tumor repopulation during radiotherapy

描述(申请人提供)：40多年前，在接受放射治疗的实验肿瘤中描述了“加速再生长”的现象。今天，在治疗过程中防止肿瘤细胞再生长的概念是放射治疗的基本原则。事实上，它是S在放射肿瘤学教科书中广泛传授的四个最重要的R之一。然而，涉及肿瘤再生长的分子机制仍然知之甚少。在这个项目中，我们提出了一个关于放射治疗过程中肿瘤再生长的分子机制的范式转换假说。我们的假设是，死亡细胞负责动员和刺激存活的肿瘤细胞通过旁分泌信号重新填充受照射的肿瘤。我们的假说是基于我们最近发现的“凤凰上升”途径，通过该途径，caspase 3激活濒死细胞的旁分泌信号级联反应，以刺激组织再生和照射肿瘤中存活的肿瘤细胞的快速增殖。我们计划开展以下深入研究，探讨caspase和其他因子在“凤凰升起”通路中对肿瘤放射治疗反应的作用(具体目标1)。此外，我们计划研究caspase下游因子在“凤凰路径”(特定目标2)中的作用。最后，我们将尝试确定抑制半胱氨酸氨基转移酶或其下游因子是否是加强癌症放射治疗的可行策略(特定目标3)。我们相信，我们的项目将为肿瘤在放射治疗后如何复发提供关键的见解。它还有可能促进新疗法的发展，以加强癌症放射治疗。

DESCRIPTION (provided by applicant): More than 40 years ago, the phenomenon of "accelerated repopulation" was described in experimental tumors undergoing radiotherapy. Today, the concept of preventing tumor cellular repopulation during treatment is a basic tenet in radiotherapy. In fact, it is one of the four all-important "R"s widely taught in radiation oncology textbooks. However, the molecular mechanisms involved in tumor repopulation are still very poorly understood. In this project, we propose a paradigm changing hypothesis with regard to the molecular mechanism of tumor repopulation during radiotherapy. Our hypothesis is that dying cells are responsible for mobilizing and stimulating the surviving tumor cells to repopulate the irradiated tumor through paracrine signaling. Our hypothesis is based on our recent discovery of the "Phoenix Rising" pathway through which caspase 3 activates paracrine signaling cascades from dying cells to stimulate tissue regeneration and the rapid proliferation of surviving tumor cells in irradiated tumors. We plan to carry out the following in-depth investigations of the roles of caspases and other factors in the "Phoenix Rising" pathway in tumor response to radiotherapy (specific aim 1). In addition, we plan to examine the roles of downstream factors of caspases in the "Phoenix Pathway" (specific aim 2). Finally we will attempt to determine if inhibition of caspases or their downstream factors is a feasible strategy to enhance cancer radiotherapy (specific aim 3). We believe our project will provide crucial insights into how tumors relapse after radiotherapy. It also has the potential to facilitate the development of new therapeutics for enhancing cancer radiotherapy.