Radiation-Induced Tumor Cell Migration

 描述(申请人提供)：放射治疗是治疗大多数癌症患者的关键组成部分。多年来，这种治疗的作用的定量模型已经被开发出来，根据给定的放射治疗中存活的细胞比例来定义放射对肿瘤的影响。然而，最近的研究表明，转移的、循环的肿瘤细胞可能会返回亲本肿瘤并重新播种，这一过程被称为“肿瘤自种”。我们假设，肿瘤自种植可能通过辐射刺激的过程为肿瘤在放射治疗后重新生长提供了一种机制。这一观点得到了我们团队的体外和体内数据的支持，这些数据表明，受辐射的肿瘤通过辐射诱导的细胞因子GM-CSF的表达来吸引迁移的肿瘤细胞。这项研究的目的是评估这一临床上重要的假说，以确定放射是否最终通过吸引循环中的肿瘤细胞而导致治疗后肿瘤的再生长。我们将通过四个具体目标来追求这一目标。第一个是通过使用肿瘤转移和放射治疗的新模型，结合生物发光成像和适形小动物放射治疗，利用皮下、原位和自发的小鼠癌症模型，严格和定量地表征辐射诱导的肿瘤自我种植。我们将评估这一过程对辐射剂量、肿瘤类型、肿瘤位置和时间的敏感性。在第二个目标中，我们将研究GM-CSF促进这一过程的分子和细胞机制，包括肿瘤细胞中受体介导的信号转导和与巨噬细胞的合作。在了解了这一机制后，特定目标3将设计出试图以临床相关的方式干扰它的治疗方法。最后，我们将通过一项先导性的临床研究，研究乳腺癌和肺癌患者中GM-CSF及其受体的信号转导，以评估这一过程的临床意义。这项工作代表了癌症放射治疗研究的新方向，并可能为一些肿瘤在放射生物学治疗过程中复发提供新的线索。了解这一过程将允许在考虑到患者的转移特征的情况下更有效地开出放射治疗处方，改善这些患者的癌症控制。此外，识别和开发能够抵消这一过程的治疗方法可能会进一步改善放射治疗后的结果。

 DESCRIPTION (provided by applicant): Radiation therapy is a critical component of treatment of the majority of cancer patients. For many years, quantitative models of the action of this therapy have been developed that define the effect of radiation on tumors in terms of the fraction of cells surviving a given radiation treatment. However, recent research has shown that metastatic, circulating tumor cells may return to the parent tumor and "re-seed" it, in a process that has been termed "tumor self-seeding". We hypothesize that tumor self-seeding may provide a mechanism for tumors to regrow after radiotherapy, through a process that is stimulated by radiation. This idea is supported by in vitro and in vivo data from our group showing that irradiated tumors attract migratory tumor cells through the radiation-inducible expression of the cytokine GM-CSF. The objective of this research is to evaluate this clinically important hypothesis, in order to determine whether radiation may ultimately contribute to tumor regrowth after treatment through attraction of circulating tumor cells. We will pursue this goal through fou specific aims. The first will be to rigorously and quantitatively characterize radiation-induced tumor self- seeding through the use of novel models of tumor metastasis and radiotherapy, utilizing subcutaneous, orthotopic, and spontaneous mouse models of cancer in conjunction with bioluminescence imaging and conformal small animal radiotherapy. We will assess the sensitivity of this process to radiation dose, tumor type, tumor location, and timing. In the second aim, we will investigate the molecular and cellular mechanisms by which GM-CSF facilitates this process, including receptor-mediated signaling in tumor cells and cooperation with macrophages. With an understanding of this mechanism, specific aim 3 will then engineer therapies that attempt to interfere with it in a clinically-relevant manner. Finally, we will investigate GM-CSF and GM-CSF receptor signaling in human breast and lung cancer patients through a pilot clinical study, in order to assess the clinical significance of this process. This work represents a new direction in the study of radiotherapy for cancer and may shed new light on why some tumors recur following radiobiologically curative courses of radiation. Understanding this process will allow more effective prescription of radiotherapy in consideration of patient's metastatic profile, improving control of cancer in these patients. Furthermore, identification and development of therapeutics that counteract this process may further enhance outcomes following radiation treatment.