Radiation-Induced Tumor Cell Migration

 描述（由申请人提供）：放射治疗是大多数癌症患者治疗的关键组成部分。多年来，已经开发了这种疗法的作用的定量模型，其根据在给定的放射治疗中存活的细胞的分数来定义放射对肿瘤的影响。然而，最近的研究表明，转移性的循环肿瘤细胞可能会返回到母体肿瘤并“重新播种”，这一过程被称为“肿瘤自我播种”。我们推测，肿瘤自我播种可能提供了一种机制，肿瘤放疗后，通过一个过程，是由辐射刺激再生。这一想法得到了我们小组的体外和体内数据的支持，这些数据表明，受辐射的肿瘤通过细胞因子GM-CSF的辐射诱导表达吸引迁移性肿瘤细胞。本研究的目的是评估这一具有临床重要性的假设，以确定放射是否可能最终通过吸引循环肿瘤细胞而促进治疗后的肿瘤再生长。我们将通过四个具体目标来实现这一目标。第一个将是通过使用肿瘤转移和放射治疗的新模型，利用皮下、原位和自发的癌症小鼠模型，结合生物发光成像和适形小动物放射治疗，严格和定量地表征辐射诱导的肿瘤自接种。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传导以及与巨噬细胞的合作。随着对这种机制的理解，具体目标3将设计出试图以临床相关方式干扰它的疗法。最后，我们将通过一项初步临床研究来研究人类乳腺癌和肺癌患者中的GM-CSF和GM-CSF受体信号传导，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一个新方向，并可能揭示为什么一些肿瘤在放射生物学治疗过程中复发。了解这一过程将允许考虑患者的转移情况更有效地处方放射治疗，改善这些患者的癌症控制。此外，识别和开发对抗这一过程的治疗方法可能会进一步增强放射治疗后的结果。

 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.