Radiation-Induced Tumor Cell Migration

辐射诱导的肿瘤细胞迁移

• 批准号: 9906603
• 负责人: EDWARD E GRAVES
• 金额: $ 7.57万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906603
• 关键词: Aftercare; Animals; Antibodies; Back; Biological; Blood specimen; Breast Cancer Model; Cancer Control; Cancer Model; Cancer Patient; Cell Differentiation process; Cell Fraction; Cells; Clinical; Clinical Research; Data; Dependence; Disease; Dose; Engineering; Exhibits; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Human; Immune; In Vitro; Investigation; Irradiated tumor; Laboratories; Lesion; Light; Location; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Normal tissue morphology; Outcome; Parents; Patient-Focused Outcomes; Patients; Physiological; Primary Neoplasm; Process; Radiation; Radiation Dose Unit; Radiation therapy; Radiobiology; Receptor Signaling; Recurrence; Research; Role; Seeds; Signal Pathway; Signal Transduction; Site; Time; Tumor Cell Migration; Work; bioluminescence imaging; cancer radiation therapy; cancer therapy; chemotherapy; clinically relevant; clinically significant; cytokine; improved; in vivo; in vivo Model; inducible gene expression; inhibitor/antagonist; innovation; insight; irradiation; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; novel; prevent; public health relevance; radiation effect; receptor; receptor-mediated signaling; subcutaneous; therapeutic development; trafficking; treatment response; tumor; tumor microenvironment

 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.

 描述（由申请人提供）：放射治疗是大多数癌症患者治疗的重要组成部分。多年来，人们已经开发了这种疗法作用的定量模型，根据给定放射治疗中存活的细胞分数来定义放射对肿瘤的影响。然而，最近的研究表明，转移性循环肿瘤细胞可能会返回母体肿瘤并“重新播种”，这一过程被称为“肿瘤自我播种”。我们假设肿瘤的自我播种可能为放疗后肿瘤通过辐射刺激的过程重新生长提供了一种机制。这个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 的辐射诱导表达来吸引迁移性肿瘤细胞。本研究的目的是评估这一临床上重要的假设，以确定辐射是否可能通过吸引循环肿瘤细胞最终促进治疗后肿瘤的再生。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新型肿瘤转移和放射治疗模型，结合生物发光成像和适形小动物放射治疗，利用皮下、原位和自发性小鼠癌症模型，严格和定量地表征辐射诱导的肿瘤自播种。我们将评估该过程对辐射剂量、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。了解这一机制后，特定目标 3 将设计出试图以临床相关方式干扰该机制的疗法。最后，我们将通过一项试点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新方向，并可能为为什么某些肿瘤在放射生物学治疗疗程后复发提供新的线索。了解这一过程将有助于根据患者的转移情况制定更有效的放射治疗处方，从而改善这些患者对癌症的控制。此外，识别和开发抵消这一过程的疗法可能会进一步改善放射治疗后的结果。