Host-tumor interactions and cancer relapse after radiation therapy

放射治疗后宿主-肿瘤相互作用和癌症复发

• 批准号: 8630517
• 负责人: Xiang-Yang Shawn Wang
• 金额: $ 31.64万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630517
• 关键词: Ablation; Address; Automobile Driving; Behavior; Biochemical; Biological Models; Cancer Patient; Cancer Relapse; Cell physiology; Cells; Clinic; Clinical; Combined Modality Therapy; Data; Development; Disease; Down-Regulation; Effectiveness; Employee Strikes; Endothelial Cells; Event; Failure; Genes; Genetic; Goals; Heat shock proteins; Image; Immune; Immune response; Immunosuppressive Agents; In Situ; Inflammation Mediators; Inflammatory; Injury; Integration Host Factors; Intensity-Modulated Radiotherapy; Lead; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Mission; Modality; Molecular; Mus; Myeloid Cells; Neoplasm Metastasis; Normal tissue morphology; Outcome; Pathology; Patients; Pattern Recognition; Phenotype; Production; Protein Binding; Public Health; Radiation; Radiation Oncology; Radiation therapy; Recovery; Recurrence; Regulation; Relapse; Research; Research Priority; Role; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Treatment Failure; Treatment outcome; Tumor Cell Invasion; Vaccines; Vascular Endothelial Cell; Work; base; cancer radiation therapy; cancer recurrence; clinically relevant; combinatorial; design; host neoplasm interaction; immune function; improved; innovation; insight; irradiation; macrophage; molecular dynamics; neoplastic cell; new therapeutic target; novel; prevent; public health relevance; response; restoration; scavenger receptor; therapeutic effectiveness; therapeutic target; tumor; tumor immunology; tumor microenvironment; tumor progression

Project Summary Although advances in radiation therapy (RT, e.g., image-guided and intensity-modulated RT) have led to improved treatment outcomes, overcoming tumor recurrence still remains a challenge for a number of cancers where RT is an important therapeutic modality. There is an increasing appreciation of how dynamic interactions between malignant tumor cells and non-transformed host cells (e.g., immune cells, endothelial cells) determine not only cancer behavior (e.g., invasion and metastasis), but also responses to therapies, including RT. However, the precise mechanisms of molecular and cellular interactions within the tumor microenvironment (TME), and their impact on post-RT relapse remain to be elucidated. The central hypothesis in this application, formulated based on our preliminary data, is that scavenger receptor A (SRA), a pattern recognition molecule primarily expressed on myeloid cells, promotes tumor recurrence by facilitating the polarization of proangiogenic, tumor-associated macrophages (TAMs) and tumor revascularization following RT. Our overall objective is to comprehensively understand a previously unrecognized role of SRA as an essential host factor in governing dynamic myeloid cell-tumor crosstalk and tumor response to RT. The rationale for the proposed research is that delineating fundamental mechanisms of SRA action in modulating the TME in response to RT has the potential for developing novel targeted approaches to reduce cancer recurrence in the clinic. We will test our hypothesis by pursuing 3 specific aims: 1) Establish a crucial role for SRA in potentiating the recovery of tumor vasculature after RT and subsequent recurrence using genetic, biochemical, and cellular approaches with clinically relevant model systems; 2) Determine the molecular and cellular basis of SRA functions in skewing tumor-associated macrophages toward an alternatively activated, proangiogenic phenotype; and 3) Validate the concept of targeting SRA in the TME to overcome post-RT recurrence by engaging multivalent antitumor mechanisms. In view of the established immunosuppressive functions of SRA, we will also evaluate the feasibility of blocking SRA activity in the TME to improve the effectiveness of a combinatorial RT and heat shock protein-based therapy. The concept of TAM-associated SRA as a critical, tumor-extrinsic determinant of treatment outcome following RT, and the idea of preventing cancer relapse by antagonizing SRA in the TME to abrogate tumor revascularization and concurrently enhance immune functions are innovative. The proposed research is significant because it is expected to advance the understanding of distinct aspects of dynamic host-tumor interactions and their implications in improving tumor response to RT. The insights gained from these studies will facilitate rational design of multimodality therapy to reduce treatment failure after RT.

项目摘要 尽管放射治疗（RT，例如，图像引导和强度调制RT）具有LED 为了改善治疗效果，克服肿瘤复发仍然是许多人面临的挑战。 RT是一种重要的治疗方式的癌症。越来越多的人认识到， 恶性肿瘤细胞和非转化宿主细胞之间的相互作用（例如，免疫细胞，内皮 细胞）不仅决定癌症行为（例如，侵袭和转移），而且对治疗的反应， 然而，肿瘤内分子和细胞相互作用的精确机制 微环境（TME），以及它们对RT后复发的影响仍有待阐明。核心假设 在本申请中，基于我们初步数据制定的是清道夫受体A（SRA）， 识别分子主要表达在骨髓细胞上，通过促进肿瘤细胞的增殖促进肿瘤复发。 肿瘤相关巨噬细胞（TAM）的促血管生成极化和肿瘤血管重建， RT.我们的总体目标是全面了解SRA作为一个 在控制动态骨髓细胞-肿瘤串扰和肿瘤对RT的反应中， 拟议研究的基本原理是，描绘SRA作用的基本机制， 对RT反应的TME具有开发新的靶向方法以减少癌症的潜力 在临床上复发。我们将通过追求3个具体目标来测试我们的假设：1）建立一个关键的角色， SRA在增强RT后肿瘤血管系统的恢复和随后的复发中使用遗传， 生物化学和细胞方法与临床相关的模型系统; 2）确定分子和 SRA的细胞基础在使肿瘤相关巨噬细胞偏向于交替活化， 促血管生成表型;和3）重申在TME中靶向SRA以克服RT后 通过参与多价抗肿瘤机制来预防复发。鉴于已建立的免疫抑制 为了了解SRA的功能，我们还将评估在TME中阻断SRA活性以改善 联合RT和基于热休克蛋白的治疗的有效性。 TAM相关SRA作为治疗结局的关键性肿瘤外在决定因素的概念 以及通过拮抗TME中的SRA以消除肿瘤来预防癌症复发的想法 同时增强免疫功能是创新的。拟议的研究是 重要的是，它有望促进对动态宿主肿瘤的不同方面的理解， 相互作用及其对改善肿瘤对RT反应的影响。从这些研究中获得的见解 将有助于合理设计多模式治疗，以减少RT后治疗失败。