The Role of Hematopoietic Stem and Progenitor Cells in Solid Tumor Growth and Response to Radiation Therapy

造血干细胞和祖细胞在实体瘤生长和放射治疗反应中的作用

基本信息

批准号：
10359313
负责人：
Gerard James Madlambayan
金额：
$ 44.98万
依托单位：
OAKLAND UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359313
关键词：
Adjuvant Adjuvant Therapy Binding Biological Assay Bone Marrow Bone Marrow Cells Cell Count Cell Differentiation process Cell Maintenance Cells Data Development Differentiation Therapy Disease Pathway Exposure to Extracellular Matrix Focal Adhesion Kinase 1 Goals Growth Hematopoietic Hematopoietic stem cells Immune In Vitro Integrin alpha Chains Integrins Investigation Knowledge Label Laminin Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Molecular Pathway interactions Patient-Focused Outcomes Patients Pharmacology Play Population Process Proliferating Protein Isoforms Radiation Interaction Radiation therapy Recovery Regimen Reporting Role Signal Pathway Signal Transduction Solid Neoplasm Source Testing Time Tumor Biology Tumor-Derived Tumor-associated macrophages base bone cell cell motility hematopoietic differentiation in vivo macrophage migration monocyte colony stimulating factor mouse model neoplastic cell novel prevent radiation response residence response stem cell function stem cells theories treatment response treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY A major component of many solid tumors, including lung cancers, are bone marrow (BM)-derived immune cells that migrate to tumors and aid in their continued growth. While the activity of these cells including tumor associated macrophages (TAMs) has been the subject of intense investigation, we recently identified that BM- derived hematopoietic stem and progenitor cells (HSPCs) are also present in growing tumors and can be functionally maintained intratumorally for long periods of time. Interestingly, the numbers of HSPCs present in tumors directly correlates to the eventual regrowth rates of tumors following radiation therapy (RT). The data suggests that HSPCs represent another important cell population involved in tumor biology, however; their mechanism of action is still unclear. Filling this gap in knowledge will add to the ever-changing understanding of tumor biology. The objective of this proposal is to determine how HSPCs are maintained in tumors and how HSPCs promote tumor regrowth post-RT. Our preliminary data support the idea that HSPCs are maintained through interactions of the integrin CD49f and laminins present within the tumor extracellular matrix. In Specific Aim 1, we will show that this interaction is indeed responsible for HSPC maintenance using in vitro and in vivo strategies that block or enhance this interaction followed by analysis of their effects on HSPC functionality. We will also define the intracellular signaling pathways involved in this process with initial studies focusing on focal adhesion kinase (FAK) signaling. These studies will characterize for the first time a tumor specific niche capable of maintaining HSPCs outside of the BM. In Specific Aim 2, we will demonstrate that tumor treatment with RT exacerbates HSPC migration to tumors and concomitantly disrupts the interaction between CD49f and laminin. We will also show that RT produces tumor microenvironments that favor the differentiation of these ‘released’ HSPCs into tumor supportive macrophages (specifically M2 polarized) to aid in tumor recovery. We will also test the effects of blocking the activity of HSPCs on tumor growth and regrowth post-RT. By completing the proposed studies, our long-term goal is to use the knowledge gained to make a significant contribution towards the development of more robust treatment strategies for patients suffering with solid tumor based cancers.

项目摘要包括肺癌在内的许多实体瘤的主要组成部分是骨髓（BM）衍生的免疫细胞迁移到肿瘤并有助于其持续生长。而这些细胞的活性在内相关的巨噬细胞（TAM）一直是激烈研究的主题，我们最近确定BM- 衍生的造血干和祖细胞（HSPC）也存在于生长的肿瘤中，可以是在功能上长时间保持肿瘤内维持。有趣的是，存在于肿瘤与放射治疗（RT）后肿瘤的事件调节率直接相关。数据但是，HSPCS代表了参与肿瘤生物学的另一个重要细胞群。他们的作用机理仍然不清楚。在知识中填补这一空白将增加对的不断变化的理解肿瘤生物学。该提案的目的是确定HSPC如何在肿瘤中保持 HSPC促进了RT后肿瘤后悔。我们的初步数据支持维护HSPC的想法通过存在于肿瘤外基质中的整合素CD49F和层粘连蛋白的相互作用。具体 AIM 1，我们将证明这种相互作用的确是使用体外和体内使用HSPC维护的原因阻止或增强这种相互作用的策略，然后分析其对HSPC功能的影响。我们还将定义此过程中涉及的细胞内信号传导途径，并以焦点为重点粘附激酶（FAK）信号传导。这些研究将首次表征肿瘤特异性的小众在BM外保持HSPC。在特定目标2中，我们将证明使用RT治疗肿瘤加剧了HSPC迁移到肿瘤的迁移，并伴随破坏CD49F和层粘连蛋白之间的相互作用。我们还将表明，RT产生肿瘤微环境，有利于分化这些“释放” HSPC进入肿瘤支撑性巨噬细胞（特别是M2极化），以帮助肿瘤恢复。我们还将测试阻断HSPC对肿瘤生长和RT改革的活性的影响。通过完成建议研究，我们的长期目标是利用所获得的知识为为患有实体瘤的患者开发更健壮的治疗策略。