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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成分是骨髓（BM）衍生的免疫细胞转移到肿瘤中帮助肿瘤继续生长。而这些细胞包括肿瘤细胞的活性相关巨噬细胞（TAMs）一直是深入研究的主题，我们最近发现BM- 衍生的造血干细胞和祖细胞（HSPC）也存在于生长的肿瘤中，在肿瘤内长时间维持功能。有趣的是，HSPC的数量存在于肿瘤的生长与放射治疗（RT）后肿瘤的最终再生长速率直接相关。数据然而，这表明HSPC代表了参与肿瘤生物学的另一个重要细胞群体;它们的作用机制尚不清楚。填补这一知识空白将增加对不断变化的肿瘤生物学该提案的目的是确定HSPC如何在肿瘤中维持，以及如何在肿瘤中维持HSPC。 HSPCs促进RT后肿瘤的再生。我们的初步数据支持HSPCs维持通过整合素CD 49 f和存在于肿瘤细胞外基质中的层粘连蛋白的相互作用。在特定目的1，我们将证明这种相互作用确实是负责HSPC维持使用体外和体内，阻断或增强这种相互作用的策略，然后分析它们对HSPC功能的影响。我们还将确定参与这一过程的细胞内信号通路，初步研究集中在焦点粘附激酶（FAK）信号传导。这些研究将首次描述一种肿瘤特异性小生境，将HSPC保持在BM之外。在具体目标2中，我们将证明用RT治疗肿瘤加剧HSPC向肿瘤的迁移，并同时破坏CD 49 f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，有利于这些“释放”的分化。 HSPC进入肿瘤支持性巨噬细胞（特别是M2极化），以帮助肿瘤恢复。我们还将测试阻断HSPCs活性对肿瘤生长和RT后再生长的影响。研究，我们的长期目标是利用所获得的知识，作出重大贡献，为患有基于实体瘤的癌症的患者开发更稳健的治疗策略。