Role of hematopoietic microenvironment in plexiform neurofibroma progression

造血微环境在丛状神经纤维瘤进展中的作用

• 批准号: 8328651
• 负责人: David W Clapp
• 金额: $ 33.17万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8328651
• 关键词: Adoptive Transfer; Adult; Animal Model; Biochemical; Biological; Biological Markers; Blood; Blood Circulation; Blood Vessels; Bone Marrow Cells; Bone Marrow Transplantation; CCL2 gene; CSF1 gene; Cell Adhesion; Cell Communication; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical Trials; Complement; Complex; Disease; Drug Delivery Systems; Dysplasia; Endothelial Cells; Endothelium; Engineering; Event; Extracellular Matrix; Gelatinase B; Genetic; Growth Factor; Harvest; Hematopoietic; Hematopoietic System; Human; Hyperplasia; In Vitro; Inflammation; Inflammatory; Integrin alpha4beta1; Integrins; Lead; MMP9 gene; Malignant - descriptor; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Medical; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Nerve; Paracrine Communication; Patients; Peptide Hydrolases; Plexiform Neurofibroma; Population; Positron-Emission Tomography; Process; Proto-Oncogene Protein c-kit; Publishing; Role; Schwann Cells; Signal Transduction; Site; Stem Cell Factor; Stromal Cells; Testing; Therapeutic; Tissues; Transplantation; Vascular Endothelial Growth Factors; Work; cohort; cytokine; in vivo; macrophage; mast cell; migration; neurofibroma; peripheral blood; peripheral blood vessel; prevent; research study; tumor; tumor progression; tumorigenic

Plexiform neurofibromas are complex tumors characterized by tumorigenic Schwann cells, inflammatory cells, neoangiogenesis and alterations of the extracellular matrix. Our previous work provided genetic, cellular, and biochemical evidence that haploinsufficiency of Nfl alters Ras activity and cell fates in mast cells and that ckit activation of the hematopoietic system is required in the initiation of plexiform tumor formation in a murine model. In this application, we propose to build oh these observations to identify the underpinning mechanisms of how c-kit mediates its biological effects, and to identify experimental processes that would complement ckit mediated experimental therapeutics in the clinic. Three basic processes will be examined. First, kit activation is known to cooperate with integrin signals in enabling myeloid cells to adhere to blood vessel walls and emigrate from the blood to the emerging tumor. We have recently established that Nf 1 +/- mast cells preferentially adhere to alpha4beta1, an integrin that has a key role in mast cell adhesion to endothelium and in local sites of inflammation. We hypothesize that alpha4beta1 is crucial in the recruitment of Nf1+/- mast cells to the tumor microenvironment in promoting local mast cell proliferation and survival, and in the secretion of molecules that promote neoangiogenesis. We propose studies to test this hypothesis in vitro and in vivo. Second, MMPs are secreted molecules that promote the release of preformed growth factors to the circulation and degrade the extracellular matrix of tissues allowing invasion of inflammatory and stromal cells leading to tumor progression. In preliminary studies we detect one specific MMP that is preferentially expressed and activated. Studies to specifically test the role of this protease are proposed. Finally, the specific downstream paracrine signals that lead to alterations of the extracellular matrix and neoangiogenesis are incompletely understood. Tumor-associated macrophages are known to enhance neoangiogenesis and facilitate malignant outgrowth. We recently established that large populations of angiogenic macrophages are found in peripheral blood and in the neurofibromas of Krox20; Nfl flox/- mice. We hypothesize that macrophage recruitment and their role in neoangiogenesis is a key downstream event following mast cell recruitment to the tumor and, therefore, processes that inhibit this activity will prevent or delay tumor progression. Adoptive transfer experiments are proposed to test this hypothesis.

丛状神经纤维瘤是一种复杂的肿瘤，其特征是致瘤雪旺细胞、炎症细胞、新血管生成和细胞外基质的改变。我们之前的工作提供了遗传、细胞和生化证据，表明 Nfl 的单倍体不足会改变肥大细胞中的 Ras 活性和细胞命运，并且在小鼠模型中，造血系统的 ckit 激活是丛状肿瘤形成启动所必需的。在此应用中，我们建议建立这些观察结果，以确定 c-kit 如何介导其生物效应的基础机制，并确定补充临床中 ckit 介导的实验治疗的实验过程。将检查三个基本过程。首先，已知试剂盒激活与整合素信号配合，使骨髓细胞粘附在血管壁上并从血液迁移到新出现的肿瘤。我们最近确定 Nf 1 +/- 肥大细胞 优先粘附α4β1，这是一种整合素，在肥大细胞与内皮细胞的粘附中起关键作用， 在局部炎症部位。我们假设 alpha4beta1 在 Nf1+/- 肥大的招募中至关重要 细胞对肿瘤微环境的影响，促进局部肥大细胞增殖和存活，并在 分泌促进新血管生成的分子。我们提出研究来在体外和体内检验这一假设。其次，MMP 是一种分泌分子，可促进预先形成的生长因子释放到循环中并降解组织的细胞外基质，从而允许炎症和基质细胞侵入，导致肿瘤进展。在初步研究中，我们检测到一种优先表达和激活的特定 MMP。提出了专门测试这种蛋白酶作用的研究。最后，导致细胞外基质改变和新血管生成的特定下游旁分泌信号尚不完全清楚。已知肿瘤相关巨噬细胞可增强新血管生成并促进恶性生长。我们最近发现，在外周血和 Krox20 神经纤维瘤中发现了大量的血管生成巨噬细胞； Nfl flox/- 小鼠。我们假设巨噬细胞募集及其在新血管生成中的作用是肥大细胞募集到肿瘤后的关键下游事件，因此，抑制这种活性的过程将阻止或延缓肿瘤进展。提出过继转移实验来检验这一假设。