Regulation of tumor angiogenesis by Id+ marrow precursor

Id 骨髓前体对肿瘤血管生成的调节

• 批准号: 6935201
• 负责人: DAVID CHARLES LYDEN
• 金额: $ 29.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-08 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935201
• 关键词: DNA binding protein; angiogenesis; apoptosis; biological signal transduction; bone marrow; cell growth regulation; cell proliferation; chemokine; flow cytometry; genetically modified animals; hematopoietic stem cells; human tissue; immunocytochemistry; laboratory mouse; neoplasm /cancer blood supply; polymerase chain reaction; receptor expression; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The objective of this proposal is to examine the role of bone marrow (BM) - derived circulating endothelial precursor cells (CEPs) and hematopoietic cells (HCs) in the post natal regulation of angiogenesis. Despite recent identification of angiogenic factors regulating embryonic development, the role of such factors and effector cells in modulation of tumor angiogenesis is not clear. We intend to define the mechanisms whereby Id gene mediation along with the upregulation of vascular endothelial growth factor receptors, VEGFR1 (Flt-l) and VEGFR2 (FIK-1, KDR) regulate survival, proliferation, mobilization, and recruitment of CEPs and HCs. We have identified circulating CEPs, AC133 (+) VEGFR2 (+), capable of being recruited from BM to tumor vasculature bed, accelerating angiogenesis. We found that signaling through VEGFR2 is essential for CEP proliferation and that VEGF induces mobilization of a subset of VEGFR1 (+) HCs that affects initiation of the tumor vascular network. Also VEGF induced Id1 and Id3 expression in both BM derived CEPs and HCs. Further angiogenic defects (tumor growth, Matrigel vascularization) in Id1 and Id3 knock out (Id1+/-Id3-/-) mice were reversible by BM transplantation. Thus the primary angiogenic defect in (Id1+/-Id3-/-) mice may be due to dysregulated VEGF/VEGFR2 and perhaps VEGF/VEGFR1 signaling, causing mobilization failure. We hypothesize that VEGF-mediated upregulation of Id1 and/or Id3 is essential for mobilization of VEGFR1(+) HCs and VEGFR2(+) CEPs. Specific aims are: Determine the temporal and spatial expression patterns of Id genes, VEGFR1, and VEGFR2 on neovessels during tumor angiogenesis, 2) Define the role of chemokine signaling pathways for the regulation of Id gene and VEGF receptor expression during the mobilization of CEPs and HCs, 3) Assess the physiological significance and contributions of BM-derived CEPs and/or HCs to tumor angiogenesis in vivo models. These experiments will lead to the understanding of the mechanisms involved in the recruitment of VEGF-responsive Id competent BM-derived precursors to the tumor vasculature bed and suggest new clinical strategies to block tumor growth.

描述（由申请人提供）：本提案的目的是检查骨髓（BM）来源的循环内皮前体细胞（CEP）和造血细胞（HC）在出生后血管生成调节中的作用。尽管最近鉴定了调节胚胎发育的血管生成因子，但这些因子和效应细胞在调节肿瘤血管生成中的作用尚不清楚。我们打算定义 Id 基因介导以及血管内皮生长因子受体、VEGFR1 (Flt-1) 和 VEGFR2 (FIK-1, KDR) 上调调节 CEP 和 HC 的存活、增殖、动员和招募的机制。我们已经鉴定出循环 CEP，AC133 (+) VEGFR2 (+)，能够从 BM 募集到肿瘤脉管系统床，加速血管生成。我们发现，通过 VEGFR2 的信号传导对于 CEP 增殖至关重要，并且 VEGF 诱导 VEGFR1 (+) HC 子集的动员，从而影响肿瘤血管网络的启动。 VEGF 还诱导 BM 衍生的 CEP 和 HC 中的 Id1 和 Id3 表达。 Id1 和 Id3 敲除 (Id1+/-Id3-/-) 小鼠中的进一步血管生成缺陷（肿瘤生长、基质胶血管化）可通过骨髓移植逆转。因此，(Id1+/-Id3-/-)小鼠中的原发性血管生成缺陷可能是由于 VEGF/VEGFR2 失调以及 VEGF/VEGFR1 信号传导失调导致的，导致动员失败。我们假设 VEGF 介导的 Id1 和/或 Id3 上调对于 VEGFR1(+) HC 和 VEGFR2(+) CEP 的动员至关重要。具体目标是：确定肿瘤血管生成过程中新生血管上 Id 基因、VEGFR1 和 VEGFR2 的时间和空间表达模式，2) 定义趋化因子信号通路在 CEP 和 HC 动员过程中调节 Id 基因和 VEGF 受体表达的作用，3) 评估 BM 衍生的 CEP 和/或 HC 对肿瘤的生理意义和贡献 血管生成体内模型。这些实验将有助于理解将 VEGF 反应性 Id 活性 BM 衍生前体招募到肿瘤脉管系统床所涉及的机制，并提出阻止肿瘤生长的新临床策略。