The Regulation of Tumor Progression by Endothelial HoxA5

内皮细胞HoxA5对肿瘤进展的调节

基本信息

批准号：
7886947
负责人：
Nancy Joan Boudreau
金额：
$ 32.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-07 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7886947
关键词：
Acute Adherens Junction Adhesions Angiogenic Factor Architecture Behavior Biological Models Blood Vessels Bone Marrow Bone Marrow Cells Cells Chronic Complex Development Disease Ectopic Expression Endothelial Cells Endothelium Environment Ephrin-A1 Epithelial Epithelial Cells Epithelium Excision Genes Goals Homeobox Immune Immune response Infiltration Interleukin-6 Investigation Laboratories Mammary Neoplasms Mammary Tumorigenesis Mammary gland Methods Modeling Mus Neoplasm Metastasis Organ Pathologic Neovascularization Permeability Phenotype Population Proteins Regulation Rest Role Skin Solid Neoplasm Staging Stimulus TEK gene Tetracyclines Therapeutic Therapeutic Agents Tissues Transgenic Mice Tumor Angiogenesis Tumor Tissue Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular Permeabilities Vascular blood supply Work Wound Healing angiogenesis anti-cancer therapeutic carcinogenesis clinical application combat in vivo migration mouse model novel novel strategies public health relevance response thrombospondin 2 transcription factor tumor tumor growth tumor progression tumorigenic vascular bed

项目摘要

DESCRIPTION (provided by applicant): Tumor growth and progression requires development of a new vascular supply. Many current anti-angiogenic therapies target VEGF, but targeting VEGF alone is not universally effective in combating angiogenesis induced by tumors in different organs or at various stages of the disease. Thus more global approaches to inhibit angiogenesis are needed. My laboratory has defined roles for the homeobox (Hox) master transcription factors, HoxD3, HoxA3 and HoxB3 in coordinately regulating endothelial cell (EC) invasion, proliferation, and adhesion during angiogenesis. In addition we have also demonstrated that other Hox factors, namely HoxD10 and HoxA5 act in a dominant manner to maintain cultured EC in a quiescent, differentiated state and resist angiogenic stimuli. To explore the anti-angiogenic and anti-tumorigenic potential of Hox genes in vivo, we will focus on HoxA5, which is highly expressed in quiescent differentiated EC, but expression is reduced in activated tumor endothelium. Ectopic expression of HoxA5 in cultured EC impairs migration, down-regulates several pro-angiogenic genes including VEGFR2, ephrin A1 and IL-6 and significantly increases levels of anti-angiogenic factors including Thrombospondin-2 (TSP-2). HoxA5 also stabilizes EC adherens junctions and reduces endothelial cell permeability. Our preliminary evidence suggests that EC HoxA5 may also suppress recruitment/infiltration of pro-angiogenic bone marrow derived cells (BMDC). Thus, we hypothesize that maintaining high levels of HoxA5 selectively in EC in the tumor microenvironment in vivo will stabilize the vasculature, inhibit angiogenesis and BMDC recruitment and impair tumor progression. We have developed a transgenic mouse model in which expression of HoxA5 is largely restricted to EC through TIE-2 driven expression of a tetracycline activator protein and HoxA5 can be activated in angiogenic conditions by removal of tetracycline. These mice have been crossed with 2 established de novo models of skin (K14-HPV16) and mammary MMTV-PyMT) carcinogenesis for further analysis of EC HoxA5 in reducing tumor angiogenesis and progression in complex and dynamic tumor microenvironments. We will also evaluate how EC HoxA5 influences recruitment of pro-angiogenic BMDC in these models. Finally we will develop methods to therapeutically restore HoxA5 expression in tumor tissues in vivo and explore the ability of HoxA5 to potentially coordinate the behavior of endothelial, epithelial cells and recruitment of BMDC within tissues to identify new approaches to treat tumors and their reactive stroma. PUBLIC HEALTH RELEVANCE: These studies will investigate the whether Hox genes which maintain a quiescent, mature phenotype in vascular endothelial cells, can be sustained in angiogenic environments and thus block tumor angiogenesis and progression. We will focus on the vascular stabilizing transcription factor, HoxA5, and using a novel transgenic mouse model, will sustain its expression in tumor endothelial cells in vivo to determine whether this impairs angiogenesis and ultimately limits tumor progression. Moreover, as this gene is normally expressed in quiescent resting vessels, but absent in tumor vessels, sustained expression would not interfere with normal vascular function. In addition we will develop two novel approaches to apply HoxA5 therapeutically to both skin and mammary tumors to further demonstrate its clinical applicability. Finally we will explore the notion that HoxA5 may act to coordinately stabilize the vasculature as well as the tumor epithelium and the pro-tumorigenic immune response thus represent a means to target the entire tumor microenvironment.

描述（由申请人提供）：肿瘤生长和进展需要开发新的血管供应。目前许多抗血管生成疗法都以 VEGF 为靶点，但单独以 VEGF 为靶点并不能普遍有效地对抗不同器官或疾病不同阶段的肿瘤诱导的血管生成。因此，需要更全面的方法来抑制血管生成。我的实验室已经确定了同源框 (Hox) 主转录因子 HoxD3、HoxA3 和 HoxB3 在协调调节血管生成过程中内皮细胞 (EC) 侵袭、增殖和粘附方面的作用。此外，我们还证明了其他Hox因子，即HoxD10和HoxA5以显性方式发挥作用，以维持培养的EC处于静止、分化状态并抵抗血管生成刺激。为了探索Hox基因在体内的抗血管生成和抗肿瘤生成潜力，我们将重点关注HoxA5，它在静止分化的EC中高表达，但在活化的肿瘤内皮中表达降低。培养的 EC 中 HoxA5 的异位表达会损害迁移，下调包括 VEGFR2、ephrin A1 和 IL-6 在内的多种促血管生成基因，并显着增加包括 Thrombospondin-2 (TSP-2) 在内的抗血管生成因子的水平。 HoxA5 还可以稳定 EC 粘附连接并降低内皮细胞通透性。我们的初步证据表明 EC HoxA5 还可能抑制促血管生成骨髓衍生细胞 (BMDC) 的招募/浸润。因此，我们假设在体内肿瘤微环境的 EC 中选择性维持高水平的 HoxA5 将稳定脉管系统，抑制血管生成和 BMDC 募集并损害肿瘤进展。我们开发了一种转基因小鼠模型，其中通过 TIE-2 驱动四环素激活蛋白的表达，HoxA5 的表达很大程度上限于 EC，并且可以通过去除四环素在血管生成条件下激活 HoxA5。这些小鼠已与 2 个已建立的皮肤 (K14-HPV16) 和乳腺 MMTV-PyMT) 致癌模型进行杂交，以进一步分析 EC HoxA5 在复杂和动态肿瘤微环境中减少肿瘤血管生成和进展的作用。我们还将评估 EC HoxA5 如何影响这些模型中促血管生成 BMDC 的募集。最后，我们将开发在体内治疗性恢复肿瘤组织中 HoxA5 表达的方法，并探索 HoxA5 潜在协调内皮细胞、上皮细胞行为和组织内 BMDC 募集的能力，以确定治疗肿瘤及其反应性基质的新方法。公共健康相关性：这些研究将调查在血管内皮细胞中维持静止、成熟表型的 Hox 基因是否可以在血管生成环境中持续存在，从而阻止肿瘤血管生成和进展。我们将重点关注血管稳定转录因子 HoxA5，并使用新型转基因小鼠模型，维持其在体内肿瘤内皮细胞中的表达，以确定这是否会损害血管生成并最终限制肿瘤进展。此外，由于该基因通常在静止的静息血管中表达，但在肿瘤血管中不存在，因此持续表达不会干扰正常的血管功能。此外，我们将开发两种新方法，将 HoxA5 应用于皮肤和乳腺肿瘤的治疗，以进一步证明其临床适用性。最后，我们将探讨 HoxA5 可能协调稳定脉管系统以及肿瘤上皮和促肿瘤免疫反应的概念，从而代表了靶向整个肿瘤微环境的一种手段。