Role of Stat3 in modulating tumor microenvironnment and angiogenesis

Stat3在调节肿瘤微环境和血管生成中的作用

• 批准号: 7214257
• 负责人: Hua E Yu
• 金额: $ 30万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214257
• 关键词: angiogenesis; neoplasm /cancer; neoplasm /cancer blood supply; role

DESCRIPTION (provided by applicant): Impairing tumor vasculature (anti-angiogenesis) is important in cancer therapy. We and others have demonstrated that Stat3, which is constitutively-activated in tumor cells and required for tumor cell survival, is indispensable for production of numerous angiogenic and invasive factors, suggesting that Stat3 is a promising target for anti-angiogenesis therapy. However, the tumor stroma, which includes diverse hematopoietic cells, also produces a wide range of angiogenic and invasive factors. Therefore, effective anti-angiogenic therapy must also target tumor stromal hematopoietic cells. We recently showed that Stat3 is persistently-activated in tumor stromal hematopoietic cells, including macrophages, neutrophils and Gr1+ myeloid cells, among others. Furthermore, preliminary data indicated that tumor stromal Gr1+ myeloid cells produce angiogenic factors in a Stat3-dependent manner, suggesting that inhibiting Stat3 may block a large array of angiogenic and invasive factors produced by various tumor hematopoietic cells. Additionally, blocking Stat3 either in tumor cells or endothelial cells abrogates tumor milieu-induced angiogenesis. Prompted by these preliminary data, we hypothesize that tumor and tumor stromal cells resonate through activated Stat3, producing angiogenic and invasive factors, including those that activate Stat3 in tumor stromal cells, to promote tumor angiogenesis and thereby strengthen the survival of a tumor and its resistance to therapy. As a result, inhibiting Stat3 will target the tumor and its microenvironment, leading to efficient impairment of tumor vasculature. We have generated extensive biological systems and reagents to test this hypothesis: mouse models to induce Stat3 ablation in hematopoietic cells at various stages of tumor development; a Stat3-specific inhibitor; a long-lived form of Stat3 RNAi coupled with nanoparticles to systemically target tumor cells; and an autochthonous mouse prostate tumor model that allows Stat3 ablation in prostate when androgen surges, and in which the hematopoietic system can also be reconstituted with Stat3-null bone marrow supplementation. With these and other biological systems and reagents, the proposed studies will define whether Stat3 is an effective target for modulating tumor microenvironment and inhibiting angiogenesis.

描述(申请人提供)：肿瘤血管受损(抗血管生成)在癌症治疗中很重要。我们和其他人已经证明，STAT3在肿瘤细胞中是结构性激活的，是肿瘤细胞生存所必需的，它是产生大量血管生成和侵袭因子所必需的，这表明STAT3是一个有希望的抗血管生成治疗的靶点。然而，包括不同造血细胞在内的肿瘤间质也会产生广泛的血管生成和侵袭因子。因此，有效的抗血管生成治疗还必须针对肿瘤基质造血细胞。我们最近发现，STAT3在肿瘤间质造血细胞中持续激活，包括巨噬细胞、中性粒细胞和Gr1+髓系细胞等。此外，初步数据表明，肿瘤基质Gr1+髓系细胞以STAT3依赖的方式产生血管生成因子，这表明抑制STAT3可能会阻断各种肿瘤造血细胞产生的大量血管生成和侵袭因子。此外，阻断肿瘤细胞或内皮细胞中的STAT3可以消除肿瘤环境诱导的血管生成。根据这些初步数据，我们假设肿瘤和肿瘤基质细胞通过激活的STAT3产生共振，产生血管生成和侵袭因子，包括那些激活肿瘤基质细胞中的STAT3的因子，以促进肿瘤血管生成，从而增强肿瘤的存活率和对治疗的抵抗力。因此，抑制STAT3将靶向肿瘤及其微环境，导致肿瘤血管的有效损伤。我们已经建立了广泛的生物系统和试剂来验证这一假设：在肿瘤发展的不同阶段诱导STAT3在造血细胞中被去除的小鼠模型；STAT3特异性抑制剂；长寿命形式的STAT3 RNAi与纳米颗粒结合以系统靶向肿瘤细胞；以及当雄激素激增时允许在前列腺中去除STAT3的固有小鼠前列腺癌模型，在该模型中，造血系统也可以通过STAT3缺失的骨髓补充来重建。有了这些和其他生物系统和试剂，拟议的研究将确定STAT3是否是调节肿瘤微环境和抑制血管生成的有效靶点。