Role of Stat3 in modulating tumor microenvironment and angiogenesis

描述（由申请人提供）：损害肿瘤血管系统（抗血管生成）在癌症治疗中很重要。 我们和其他人已经证明，Stat 3，这是组成性激活的肿瘤细胞和肿瘤细胞的生存所需的，是必不可少的许多血管生成和侵袭性因子的生产，这表明Stat 3是一个有前途的目标抗血管生成治疗。 然而，肿瘤间质，其中包括不同的造血细胞，也产生了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靶向肿瘤基质造血细胞。 我们最近发现，Stat 3在肿瘤基质造血细胞中持续活化，包括巨噬细胞、中性粒细胞和Gr 1+骨髓细胞等。 此外，初步数据表明，肿瘤基质Gr 1+骨髓细胞以Stat 3依赖性方式产生血管生成因子，这表明抑制Stat 3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Stat 3可消除肿瘤微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Stat 3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Stat 3的因子，以促进肿瘤血管生成，从而增强肿瘤的存活率及其对治疗的抵抗力。 因此，抑制Stat 3将靶向肿瘤及其微环境，导致肿瘤血管系统的有效损伤。 我们已经产生了广泛的生物系统和试剂来测试这一假设：在肿瘤发展的各个阶段诱导造血细胞中Stat 3消融的小鼠模型; Stat 3特异性抑制剂;与纳米颗粒偶联的Stat 3 RNAi的长寿命形式，以全身靶向肿瘤细胞;以及当雄激素激增时允许前列腺中Stat 3消融的自体小鼠前列腺肿瘤模型，并且其中造血系统也可以用Stat 3缺失的骨髓补充物重建。 通过这些和其他生物系统和试剂，拟议的研究将确定Stat 3是否是调节肿瘤微环境和抑制血管生成的有效靶点。

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.