Involvement of VEGF receptors or inflammatory cytokines in tumor angiogenesis as a cancer therapy

血管生成与肿瘤、糖尿病视网膜病变、类风湿性关节炎等生理病理密切相关。了解这些血管生成疾病的分子机制，将为治疗这些疾病提供新的思路。A）血管生成是一个复杂的过程，与环境刺激和宿主基质细胞相互作用。观察到单核细胞/巨噬细胞的浸润与肿瘤血管生成状态密切相关。结果发现：（1）巨噬细胞浸润与恶性程度及微血管密度密切相关，（2）浸润的巨噬细胞表达胸苷磷酸化酶（TP）和血红素氧合酶-1（HO-1），可作为肿瘤浸润巨噬细胞的生物学标志; 3）各种细胞因子中干扰素-γ（IFN-γ）最有效地通过TP基因启动子区的GAS元件表达TP。B）在糖尿病视网膜病变患者中，我们已经发现视网膜血管周围VEGF的表达增加和晚期糖基化终产物（AGES）的积累。我们观察到AGES是糖尿病眼VEGF表达的主要刺激物，血糖控制剂可通过抑制视网膜内皮细胞的信号转导来降低新生血管的发生率。C）风湿性关节炎（RA）是一种关节炎性疾病，其特征是滑膜组织中广泛的新生血管形成，导致血管翳形成，并伴有大量新形成的血管和骨吸收破骨细胞。我们发现，血管生成抑制剂可以防止实验性关节炎中骨和关节的破坏。血管生成抑制剂可能成为治疗RA的新策略之一。

Angiogenesis is closely associated with physiolocical condition such as tumor, diabetic retinopathy and rheumatoid arthritis. To understand the molecular mechanism invoived in these angiogenesis disease leads to a new therapy.A) Angiogenesis is a complex process in cross-talks with environmental stimuli and stroma cells in host. It was observed that infiltration of monocytes/macrophages are closely associated with tumor angiogenesis status. We found that 1) infiltration of macrophages was closely associated with malignancy and microvessel density in human melanoma ; 2) infiltrated macrophage express thymidine phosphorylase (TP) and heme oxygenase-1 (HO-1), which could be the biological markers of tumor infiltrating macrophage ; 3) of various cytokines interferon-γ(IFN-γ) most effectively the expression of TP through GAS element in the promoter region of TP gene.B) In patients with diabetic retinopathy, we have found increased expression of VEGF around retinal vessels and accumulation of advanced glycation end products (AGES). We observed that AGES were the major stimulus for expression of VEGF and that glycemic control agents could reduce the incidence of neovascularization through inhibition of signaling transduction of retinal endothelial cells in diabetic eyes.C) Rheumatoid arthritis (RA) is an arthritic disease characterized by extensive neovascularization in synovial tissue leading to pannus formation with large number of newly-formed blood vessels and bone resorbing osteoclasts. We found that angiogenesis inhibitor prevented bone and joint destruction in experimental arthritis. Angiogenesis inhibitor might be one of the new strategy for treatment of RA.