IL12, IP10, AND IL15 ARE POTENT REGULATORS OF ANGIOGENE

在对实验性无胸腺小鼠模型的其他研究过程中，肿瘤消退与内皮细胞损伤和血管内血栓形成相关的广泛组织坏死相关。 这表明组织缺血可能是肿瘤消退的中心，并表明不平衡的血管生成可能是肿瘤消退的原因。 对消退的肿瘤组织中细胞因子表达的分析显示存在多种炎性细胞因子，包括TNF-α和IL-6，以及CXC趋化因子IP-10和Mig。 使用细胞因子、趋化因子和中和抗体的其他研究表明，通过已知的介质不能实现完全的肿瘤消退。特别是，在持续实现肿瘤坏死的同时，还观察到肿瘤组织再生长。因此，我们寻找可能抑制内皮细胞增殖的介质，而不是破坏现有肿瘤血管系统的药物。使用EB病毒永生化的VDS-O细胞系，我们已经纯化了内皮细胞抑制剂，并确定了它的钙网蛋白和N-末端钙网蛋白片段。纯化的重组钙网蛋白和钙网蛋白N端结构域（氨基酸1-180）抑制内皮细胞的增殖，但不抑制其他谱系的细胞，并抑制体内血管生成。 vasostatin对人伯基特淋巴瘤、结肠癌、肺腺癌等多种恶性肿瘤细胞株的生长有明显的抑制作用。 与其他血管生成抑制剂相比，钙网蛋白和钙网蛋白的N-末端结构域是易于产生和递送的可溶性和稳定的分子。钙网蛋白和钙网蛋白N结构域作为特异性靶向内皮细胞的血管生成抑制剂，具有独特的肿瘤治疗潜力。 正在进行的和未来的研究集中在了解这些分子的作用机制，并在实验小鼠模型中开发其作为抗癌剂的潜力。

In the course of other studies on an experimental athymic mouse model, tumor regression was associated with extensive tissue necrosis associated with endothelial cell damage and intravascular thrombosis. This suggested that tissue ischemia might be central to tumor regression, and suggested that unbalanced angiogenesis might be responsible for tumor regression. Analysis of cytokine expression in the regressing tumor tissues showed the presence of a variety of inflammatory cytokines , including TNF-alpha and IL-6, and , in addition, the CXC chemokines IP-10 and Mig. Additional studies using cytokines, chemokines and neutralizing antibodies have demonstrated that complete tumor regressions could not be achieved through known mediators. In particlular, while tumor necrosis was consistently achieved, tumor tissue regrowth was also noted. We therefore looked for mediators that might inhibit endothelial cell proliferation rather than agents that would damage exsisting tumor vasculature. Using the EBV-immortalized VDS-O cell line, we have purified an endothelial cell inhibitor and have identified it calreticulin and an N-terminal calreticulin fragment. The purified recombinant calreticulin and N-terminal domain of calreticulin (amino acids 1-180) inhibited the proliferation of endothelial cells, but not cells of other lineages, and suppressed angiogenesis in vivo. When inoculated into athymic mice, vasostatin significantly inhibited the growth of human Burkitt lymphoma, colon carcinoma, lung adenocarcinoma and other malignant cell lines. Compared to other inhibitors of angiogenesis, calreticlulin and the N-terminal domain of calreticulin are soluble and stable molecules that are easy to produce and deliver. As angiogenesis inhibitors that specifically target endothelial cells, calreticulin and calreticulin N-domain have a unique potential as cancer therapeutics. Ongoing and future studies are focused on understanding the mechanism of action of these molecules and exploiting their potential as anticancer agents in experimental murine models.