IL12, IP10, AND IL15 ARE POTENT REGULATORS OF ANGIOGENE

IL12、IP10 和 IL15 是血管生成的有效调节剂

• 批准号: 6161314
• 负责人: G TOSATO
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161314
• 关键词: B lymphocyte; CD antigens; Epstein Barr virus; SCID mouse; T lymphocyte; angiogenesis; angiogenesis inhibitors; antineoplastics; athymic mouse; autocrine; bioassay; biological models; cell growth regulation; cell line; chemokine; cytotoxic T lymphocyte; deficient growth media; growth factor; growth inhibitors; immunomodulators; immunoregulation; interferon gamma; interleukin 1; interleukin 12; interleukin 15; interleukin 6; lactates; leukocyte activation /transformation; lymphocyte proliferation; method development; mixed tissue /cell culture; neoplasm /cancer remission /regression; thioredoxin; virus infection mechanism

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.

在对实验性胸腺小鼠模型的其他研究中，肿瘤消退与广泛的组织坏死相关，并伴有内皮细胞损伤和血管内血栓形成。这表明组织缺血可能是肿瘤消退的核心，血管生成不平衡可能是肿瘤消退的原因。对消退肿瘤组织中细胞因子表达的分析显示，存在多种炎症因子，包括tnf - α和IL-6，此外还有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，通过已知的介质无法实现完全的肿瘤消退。尤其值得注意的是，在肿瘤坏死持续实现的同时，肿瘤组织也出现了再生。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的介质。利用ebv永生化的VDS-O细胞系，我们纯化了一种内皮细胞抑制剂，并鉴定了它的钙网蛋白和n端钙网蛋白片段。纯化后的重组钙网蛋白和钙网蛋白n端结构域（氨基酸1-180）对内皮细胞增殖有抑制作用，但对其他细胞系细胞无抑制作用，并抑制血管生成。接种于胸腺小鼠后，血管抑素显著抑制人伯基特淋巴瘤、结肠癌、肺腺癌等恶性细胞系的生长。与其他血管生成抑制剂相比，钙网蛋白和钙网蛋白的n端结构域是可溶的、稳定的分子，易于生产和递送。钙网蛋白和钙网蛋白n结构域作为一种特异性靶向内皮细胞的血管生成抑制剂，具有独特的癌症治疗潜力。目前和未来的研究重点是了解这些分子的作用机制，并在实验小鼠模型中开发它们作为抗癌药物的潜力。