CHEMOKINE TUMOR INTERACTIONS AND IDENTIFICATION OF CHEMOKINE ANTAGONISTS

趋化因子肿瘤相互作用和趋化因子拮抗剂的鉴定

• 批准号: 2463815
• 负责人: J M WANG
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/2463815
• 关键词: HIV envelope protein gp120; cell motility; chemokine; chemotaxis; dendritic cells; epithelioma; human tissue; inhibitor /antagonist; metastasis; peptide analog; tissue /cell culture; transfection

Our studies of the interactions of chemokines with epithelial tumor cells show that some tumor cells produce chemokines, while some express receptors for chemokines and are chemoattracted by them. Moreover, some tumor cell types are stimulated to proliferate by chemokines. Furthermore some organs produce chemotactic factors that attract metastatic T cell tumor variants. Purification studies have implicated several chemokines namely RANTES and JE/MCP1 as possible contributors to the metastatic spread of these tumor cells. In addition, a metastatic tumor variant produces factor(s) promoting their own mobility. We plan to further identify these tumor cell attractants and motility promoters and to establish whether they are playing a role in the metastatic process. Several of the chemokines (e.g., MCP-1 and IL-8) have been reported to enhance tumor immune responses. Since dendritic cells (DC), the most effective antigen presenting cell (APC), contribute to tumor immunity, we just completed a study of the effects of chemokines on DC. A number of the C-C chemokines (e.g., MCP-1, MCP-2, MCP-3, MIP1alpha and RANTES) are chemotactic for human DC, suggesting that they may contribute to the mobilization of these potent APC. We plan to exploit these observations by studying the immune response to murine tumors transfected with the most potent chemoattractants of DC. Studies also have been initiated to develop mutated variants and peptide analogues of chemokines and their receptors. These experiments have only generated weak antagonists to date. The possibility that some anti-inflammatory plant extracts may contain natural inhibitors of proinflammatory chemoattractants is also being evaluated. Some components in extracts of Aloe contain inhibitors of chemokines. Most recently we have initiated studies to establish whether HIV-1 envelope proteins interfere with chemokines. In fact, gp120 can competitively inhibit the binding of MIP1alpha and RANTES to human monocytes. Further purification and characterization studies are needed to identify the responsible molecular entities.

我们对趋化因子与上皮肿瘤相互作用的研究 细胞显示，一些肿瘤细胞产生趋化因子，而另一些则表达 趋化因子受体并被趋化因子吸引。 而且， 一些肿瘤细胞类型受趋化因子刺激增殖。 此外，一些器官会产生趋化因子，吸引 转移性 T 细胞肿瘤变体。 纯化研究表明 几种趋化因子，即 RANTES 和 JE/MCP1 可能是贡献者 这些肿瘤细胞的转移扩散。 此外，还有一个 转移性肿瘤变异产生促进自身的因子 流动性。 我们计划进一步鉴定这些肿瘤细胞引诱剂并 动力促进剂并确定它们是否在 转移过程。 一些趋化因子（例如 MCP-1 和 IL-8）已被报道可增强肿瘤免疫反应。 自从 树突状细胞（DC），最有效的抗原呈递细胞（APC）， 有助于肿瘤免疫，我们刚刚完成了一项效果研究 DC 上的趋化因子。 许多 C-C 趋化因子（例如 MCP-1、 MCP-2、MCP-3、MIP1alpha 和 RANTES) 对人类 DC 具有趋化性， 表明它们可能有助于动员这些强大的力量 装甲运兵车。 我们计划通过研究免疫来利用这些观察结果 对转染最有效的小鼠肿瘤的反应 DC的化学引诱剂。 还已开始研究开发 趋化因子的突变变体和肽类似物及其 受体。 这些实验只产生了微弱的拮抗剂 日期。 某些抗炎植物提取物可能 还含有促炎化学引诱剂的天然抑制剂 正在评估中。 芦荟提取物中的一些成分含有 趋化因子抑制剂。 最近我们发起了研究 确定 HIV-1 包膜蛋白是否干扰趋化因子。 事实上，gp120 可以竞争性抑制 MIP1α 和 RANTES 至人类单核细胞。 进一步纯化和表征 需要研究来确定负责的分子实体。