Investigations into the influence of pretubulysin and archazolid on endothelial processes responsible for tumor cell adhesion and transmigration

研究 pretubulysin 和 archazolid 对负责肿瘤细胞粘附和迁移的内皮过程的影响

• 批准号: 187865029
• 负责人: Professor Dr. Robert Fürst
• 金额: --
• 依托单位: Forschungsgebiet Pharmazeutische Biologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/187865029?language=en
• 关键词: Investigations; into; influence; pretubulysin; archazolid

Metastasis, i.e. the formation of a secondary tumor at a distant place via the hematogenic or lymphogenic way of dissemination, is the main cause for death in cancer patients. Thus, the development and characterization of anti-metastatic agents is a major task in cancer research. This research group has shown that the myxobacterial compounds archazolid and pretubulysin, besides direct effects on tumor cells and the tumor vasculature (endothelial cells), can prevent cancer cell dissemination. This project aims to characterize the action of the two compounds on endothelial cells responsible for the inhibition of cancer cell extravasation, a key step in metastasis, and to analyze the mechanisms involved. We have found that archazolid and pretubulysin induce the adhesion of tumor cells (MDA-MB-231 breast cancer cells) to the endothelium, inhibit their transmigration (diapedesis), and affect the CXCL12/CXCR4 system. Thus, we will focus on the involvement of (i) cell adhesion molecules and (ii) the mentioned chemokine system and will elucidate the underlying signaling pathways. Also leukocytes will be taken into account, since they can facilitate extravasation events. Moreover, further aims are to characterize the anti-angiogenic potential of soraphen A and to test novel pretubulysin and chondramide derivatives for their effects on important endothelial functions (endothelial cell-tumor cell and endothelial cell-leukocyte interaction, angiogenesis).

转移，即通过造血或淋巴途径在远处形成继发性肿瘤，是癌症患者死亡的主要原因。因此，抗转移剂的开发和表征是癌症研究中的主要任务。该研究小组已经表明，粘细菌化合物archazolid和pretubulysin除了直接作用于肿瘤细胞和肿瘤血管系统（内皮细胞）外，还可以防止癌细胞扩散。该项目旨在表征这两种化合物对负责抑制癌细胞外渗（转移的关键步骤）的内皮细胞的作用，并分析所涉及的机制。我们已经发现，archazolid和pretubulysin诱导肿瘤细胞（MDA-MB-231乳腺癌细胞）粘附到内皮，抑制其迁移（渗出），并影响CXCL 12/CXCR 4系统。因此，我们将重点关注（i）细胞粘附分子和（ii）上述趋化因子系统的参与，并阐明潜在的信号通路。还将考虑白细胞，因为它们可以促进外渗事件。此外，进一步的目的是表征soraphen A的抗血管生成潜力，并测试新的pretubulysin和chondramide衍生物对重要内皮功能（内皮细胞-肿瘤细胞和内皮细胞-白细胞相互作用，血管生成）的作用。