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

转移，即通过血源性或淋巴源性扩散方式在远处形成继发性肿瘤，是癌症患者死亡的主要原因。因此，抗转移药物的开发和表征是肿瘤研究中的一个主要任务。该研究小组已经证明，粘细菌化合物古唑醇和管溶素前，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。本项目旨在表征这两种化合物对内皮细胞的作用，并分析其机制。内皮细胞负责抑制癌细胞外渗，这是转移的关键步骤。我们发现，古拉唑醇和管溶素前体能诱导肿瘤细胞(MDA-MB-231乳腺癌细胞)与内皮细胞黏附，抑制其迁移(插管)，并影响CXCL12/CXCR4系统。因此，我们将集中于(I)细胞黏附分子和(Ii)上述趋化因子系统的参与，并将阐明潜在的信号通路。白细胞也将被考虑在内，因为它们可以促进外渗事件。此外，进一步的目的是表征索拉芬A的抗血管生成潜力，并测试新的管溶素前和软骨酰胺衍生物对重要的内皮功能(内皮细胞-肿瘤细胞和内皮细胞-白细胞相互作用，血管生成)的影响。

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).