Interaction between the microglia and blood vessels in malignant brain tumors - significance for brain tumor angiogenesis, vascular modulation, and brain tumor growth
Final Report Abstract
In summary, we have studied the role of EphrinB2/EphB4 signaling for vascular morphogenesis and tumor cell behaviour. We could show that activation of EphrinB2 lead to intussuceptive vessel growth and stimulates also lymphangiogenesis. On the tumor cell side we could show that EphB4 mediates brain tumor cell migration and invasion, playing a central role in determining their specific invasive pattern in vivo. This is of high interest since it might help to understand the growth patterns of glioma within their ontogenetic compartments. This proinvasive effect of EphB4 is partly dependent on its tyrosine kinase and partly independent of the tyrosine kinase. We could also show that EphrinB2/EphB4 signalling might also affect the recruitment of resident brain immune cells to the vascular niche which made us analyse the role of the microglia for tumor bain angiogenesis in more detail during the 2nd funding period. We found an increased number of microglia cells in the tumor area, expressing Iba-1, CD11b and CD68. These Iba-1+ cells had a preference for the perivascular niche and were tightly associated with the endothelial cells of the tumor blood vessels. Furthermore, we could show that these cells express high levels of pro-angiogenic cytokines. Their role for brain tumor angiogenesis could be confirmed by depletion of microglia cells by ganciclovir in the CD11b- HSVTK transgenic mouse model. Here, we had to change our proposed experimental strategy since the microglia depletion in the tumor model was attenuated by a rapid repopulation by macrophages/monocytes, most likely due to the disturbed blood-brain-barrier in the tumor. Nevertheless, successful depletion of microglia via the local delivery of GCV into the brain resulted in a reduced tumor vessel density and a smaller tumor size. In a set of in vitro assays we finally developed a model in that tumor cells attract microglial cells, which secrete proangiogenic cytokines activating endothelial cells and promoting formation of tumor blood vessels. Thus, microglial cells and their cytokines might represent future targets for interfering with brain tumor growth and progression.
