Neue Aspekte der Adhäsion und Migration von Meningeomzellen und ihre therapeutische Nutzbarkeit

Abstract

Meningiomas are among the most frequent intracerebral or intraspinal tumors in humans. While the vast majority (80%) corresponds to benignant tumors of WHO grade I, 15-20% belong to atypical tumors of WHO grade II and 2-3% to anaplastic forms of grade III, both with worse prognosis and exhibiting a more aggressive tumor growth with higher recurrence rates. A focus of the presented PhD thesis was to search for new molecules and mechanisms associated with adhesion and migration, which may be differentially expressed between meningiomas of WHO grades II and III on one side, versus grade I on the other. A promising candidate miRNA, i.e. miR-145, which seemed to fulfill these criteria, was analyzed in more detail. In a human tumor series it could be shown that miR-145 was not only generally reduced in meningiomas, but -most importantly- was reduced in grades II and III as compared to grade I. Using an orthotopic and thereby most representative mouse xenograft model, it was further shown that the reconstitution of miR-145 in the xenografted meningioma cells led to a significant suppression of intracranial tumor growth, as visualized by MRI with p ≤ 0.01 (0.05) on days 7 (14) after tumor inoculation. These experiments supported in vivo the character of miR-145 as a tumor suppressor. Xenografts with reconstituted miR-145 also exhibited a lower degree of tongue-like brain invasion, as visualized by histology. An important aspect was the identification of downstream-targets of miR-145, which may play a role in cell adhesion, in the interaction between meningioma cells and extracellular matrix or in motility. In a direct comparison between syngeneic meningioma cells with high or low miR-145 level only a few differentially expressed genes of the aforementioned type were found. The strongest fold-change showed COL5A1 (collagen type 5). This gene represented a potential candidate, the enhanced expression of which in miR-145 deficient meningioma cells may trigger enhanced motility. Its mRNA levels were inverse to miR-145 in human meningioma samples. COL5A1 is essential for the nucleation of collagen fibrillogenesis and thus a factor with an impact on cell motility in matrices containing collagen. Experiments trying to directly inhibit motility by the pentapeptide cilengitide with or without total brain irradiation did not result in a significantly prolonged survival in the orthotopic mouse model by the drug, but showed solely an effect of irradiation (p ≤ 0.001 in log-rank).