Artikel
Dominant-negative inhibition of the receptor tyrosine kinase AXL suppresses glioma cell migration and invasion, and prolongs survival
Dominant-negative Blockade der Rezeptor-Tyrosinkinae AXL unterdrückt Gliomzell-Migration und -Invasion und verlängert das Überleben
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Autoren
Veröffentlicht: | 23. April 2004 |
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Gliederung
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Objective
Receptor tyrosine kinases (RTKs) play an important role in growth and progression of brain tumors. Our previous work has shown that the RTK AXL, whose biological function has remained obscure so far, is overexpressed by glioma cell lines. The aim of the present study was to analyse the role of AXL in glioma biology.
Methods
Two glioma cell lines, one expressing high levels of AXL (i.e. SF126) and the other lacking intrinsic AXL (i.e. SF767) were transfected to overexpress either the human wild-type form (AXL-WT) or a truncated, dominant-negative mutant form (AXL-DN). Glioma cell morphology and cell behavior with respect to proliferation, aggregability, migration, and invasion were assessed in vitro. To study the relevance of AXL for tumor growth the glioma cell lines were implanted subcutaneously and into the brains of nude mice. Finally, glioma cells were implanted into the dorsal skinfold chamber model to assess tumor cell behavior, tumor angiogenesis, and tumor perfusion in vivo by intravital multi-fluorescence microscopy.
Results
SF126-AXL-DN cells were characterized by reduced cell-to-cell contacts, a moderately reduced proliferative activity, and most importantly by a severe impairment of tumor cell migration and tumor cell invasion. In vivo, subcutaneous SF126-AXL-DN tumor growth was reduced by 97% und tumor cell invasion into the adjacent tissue was suppressed. Finally, survival following intracerebral implantation of SF126-AXL-DN cells was significantly prolonged compared to SF126-AXL-WT cells. In contrast, inhibition of AXL signaling in SF767 cells had no significant effects.
Conclusions
Our study provides evidence that AXL modulates migration and invasion of glioma cells and that inhibition of AXL signalling suppresses tumor expansion by blocking tumor cell invasion. AXL may represent a novel target for the treatment of malignant glioma.