Dominant-Negative Inhibition of the Axl Receptor Tyrosine Kinase Suppresses Brain Tumor Cell Growth and Invasion and Prolongs Survival

Malignant gliomas remain incurable brain tumors because of their diffuse-invasive growth. So far, the genetic and molecular events underlying gliomagenesis are poorly understood. In this study, we have identified the receptor tyrosine kinase Axl as a mediator of glioma growth and invasion. We demons...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 15; pp. 5799 - 5804
Main Authors:	Vajkoczy, Peter, Knyazev, Pjotr, Kunkel, Andrea, Capelle, Hans-Holger, Behrndt, Sandra, von Tengg-Kobligk, Hendrik, Kiessling, Fabian, Eichelsbacher, Uta, Essig, Marco, Read, Tracy-Ann, Erber, Ralf, Ullrich, Axel
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 11-04-2006
Subjects:	Animals Biological Sciences Brain cancer Brain Neoplasms - drug therapy Brain Neoplasms - pathology Cell aggregates Cell Division Cell growth Cell Line, Tumor Cell lines Cell Movement Cells Cellular biology Enzyme Inhibitors - therapeutic use Enzymes Glioma Glioma - drug therapy Glioma - pathology Humans Medulloblastoma Mice Neoplasm Invasiveness Neoplasms, Experimental Neuroblastoma Neurons Oligonucleotide Array Sequence Analysis Oncogene Proteins - antagonists & inhibitors Oncogene Proteins - genetics Proto-Oncogene Proteins Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - genetics Receptors RNA, Messenger - genetics Signal transduction Survival Analysis Transplantation, Heterologous Tumor cell line Tumors
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Summary:	Malignant gliomas remain incurable brain tumors because of their diffuse-invasive growth. So far, the genetic and molecular events underlying gliomagenesis are poorly understood. In this study, we have identified the receptor tyrosine kinase Axl as a mediator of glioma growth and invasion. We demonstrate that Axl and its ligand Gas6 are overexpressed in human glioma cell lines and that Axl is activated under baseline conditions. Furthermore, Axl is expressed at high levels in human malignant glioma. Inhibition of Axl signaling by overexpression of a dominant-negative receptor mutant (AXL-DN) suppressed experimental gliomagenesis (growth inhibition >85%, P < 0.05) and resulted in long-term survival of mice after intracerebral glioma cell implantation when compared with Axl wild-type (AXL-WT) transfected tumor cells (survival times: AXL-WT, 10 days; AXL-DN, >72 days). A detailed analysis of the distinct hallmarks of glioma pathology, such as cell proliferation, migration, and invasion and tumor angiogenesis, revealed that inhibition of Axl signaling interfered with cell proliferation (inhibition 30% versus AXL-WT), glioma cell migration (inhibition 90% versus mock and AXL-WT, P < 0.05), and invasion (inhibition 62% and 79% versus mock and AXL-WT, respectively; P < 0.05). This study describes the identification, functional manipulation, in vitro and in vivo validation, and preclinical therapeutic inhibition of a target receptor tyrosine kinase mediating glioma growth and invasion. Our findings implicate Axl in gliomagenesis and validate it as a promising target for the development of approaches toward a therapy of these highly aggressive but, as yet, therapy-refrac-tory, tumors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Communicated by Erkki Ruoslahti, The Burnham Institute, La Jolla, CA, January 9, 2006 Author contributions: P.V. and A.U. designed research; P.V., A.K., H.-H.C., S.B., H.v.T.-K., F.K., U.E., P.K., M.E., T.-A.R., and R.E. performed research; U.E., P.K., and A.U. contributed new reagents/analytic tools; P.V., A.K., H.-H.C., and T.-A.R. analyzed data; and P.V., R.E., and A.U. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0510923103