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-refractory,
tumors.