The authors set out to identify genes that are differentially expressed in highly invasive versus non-invasive glioma cells by injecting green fluorescent protein (GFP)-expressing human glioma cells into the brain of immunocompromised mice. GFP-positive cells that migrated away from the resulting tumour cell mass were collected, expanded in culture and re-injected into mice to further select for highly invasive cells. Cells from the main tumor mass were also cultured, for comparative purposes. Microarray analysis of the highly invasive and non-invasive cell lines obtained using this protocol revealed significant differences in the expression of approximately 30 genes. The gene that encodes p75NTR was one of the most overexpressed in the invasive cell populations and was chosen for further investigation. In neurons, p75NTR is known to have roles in diverse functions, including axonal outgrowth, neuronal survival and cell death (depending on the cellular context). It has also been shown to promote tumorigenesis in other types of cancer, but has never before been implicated in brain tumours.
The culture medium of the established cell lines tested positive for neurotrophins, suggesting that p75NTR could be activated by autocrine or paracrine signals in vivo. To assess whether the invasiveness of glioma cells depends on the expression and function of p75NTR, the authors compared the migration and invasion of highly invasive and non-invasive cell lines in the presence of nerve growth factor (NGF), a p75NTR ligand, using standard in vitro assays. NGF increased the invasion potential of only the p75NTR-overexpressing, highly invasive cells, suggesting that p75NTR mediates invasiveness, and that it does so in a neurotrophin-dependent manner.
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