L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor.
The L1CAM cell adhesion/recognition molecule (L1, CD171) and fibroblast growth factor receptor (FGFR) both are expressed by human high-grade glioma cells, but their potential actions in controlling cell behavior have not been linked. L1 actions in cancer cells have been attributed mainly to integrin receptors, and we demonstrated previously that ... L1-stimulated glioma cell migration correlates with integrin expression, increased focal adhesion kinase activation and focal complex turnover. Our analyses of datasets revealed FGFR is overexpressed in glioma regardless of grade, while ADAM10 metalloprotease expression increases with glioma grade. Here, we used dominant-negative and short hairpin RNA approaches to inhibit the activation of FGFR1 and expression of L1, respectively. An L1 peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1 activity, also were used to elucidate the involvement of L1-FGFR interactions on glioma cell behavior. Time-lapse cell motility studies and flow cytometry cell cycle analyses showed that L1 operates to increase glioma cell motility and proliferation through FGFR activation. Shutdown of both L1 expression and FGFR activity in glioma cells resulted in a complete termination of cell migration in vitro. These studies show for the first time that soluble L1 ectodomain (L1LE) acts on glioma cells through FGFRs, and that FGFRs are used by glioma cells for increasing motility as well as proliferation in response to activation by L1LE ligand. Thus, effective treatment of high-grade glioma may require simultaneous targeting of L1, FGFRs, and integrin receptors, which would reduce glioma cell motility as well as proliferation.
Mesh Terms:
ADAM Proteins, ADAM10 Protein, Amyloid Precursor Protein Secretases, Apoptosis, Blotting, Western, Brain Neoplasms, Cell Cycle, Cell Movement, Cell Proliferation, Flow Cytometry, Glioma, Humans, Membrane Proteins, Neoplasm Grading, Neural Cell Adhesion Molecule L1, Peptide Fragments, Pyrimidines, Receptor, Fibroblast Growth Factor, Type 1, Tumor Cells, Cultured
ADAM Proteins, ADAM10 Protein, Amyloid Precursor Protein Secretases, Apoptosis, Blotting, Western, Brain Neoplasms, Cell Cycle, Cell Movement, Cell Proliferation, Flow Cytometry, Glioma, Humans, Membrane Proteins, Neoplasm Grading, Neural Cell Adhesion Molecule L1, Peptide Fragments, Pyrimidines, Receptor, Fibroblast Growth Factor, Type 1, Tumor Cells, Cultured
Clin. Exp. Metastasis
Date: Apr. 01, 2013
PubMed ID: 23212305
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