Role of L1-FGFR interaction in glioma progression
Date
2011
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
The L1CAM cell adhesion/recognition molecule (L1CAM, CD171) and Fibroblast Growth Factor Receptor (FGFR) are expressed by human high-grade glioma cells. L1CAM is a cell adhesion molecule that has homophilic interactions as well as heterophilic interactions with FGFR and integrins. Our lab previously showed that L1CAM cleavage is associated with an increased rate of migration of glioma cells and this correlates with increased focal adhesion kinase (FAK) activation. FGFR activation via its canonical FGF ligand leads to the transmission of intercellular signals responsible for cell proliferation, migration and survival. It has been observed that FGFR1 is expressed in glioma tissues, but is absent in the normal surrounding brain tissue. Analyzing datasets from a wide range of clinical samples showed that FGFR1 is over expressed in glioma samples regardless of its grade, while there is a gradual increase in the expression level of ADAM10 with the progression of glioma to various grades. In this study I used short hairpin RNA (shRNA) and dominant-negative approaches to inhibit the expression and activation of L1CAM and FGFR1, respectively. An L1-CHD peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1, also were used to elucidate the involvement of L1-
FGFR interactions on glioma cell behavior. Migration studies and cell cycle analyses showed the relevance in the contribution of L1CAM towards FGFR activation. Also. L1CAM interaction with FGFR had no effect on cell proliferation on subconfluent cultures, while blocking L1-FGFR on confluent glioma cell decreased the S phase to 43% compared to the untreated. It was also observed that L1CAM attenuated cells exhibited almost the same amount of reduction in migration as in cells deprived of FGFR signaling. While specifically blocking L1-FGFR interaction there was a decrease of 50% in migration rate in T98G cells compared to the control cells, and there was a decrease in 24% in U-118/L1LE cells compared to the control cells. This study showed that treatment of glioma cells through FGFR inactivation by targeting only its native FGF ligand might be ineffective due to a major contribution of the receptor activation through L1CAM. Both L1CAM and FGFR1 shutdown glioma cells exhibited a complete termination of cell migration in vitro. These results indicate that L1CAM modulates motility and proliferation of human glioma cells via signaling through the FGFR. This could justify the relevance of targeting a cell adhesion molecule as well as a robust receptor in the treatment of malignant gliomas by disrupting cell invasion and growth.