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Regulatory effect of nerve growth factor in 9β1 integrin–dependent progression of glioblastoma

Department of Neuroscience, Center for Neurovirology and Cancer Biology, School of Medicine, Temple University, Philadelphia, PA, USA (M.C.B., I.S., G.P.T., L.D.V., C.M.); and School of Pharmacy, the Hebrew University of Jerusalem, Jerusalem, Israel (P.L.)

Address correspondence to Cezary Marcinkiewicz, Department of Neuroscience, Temple University, 1900 N. Twelfth Street, Philadelphia, PA 19122, USA (cmarcink{at}temple.edu).

In the present study we described the role of 9β1 integrin in glioblastoma progression following its interaction with nerve growth factor (NGF). The level of expression of 9β1 on astrocytomas is correlated with increased grade of this brain tumor and is highest on glioblastoma, whereas normal astrocytes do not express this integrin. Two glioblastoma cell lines, LN229 and LN18, that are 9β1 integrin positive and negative, respectively, were used for 9β1 integrin–dependent NGF-induced tumor progression. NGF was a significant promoter of promigratory and pro-proliferative activities of glioblastoma cells through direct interaction with 9β1 integrin and activation of MAPK Erk1/2 pathway. The level of NGF increases approximately threefold in the most malignant glioma tissue when compared with normal brain. This increase is related to secretion of NGF by tumor cells. Specific inhibitors of 9β1 integrin or gene silencing inhibited NGF-induced proliferation of LN229 cell line to the level shown by LN18 cells. VLO5 promoted 9β1-dependent programmed cell death by induction of intrinsic apoptosis pathway in cancer cells. LN229 cells were rescued from proapoptotic effect of VLO5 by the presence of NGF. This disintegrin significantly inhibited tumor growth induced by implantation of LN229 cells to the chorioallantoic membrane (CAM) of quail embryonic model, and this inhibitory effect was significantly abolished by the presence of NGF. 9β1 integrin appears to be an interesting target for blocking the progression of malignant gliomas, especially in light of the stimulatory effect of NGF on the development of these tumors and its ability to transfer proapoptotic signals in cancer cells.

Key Words: apoptosis • disintegrins • glioblastoma • integrins • nerve growth factor

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