Regulatory effect of nerve growth factor in 91 integrin-dependent progression of glioblastoma

¹ Department of Neuroscience, Center for Neurovirology and Cancer Biology, Temple University, School of Medicine, Philadelphia, PA 19122, USA
² The Hebrew University of Jerusalem, School of Pharmacy, Jerusalem 91120, Israel

^* To whom correspondence should be addressed. E-mail: cmarcink{at}temple.edu.

	Abstract

In the presented study we described the role of 91 integrin in glioblastoma progression following its interaction with NGF. The level of expression of 91 on astrocytomas is correlated with increased grade of this brain tumor, and is the highest on glioblastoma, whereas normal astrocytes do not express this integrin. Two glioblastoma cell lines, LN229 and LN18 that are 91 integrin positive or negative, respectively, were used for 91 integrin-dependent NGF-induced tumor progression. NGF was a significant promoter of pro-migratory and proproliferative activities of glioblastoma cells through direct interaction with 91 integrin and activation of MAPK Erk1/2 pathway. The level of NGF increases approximately 3 fold in the most malignant glioma tissue if compared with normal brain. This increase is related to secretion of NGF by tumoral cells. Specific inhibitors of 91 integrin or gene silencing inhibited NGF- induced proliferation of LN229 cell line to the level showed by LN18 cells. VLO5 promoted 91-dependent programmed cell death by induction of intrinsic apoptosis pathway in cancer cells. LN229 cells were rescued from pro-apoptotic effect of VLO5 by the presence of NGF. This disintegrin significantly inhibited tumor growth induced by implantation of LN229 cells to the CAM of quail embryonic model and this inhibitory effect was significantly abolished by the presence of NGF. 91 integrin appears to be an interesting target for blocking of progression malignant gliomas, especially in light of the stimulatory effect of NGF on development of this tumor and ability to transfer pro-apoptotic signal in cancer cells.

Key Words: apoptosis, disintegrins, glioblastoma, integrins, NGF

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