Glioma stem cell invasion through regulation of the interconnected ERK, integrin α6 and N-cadherin signaling pathway

The recent characterization of glioma stem cells (GSCs) prompts a necessary examination of the signaling pathways that facilitate invasiveness. Molecular crosstalk between expression mechanisms has been identified in a range of cancers, including glioblastoma multiforme. However, hardly any literature exists that addresses whether cancer stem cells utilize these same interconnected pathways. Protein factors commonly implicated in malignant tumors include extracellular signal-regulated kinase (ERK), N-cadherin, and integrin alpha 6. Although studies have reported the molecular crosstalk involved among these proteins, the present study illustrates the importance of the ERK transduction pathway in N-cadherin and integrin alpha 6 regulated invasion in GSCs. Conversely, the data also suggests that GSCs rely on N-cadherin and integrin alpha 6 interaction to regulate ERK signaling. Moreover, confocal visualization revealed the co-localization of N-cadherin and integrin alpha 6 in GSCs and clinical surgical biopsies extracted from glioma patients. Interestingly. ERK knockdown reduced this co-localization. Upon co-culturing GSCs with human umbilical cord blood stem cells (hUCBSCs), we observed a subsequent decrease in pERK, N-cadherin and integrin alpha 6 expression. In addition, co-culturing hUCBSCs with GSCs decreased co-localization of N-cadherin and integrin alpha 6 in GSCs. Our results demonstrate the dynamic interplay among ERK, N-cadherin and integrin alpha 6 in GSC invasion and also reveal the therapeutic potential of hUCBSCs in treating the molecular crosstalk observed in GSC-regulated invasion. (C) 2012 Elsevier Inc. All rights reserved.