ADAM-9 is a novel mediator of tenascin-C-stimulated invasiveness of brain tumor-initiating cells.

Abstract

BACKGROUND:

Tenascin-C (TNC), an extracellular matrix protein overexpressed in malignant gliomas, stimulates invasion of conventional glioma cell lines (U251, U87). However, there is a dearth of such information on glioma stemlike cells. Here, we have addressed whether and how TNC may regulate the invasiveness of brain tumor-initiating cells (BTICs) that give rise to glioma progenies.

METHODS:

Transwell inserts coated with extracellular matrix proteins were used to determine the role of TNC in BTIC invasion. Microarray analysis, lentiviral constructs, RNA interference-mediated knockdown, and activity assay ascertained the role of proteases in TNC-stimulated BTIC invasion in culture. Involvement of proteases was validated using orthotopic brain xenografts in mice.

RESULTS:

TNC stimulated BTIC invasiveness in a metalloproteinase-dependent manner. A global gene expression screen identified the metalloproteinase ADAM-9 as a potential regulator of TNC-stimulated BTIC invasiveness, and this was corroborated by an increase of ADAM-9 protein in 4 glioma patient-derived BTIC lines. Notably, RNA interference to ADAM-9, as well as inhibition of mitogen-activated protein kinase 8 (c-Jun NH2-terminal kinase), attenuated TNC-stimulated ADAM-9 expression, proteolytic activity, and BTIC invasiveness. The relevance of ADAM-9 to tumor invasiveness was validated using resected human glioblastoma specimens and orthotopic xenografts where elevation of ADAM-9 and TNC expression was prominent at the invasive front of the tumor.

CONCLUSIONS:

This study has identified TNC as a promoter of the invasiveness of BTICs through a mechanism involving ADAM-9 proteolysis via the c-Jun NH2-terminal kinase pathway.

• Authors: Susobhan Sarkar, Franz J Zemp, Donna Senger, Stephen M Robbins, V Wee Yong
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 8 Pg. 1095-105 (Aug 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25646025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Membrane Proteins
• Tenascin
• ADAM Proteins
• ADAM9 protein, human

Topics

• ADAM Proteins (metabolism)
• Animals
• Brain Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Glioblastoma (metabolism, pathology)
• Humans
• MAP Kinase Signaling System
• Membrane Proteins (metabolism)
• Mice
• Neoplasm Invasiveness
• Neoplastic Stem Cells (metabolism, pathology)
• Tenascin (pharmacology, physiology)