RRC ID 6767
Author Hasebe Y, Egawa K, Shibanuma M, Nose K.
Title Induction of matrix metalloproteinase gene expression in an endothelial cell line by direct interaction with malignant cells.
Journal Cancer Sci
Abstract Mouse endothelial TKD2 cells in monolayers were cocultured with various human cell lines for 24 h, and the expression of several secreted matrix metalloproteinases (MMP) and cell adhesion molecules was examined by real-time reverse transcription-polymerase chain reaction using mouse-specific primers. Coculture with normal fibroblasts did not elicit the expression of these molecules, but coculture with cancer cells induced the expression of MMP-3, MMP-9 and MMP-10 mRNA in endothelial cells, and in normal mouse embryonic fibroblasts. The induction of MMP mRNA was dependent on direct cell adhesion, as separate culture of A549 cells in Boyden chambers did not induce MMP mRNA, and neutralizing antibody against VLA-4 abolished the induction. An inhibitor of phosphatidylinositol-3-phosphate kinase strongly suppressed the induction of MMP-3, MMP-9 and MMP-10 mRNA, and expression of the dominant-negative mutant of phosphatidylinositol-3-phosphate kinase also decreased the induction. It was suggested that intracellular reactive oxygen species (ROS) levels were increased in TKD2 cells following adhesion to cancer cells. ROS scavengers decreased the levels of MMP induction, and roterone, an inhibitor of mitochondrial complex I, strongly suppressed the induction of MMP-3, MMP-9 and MMP-10. The depletion of mitochondria in TKD2 cells decreased the induction of MMP-9, but the induction of MMP-3 and MMP-10 was not affected. These results indicate that the adhesion of cancer cells to endothelial cells activates several distinct signaling pathways to induce MMP gene expression, and the pathways for MMP-3, MMP-9 and MMP-10 are partly different. For the induction of MMP-9, mitochondria participate in induction, possibly through the production of ROS.
Volume 98(1)
Pages 58-67
Published 2007-1
DOI 10.1111/j.1349-7006.2006.00344.x
PMID 17054435
MeSH Animals Cell Adhesion / drug effects Cell Adhesion / physiology* Cell Adhesion Molecules / biosynthesis Cell Line, Tumor Cells, Cultured Coculture Techniques Endothelial Cells / drug effects Endothelial Cells / metabolism* Fibroblasts / metabolism Free Radical Scavengers / pharmacology Gene Expression / drug effects Humans Matrix Metalloproteinases / biosynthesis* Matrix Metalloproteinases / drug effects Matrix Metalloproteinases / genetics Membrane Potentials / drug effects Membrane Potentials / physiology Mice Mitochondria / drug effects Mitochondria / metabolism Neoplasm Metastasis / physiopathology* Neoplasms / physiopathology* Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction
IF 4.751
Times Cited 15
Human and Animal Cells