title: Matrix metalloproteinase-1-mediated mesenchymal stem cell tumor tropism is dependent on crosstalk with stromal derived growth factor 1/C-X-C chemokine receptor 4 axis.
abstract: Human bone marrow-derived mesenchymal stem cells (MSCs) have the unique ability to home toward injuries or tumor sites. We have previously shown that the tumor-tropic property is dependent on the intrinsic expression and activity of the matrix remodeling gene, matrix metalloproteinase 1 (MMP-1). Herein, crosstalk between MMP-1/protease activated receptor 1 (PAR-1) and the G-protein coupled receptor stromal-derived growth factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR-4) in facilitating cell migration was investigated. Gain-of-function and RNA interference (RNAi) technology were used to evaluate the interplay between the key players. The downstream effect on the tumor-tropic migration of MSCs was investigated using modified Boyden chamber assay. Neutralizing PAR-1 activation using monoclonal antibody and targeted knockdown of MMP-1 using RNAi resulted in decreased expression of SDF-1, which was not observed in control-RNAi-transfected cells. Overexpression of CXCR-4 failed to promote MSC migration; the percentage of migrated cells toward tumor cell conditioned medium was similar to the vector-transduced and the CXCR-4-transduced MSCs. Furthermore, inhibition of SDF-1/CXCR-4 signaling using AMD3100 reduced MSC migration through the deregulation of MMP-1 promoter activities, protein expression, and metalloproteinase activity. Collectively, our results showed that MMP-1-mediated MSC tumor tropism is dependent on crosstalk with the SDF-1/CXCR-4 axis.
authors.affiliation: Laboratory of Cancer Gene Therapy and.
authors.forename: Ivy A W
authors.initials: IA
authors.lastname: Ho
authors.affiliation: Laboratory of Cancer Gene Therapy and.
authors.forename: Yulyana
authors.initials: Y
authors.lastname: Yulyana
authors.affiliation: Laboratory of Cancer Gene Therapy and.
authors.forename: Kian C
authors.initials: KC
authors.lastname: Sia
authors.affiliation: Laboratory of Cancer Gene Therapy and.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Newman
authors.affiliation: Department of Orthopedics, Singapore General Hospital, Singapore;
authors.forename: Chang M
authors.initials: CM
authors.lastname: Guo
authors.affiliation: Bek Chai Heah Laboratory of Cancer Genomics, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore; Cancer and Stem Cells Biology Program, Duke-National University of Singapore Graduate Medical School, and Department of Biochemistry and Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore.
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Laboratory of Cancer Gene Therapy and Cancer and Stem Cells Biology Program, Duke-National University of Singapore Graduate Medical School, and Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and cmrlyp@nccs.com.sg.
authors.forename: Paula Y P
authors.initials: PY
authors.lastname: Lam
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology; D008875:Middle Aged; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D044463:Receptor, PAR-1; D019718:Receptors, CXCR4; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: CXCR-4; MMP-1; MSCs; SDF-1; migration