The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase.
Chemokines have been found to alter tumor growth and metastasis. We have described previously that a particular chemokine receptor, CXCR4, was predominantly expressed on various glioma cell lines and in resected glioblastoma specimens. Herein, we have tested the ligand of CXCR4, stromal cell derived factor-1alpha (SDF-1alpha, CXCL12), on the response of human glioma cells. We found that SDF-1alpha increased the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9. The SDF-1alpha enhanced MT2-MMP expression was blocked by a CXCR4 antagonist, AMD3100. Functional invasion assays showed that SDF-1alpha stimulated glioma cells to invade through matrigel-coated chambers and this effect was inhibited in glioma cells by the stable downregulation of MT2-MMP expression using small interfering RNA (siRNA). In vivo and at asymptomatic stages following intracerebral implant of cells, mice harboring MT2-MMP siRNA downregulated clones had smaller and less invasive tumors compared with mice implanted with non-specific siRNA control cells. Analyses at symptomatic stages demonstrate that mice with MT2-MMP siRNA clones survive longer than mice harboring control cells. These results highlight MT2-MMP as an effector of CXCR4 signaling in glioma cells, and they reveal the novel role of MT2-MMP in modulating tumor activity.
Zhang
Jing
J
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Sarkar
Susobhan
S
Yong
V Wee
VW
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D015153:Blotting, Western; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D003094:Collagen / Q000737:chemistry; D000080027:Cyclams; D004338:Drug Combinations; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000737:chemistry; D053517:Matrix Metalloproteinase 15; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000737:chemistry; D034741:RNA, Small Interfering / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D004338:Drug Combinations; D006571:Heterocyclic Compounds; D007797:Laminin; C507098:MMP15 protein, human; C507100:Mmp15 protein, mouse; D011509:Proteoglycans; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C059485:matrigel; D003094:Collagen; D053517:Matrix Metalloproteinase 15; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C088327:plerixafor