title: An extensive invasive intracranial human glioblastoma xenograft model: role of high level matrix metalloproteinase 9.
abstract: The lack of an intracranial human glioma model that recapitulates the extensive invasive and hypervascular features of glioblastoma (GBM) is a major hurdle for testing novel therapeutic approaches against GBM and studying the mechanism of GBM invasive growth. We characterized a high matrix metalloproteinase-9 (MMP-9) expressing U1242 MG intracranial xenograft mouse model that exhibited extensive individual cells and cell clusters in a perivascular and subpial cellular infiltrative pattern, geographic necrosis and infiltrating tumor-induced vascular proliferation closely resembling the human GBM phenotype. MMP-9 silencing cells with short hairpin RNA dramatically blocked the cellular infiltrative pattern, hypervascularity, and cell proliferation in vivo, and decreased cell invasion, colony formation, and cell motility in vitro, indicating that a high level of MMP-9 plays an essential role in extensive infiltration and hypervascularity in the xenograft model. Moreover, epidermal growth factor (EGF) failed to stimulate MMP-9 expression, cell invasion, and colony formation in MMP-9-silenced clones. An EGF receptor (EGFR) kinase inhibitor, a RasN17 dominant-negative construct, MEK and PI3K inhibitors significantly blocked EGF/EGFR-stimulated MMP-9, cell invasion, and colony formation in U1242 MG cells, suggesting that MMP-9 is involved in EGFR/Ras/MEK and PI3K/AKT signaling pathway-mediated cell invasion and anchorage-independent growth in U1242 MG cells. Our data indicate that the U1242 MG xenograft model is valuable for studying GBM extensive invasion and angiogenesis as well as testing anti-invasive and anti-angiogenic therapeutic approaches.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA. yz5u@virginia.edu
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Aizhen
authors.initials: A
authors.lastname: Xiao
authors.forename: Charles G
authors.initials: CG
authors.lastname: diPierro
authors.forename: Joan E
authors.initials: JE
authors.lastname: Carpenter
authors.forename: Rana
authors.initials: R
authors.lastname: Abdel-Fattah
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Redpath
authors.forename: Maria-Beatriz S
authors.initials: MB
authors.lastname: Lopes
authors.forename: Isa M
authors.initials: IM
authors.lastname: Hussaini
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins