This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deryugina, E. I. Articles by Strongin, A. Y. Search for Related Content PubMed PubMed Citation Articles by Deryugina, E. I. Articles by Strongin, A. Y.

Up-Regulation of Vascular Endothelial Growth Factor by Membrane-type 1 Matrix Metalloproteinase Stimulates Human Glioma Xenograft Growth and Angiogenesis¹

The Extracellular Matrix Biology Program, The Burnham Institute, La Jolla, California 92037

Membrane-type (MT) 1 matrix metalloproteinase (MMP) is up-regulated in many tumor types and has been implicated in tumor progression and metastasis. MT1-MMP is critical for pericellular degradation of the extracellular matrix, thereby promoting tumor cell invasion and dissemination. To grow efficiently in vivo, tumor cells induce angiogenesis in both primary solid tumors and metastatic foci. The present study describes a functional link between the expression of MT1-MMP and vascular endothelial growth factor (VEGF) production in human glioma U251 xenografts in athymic mice. To investigate the effects of MT1-MMP on VEGF expression, U251 cells were stably transfected with MT1-MMP to generate the U-MT cell line overexpressing the enzyme. In vitro, the U-MT cells had an increased rate of proliferation and migration as well as the ability to activate the MMP-2 proenzyme and directionally remodel a three-dimensional collagen matrix. These findings suggested higher tumorigenicity of U-MT cells relative to the vector-control U-neo cells. In agreement with the in vitro data, U-MT xenografts in BALB/c nu/nu mice displayed markedly increased growth rates and elevated levels of angiogenesis. In contrast, U-neo cells formed small, minimally vascularized tumors. The elevated angiogenesis in U-MT xenografts was associated with an up-regulation of VEGF expression in tumor cells. In addition, U-MT cells in vitro secreted twice as much VEGF as the control cells. GM6001, a hydroxamate inhibitor of MMP activity, down-regulated the production of VEGF in U-MT cells to the levels observed in the U-neo control. Our results demonstrate that the enhanced tumorigenicity of glioma cells overexpressing MT1-MMP involves stimulation of angiogenesis through the up-regulation of VEGF production.

This article has been cited by other articles:

				D. V. Rozanov, A. Y. Savinov, R. Williams, K. Liu, V. S. Golubkov, S. Krajewski, and A. Y. Strongin Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene Network in Cancer Cancer Res., June 1, 2008; 68(11): 4086 - 4096. [Abstract] [Full Text] [PDF]

				H. G. Yu, X. Liu, S. Kiss, E. Connolly, E. S. Gragoudas, N. A. Michaud, O. V. Bulgakov, M. Adamian, M. M. DeAngelis, J. W. Miller, et al. Increased Choroidal Neovascularization following Laser Induction in Mice Lacking Lysyl Oxidase-like 1 Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2599 - 2605. [Abstract] [Full Text] [PDF]

				Y. Wen, V. S. Golubkov, A. Y. Strongin, W. Jiang, and J. C. Reed Interaction of Hepatitis B Viral Oncoprotein with Cellular Target HBXIP Dysregulates Centrosome Dynamics and Mitotic Spindle Formation J. Biol. Chem., February 1, 2008; 283(5): 2793 - 2803. [Abstract] [Full Text] [PDF]

				P. Nangia-Makker, T. Raz, L. Tait, V. Hogan, R. Fridman, and A. Raz Galectin-3 Cleavage: A Novel Surrogate Marker for Matrix Metalloproteinase Activity in Growing Breast Cancers Cancer Res., December 15, 2007; 67(24): 11760 - 11768. [Abstract] [Full Text] [PDF]

				J. R. Basile, K. Holmbeck, T. H. Bugge, and J. S. Gutkind MT1-MMP Controls Tumor-induced Angiogenesis through the Release of Semaphorin 4D J. Biol. Chem., March 2, 2007; 282(9): 6899 - 6905. [Abstract] [Full Text] [PDF]

				L. Ramont, S. Brassart-Pasco, J. Thevenard, A. Deshorgue, L. Venteo, J. Y. Laronze, M. Pluot, J.-C. Monboisse, and F.-X. Maquart The NC1 domain of type XIX collagen inhibits in vivo melanoma growth Mol. Cancer Ther., February 1, 2007; 6(2): 506 - 514. [Abstract] [Full Text] [PDF]

				A. G. Remacle, A. V. Chekanov, V. S. Golubkov, A. Y. Savinov, D. V. Rozanov, and A. Y. Strongin O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) J. Biol. Chem., June 23, 2006; 281(25): 16897 - 16905. [Abstract] [Full Text] [PDF]

				V. Chabottaux, N. E. Sounni, C. J. Pennington, W. R. English, F. van den Brule, S. Blacher, C. Gilles, C. Munaut, E. Maquoi, C. Lopez-Otin, et al. Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases. Cancer Res., May 15, 2006; 66(10): 5165 - 5172. [Abstract] [Full Text] [PDF]

				V. W.M. van Hinsbergh, M. A. Engelse, and P. H.A. Quax Pericellular Proteases in Angiogenesis and Vasculogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 716 - 728. [Abstract] [Full Text] [PDF]

				V. S. Golubkov, A. V. Chekanov, S. J. Doxsey, and A. Y. Strongin Centrosomal Pericentrin Is a Direct Cleavage Target of Membrane Type-1 Matrix Metalloproteinase in Humans but Not in Mice: POTENTIAL IMPLICATIONS FOR TUMORIGENESIS J. Biol. Chem., December 23, 2005; 280(51): 42237 - 42241. [Abstract] [Full Text] [PDF]

				E. I. Deryugina, A. Zijlstra, J. J. Partridge, T. A. Kupriyanova, M. A. Madsen, T. Papagiannakopoulos, and J. P. Quigley Unexpected Effect of Matrix Metalloproteinase Down-Regulation on Vascular Intravasation and Metastasis of Human Fibrosarcoma Cells Selected In vivo for High Rates of Dissemination Cancer Res., December 1, 2005; 65(23): 10959 - 10969. [Abstract] [Full Text] [PDF]

				A. G. Remacle, D. V. Rozanov, P. C. Baciu, A. V. Chekanov, V. S. Golubkov, and A. Y. Strongin The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP) J. Cell Sci., November 1, 2005; 118(21): 4975 - 4984. [Abstract] [Full Text] [PDF]

				T. Nonaka, K. Nishibashi, Y. Itoh, I. Yana, and M. Seiki Competitive disruption of the tumor-promoting function of membrane type 1 matrix metalloproteinase/matrix metalloproteinase-14 in vivo Mol. Cancer Ther., August 1, 2005; 4(8): 1157 - 1166. [Abstract] [Full Text] [PDF]

				E. W. Newcomb, M. A. Ali, T. Schnee, L. Lan, Y. Lukyanov, M. Fowkes, D. C. Miller, and D. Zagzag Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1{alpha} expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy Neuro-oncol, July 1, 2005; 7(3): 225 - 235. [Abstract] [PDF]

				V. S. Golubkov, S. Boyd, A. Y. Savinov, A. V. Chekanov, A. L. Osterman, A. Remacle, D. V. Rozanov, S. J. Doxsey, and A. Y. Strongin Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Exhibits an Important Intracellular Cleavage Function and Causes Chromosome Instability J. Biol. Chem., July 1, 2005; 280(26): 25079 - 25086. [Abstract] [Full Text] [PDF]

				D. Voskas, N. Jones, P. Van Slyke, C. Sturk, W. Chang, A. Haninec, Y. O. Babichev, J. Tran, Z. Master, S. Chen, et al. A Cyclosporine-Sensitive Psoriasis-Like Disease Produced in Tie2 Transgenic Mice Am. J. Pathol., March 1, 2005; 166(3): 843 - 855. [Abstract] [Full Text] [PDF]

				L. Labrecque, C. Nyalendo, S. Langlois, Y. Durocher, C. Roghi, G. Murphy, D. Gingras, and R. Beliveau Src-mediated Tyrosine Phosphorylation of Caveolin-1 Induces Its Association with Membrane Type 1 Matrix Metalloproteinase J. Biol. Chem., December 10, 2004; 279(50): 52132 - 52140. [Abstract] [Full Text] [PDF]

				P. Wang, J. Nie, and D. Pei The Hemopexin Domain of Membrane-type Matrix Metalloproteinase-1 (MT1-MMP) Is Not Required for Its Activation of proMMP2 on Cell Surface but Is Essential for MT1-MMP-mediated Invasion in Three-dimensional Type I Collagen J. Biol. Chem., December 3, 2004; 279(49): 51148 - 51155. [Abstract] [Full Text] [PDF]

				D. V. Rozanov, S. Sikora, A. Godzik, T. I. Postnova, V. Golubkov, A. Savinov, S. Tomlinson, and A. Y. Strongin Non-proteolytic, Receptor/Ligand Interactions Associate Cellular Membrane Type-1 Matrix Metalloproteinase with the Complement Component C1q J. Biol. Chem., November 26, 2004; 279(48): 50321 - 50328. [Abstract] [Full Text] [PDF]

				I. S. Aljada, N. Ramnath, K. Donohue, S. Harvey, J. J. Brooks, S. M. Wiseman, T. Khoury, G. Loewen, H. K. Slocum, T. M. Anderson, et al. Upregulation of the Tissue Inhibitor of Metalloproteinase-1 Protein Is Associated With Progression of Human Non-Small-Cell Lung Cancer J. Clin. Oncol., August 15, 2004; 22(16): 3218 - 3229. [Abstract] [Full Text] [PDF]

				T. E. Van Meter, W. C. Broaddus, H. K. Rooprai, G. J. Pilkington, and H. L. Fillmore Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas Neuro-oncol, July 1, 2004; 6(3): 188 - 199. [Abstract] [PDF]

				A. Zijlstra, R. T. Aimes, D. Zhu, K. Regazzoni, T. Kupriyanova, M. Seandel, E. I. Deryugina, and J. P. Quigley Collagenolysis-dependent Angiogenesis Mediated by Matrix Metalloproteinase-13 (Collagenase-3) J. Biol. Chem., June 25, 2004; 279(26): 27633 - 27645. [Abstract] [Full Text] [PDF]

				E. Maquoi, N. E. Sounni, L. Devy, F. Olivier, F. Frankenne, H.-W. Krell, F. Grams, J.-M. Foidart, and A. Noel Anti-Invasive, Antitumoral, and Antiangiogenic Efficacy of a Pyrimidine-2,4,6-trione Derivative, an Orally Active and Selective Matrix Metalloproteinases Inhibitor Clin. Cancer Res., June 15, 2004; 10(12): 4038 - 4047. [Abstract] [Full Text] [PDF]

				A Noel, C Maillard, N Rocks, M Jost, V Chabottaux, N E Sounni, E Maquoi, D Cataldo, and J M Foidart Membrane associated proteases and their inhibitors in tumour angiogenesis J. Clin. Pathol., June 1, 2004; 57(6): 577 - 584. [Abstract] [Full Text] [PDF]

				N. E. Sounni, C. Roghi, V. Chabottaux, M. Janssen, C. Munaut, E. Maquoi, B. G. Galvez, C. Gilles, F. Frankenne, G. Murphy, et al. Up-regulation of Vascular Endothelial Growth Factor-A by Active Membrane-type 1 Matrix Metalloproteinase through Activation of Src-Tyrosine Kinases J. Biol. Chem., April 2, 2004; 279(14): 13564 - 13574. [Abstract] [Full Text] [PDF]

				J. Schoenberger, D. Grimm, P. Kossmehl, M. Infanger, E. Kurth, and C. Eilles Effects of PTK787/ZK222584, a Tyrosine Kinase Inhibitor, on the Growth of a Poorly Differentiated Thyroid Carcinoma: An Animal Study Endocrinology, March 1, 2004; 145(3): 1031 - 1038. [Abstract] [Full Text] [PDF]

				C. Johnson, H.-J. Sung, S. M. Lessner, M. E. Fini, and Z. S. Galis Matrix Metalloproteinase-9 Is Required for Adequate Angiogenic Revascularization of Ischemic Tissues: Potential Role in Capillary Branching Circ. Res., February 6, 2004; 94(2): 262 - 268. [Abstract] [Full Text] [PDF]

				Y. N. Ye, E. S. L. Liu, V. Y. Shin, W. K. K. Wu, J. C. Luo, and C. H. Cho Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 66 - 72. [Abstract] [Full Text] [PDF]

				K. Ohno-Matsui, T. Uetama, T. Yoshida, M. Hayano, T. Itoh, I. Morita, and M. Mochizuki Reduced Retinal Angiogenesis in MMP-2-Deficient Mice Invest. Ophthalmol. Vis. Sci., December 1, 2003; 44(12): 5370 - 5375. [Abstract] [Full Text] [PDF]

				A. Jiang and D. Pei Distinct Roles of Catalytic and Pexin-like Domains in Membrane-type Matrix Metalloproteinase (MMP)-mediated Pro-MMP-2 Activation and Collagenolysis J. Biol. Chem., October 3, 2003; 278(40): 38765 - 38771. [Abstract] [Full Text] [PDF]

				A. Remacle, G. Murphy, and C. Roghi Membrane type I-matrix metalloproteinase (MT1-MMP) is internalised by two different pathways and is recycled to the cell surface J. Cell Sci., October 1, 2003; 116(19): 3905 - 3916. [Abstract] [Full Text] [PDF]

				B. Annabi, Y.-T. Lee, S. Turcotte, E. Naud, R. R. Desrosiers, M. Champagne, N. Eliopoulos, J. Galipeau, and R. Beliveau Hypoxia Promotes Murine Bone-Marrow-Derived Stromal Cell Migration and Tube Formation Stem Cells, May 1, 2003; 21(3): 337 - 347. [Abstract] [Full Text] [PDF]