Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12657
Title: Blockade of MMP14 activity in murine breast carcinomas: implications for macrophages, vessels, and radiotherapy.
Authors: Ager, Eleanor I;Kozin, Sergey V;Kirkpatrick, Nathaniel D;Seano, Giorgio;Kodack, David P;Askoxylakis, Vasileios;Huang, Yuhui;Goel, Shom;Snuderl, Matija;Muzikansky, Alona;Finkelstein, Dianne M;Dransfield, Daniel T;Devy, Laetitia;Boucher, Yves;Fukumura, Dai;Jain, Rakesh K
Affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston MA (EIA, SVK, NDK, GS, DPK, VA, YH, SG, MS, YB, DF, RKJ); Department of Surgery (Austin Health), University of Melbourne, Studley Road Heidelberg, VIC, Australia (EIA); Novogen, Hornsby, NSW, Australia (EIA); Novartis Institutes for BioMedical Research, Cambridge, MA (NDK); Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia (SG); Department of Biostatistics, Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts (AM, DMF); Department of Pathology, NYU Langone Medical Center and Medical School, New York, NY (MS); Dyax Corp., Burlington, MA (DTD, LD); Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (SG); Tokai Pharmaceuticals, Inc., Cambridge, MA (DTD); Merck Serono S. A., Geneva, Switzerland (LD).
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston MA (EIA, SVK, NDK, GS, DPK, VA, YH, SG, MS, YB, DF, RKJ); Department of Surgery (Austin Health), University of Melbourne, Studley Road Heidelberg, VIC, Australia (EIA); Novogen, Hornsby, NSW, Australia (EIA); Novartis Institutes for BioMedical Research, Cambridge, MA (NDK); Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia (SG); Department of Biostatistics, Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts (AM, DMF); Department of Pathology, NYU Langone Medical Center and Medical School, New York, NY (MS); Dyax Corp., Burlington, MA (DTD, LD); Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (SG); Tokai Pharmaceuticals, Inc., Cambridge, MA (DTD); Merck Serono S. A., Geneva, Switzerland (LD). jain@steele.mgh.harvard.edu dai@steele.mgh.harvard.edu.
Issue Date: 20-Feb-2015
Citation: Journal of the National Cancer Institute 2015; 107(4):
Abstract: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects.Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor β (TGFβ) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided.DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFβ and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm(3): control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors.MMP14 blockade decreased immunosuppressive TGFβ, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumors.
Internal ID Number: 25710962
URI: http://ahro.austin.org.au/austinjspui/handle/1/12657
DOI: 10.1093/jnci/djv017
URL: http://www.ncbi.nlm.nih.gov/pubmed/25710962
Type: Journal Article
Subjects: Amidines.pharmacology
Animals
Antibodies, Monoclonal.pharmacology.therapeutic use
Antineoplastic Agents.pharmacology.therapeutic use
Benzylamines.pharmacology
Breast Neoplasms.blood supply.drug therapy.immunology.metabolism.radiotherapy
Cell Line, Tumor
Dose Fractionation
Enzyme Inhibitors.pharmacology.therapeutic use
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Immunoglobulin G.blood
Macrophages.drug effects.enzymology
Mammary Neoplasms, Experimental
Matrix Metalloproteinase 14.drug effects.metabolism
Mice
Neovascularization, Pathologic
Nitric Oxide Synthase Type II.antagonists & inhibitors.drug effects.metabolism
Phenotype
Signal Transduction.drug effects
Smad2 Protein.metabolism
Smad3 Protein.metabolism
Transforming Growth Factor beta.metabolism
Up-Regulation
Appears in Collections:Journal articles

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