title: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.
abstract: The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.
authors.affiliation: E.L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozin
authors.forename: Ricky T
authors.initials: RT
authors.lastname: Tong
authors.forename: Sung-Suk
authors.initials: SS
authors.lastname: Chae
authors.forename: Michael F
authors.initials: MF
authors.lastname: Booth
authors.forename: Igor
authors.initials: I
authors.lastname: Garkavtsev
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D042683:Angiopoietin-1 / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000941:Antigens / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000737:chemistry / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D024141:Collagen Type IV / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy / Q000379:methods; D004151:Dipeptides / Q000494:pharmacology; D036388:Ephrin-B2 / Q000235:genetics; D005451:Fluorescein Angiography; D005720:Gamma Rays / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D020286:Pericytes / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D011509:Proteoglycans / Q000032:analysis; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D000911:Antibodies, Monoclonal; D000941:Antigens; D024141:Collagen Type IV; D004151:Dipeptides; D036388:Ephrin-B2; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D010100:Oxygen; D011509:Proteoglycans; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099216:Chondroitin Sulfate Proteoglycan 4; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide