Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.
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.
Winkler
Frank
F
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.
Kozin
Sergey V
SV
Tong
Ricky T
RT
Chae
Sung-Suk
SS
Booth
Michael F
MF
Garkavtsev
Igor
I
Xu
Lei
L
Hicklin
Daniel J
DJ
Fukumura
Dai
D
di Tomaso
Emmanuelle
E
Munn
Lance L
LL
Jain
Rakesh K
RK
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
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