Rapid vascular regrowth in tumors after reversal of VEGF inhibition.
Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.
Mancuso
Michael R
MR
Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, UCSF, San Francisco, California 94143-0452, USA.
Davis
Rachel
R
Norberg
Scott M
SM
O'Brien
Shaun
S
Sennino
Barbara
B
Nakahara
Tsutomu
T
Yao
Virginia J
VJ
Inai
Tetsuichiro
T
Brooks
Peter
P
Freimark
Bruce
B
Shalinsky
David R
DR
Hu-Lowe
Dana D
DD
McDonald
Donald M
DM
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000077784:Axitinib; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D024141:Collagen Type IV / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D007340:Insulinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009930:Organic Chemicals / Q000494:pharmacology; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D024141:Collagen Type IV; D007093:Imidazoles; D007191:Indazoles; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C113282:prinomastat; D000077784:Axitinib; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2