Regression of established tumors and metastases by potent vascular endothelial growth factor blockade.
Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and tumorigenesis. To date, studies of VEGF antagonists have primarily focused on halting progression in models of minimal residual cancer. Consistent with this focus, recent clinical trials suggest that blockade of VEGF may impede cancer progression, presumably by preventing neoangiogenesis. However, VEGF is also a key mediator of endothelial-vascular mural cell interactions, a role that may contribute to the integrity of mature vessels in advanced tumors. Here, we report that high-affinity blockade of VEGF, using the recently described VEGF-Trap, abolishes mature, preexisting vasculature in established xenografts. Eradication of vasculature is followed by marked tumor regression, including regression of lung micrometastases. Thus, the contribution of relatively low levels of VEGF to vessel integrity may be critical to maintenance of even very small tumor masses. Potent blockade of VEGF may provide a new therapeutic option for patients with bulky, metastatic cancers.
Huang
Jianzhong
J
Division of Pediatric Surgery, Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Frischer
Jason S
JS
Serur
Anna
A
Kadenhe
Angela
A
Yokoi
Akiko
A
McCrudden
Kimberly W
KW
New
Tamara
T
O'Toole
Kathleen
K
Zabski
Stephanie
S
Rudge
John S
JS
Holash
Jocelyn
J
Yancopoulos
George D
GD
Yamashiro
Darrell J
DJ
Kandel
Jessica J
JJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009130:Muscle, Smooth / Q000378:metabolism; D009336:Necrosis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D010477:Perfusion; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000199:Actins; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011993:Recombinant Fusion Proteins; C475927:VEGF-Trap fusion protein, recombinant; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor