title: Regression of established tumors and metastases by potent vascular endothelial growth factor blockade.
abstract: 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.
authors.affiliation: Division of Pediatric Surgery, Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
authors.forename: Anna
authors.initials: A
authors.lastname: Serur
authors.forename: Angela
authors.initials: A
authors.lastname: Kadenhe
authors.forename: Akiko
authors.initials: A
authors.lastname: Yokoi
authors.forename: Kimberly W
authors.initials: KW
authors.lastname: McCrudden
authors.forename: Tamara
authors.initials: T
authors.lastname: New
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Toole
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zabski
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
mesh_terms: 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
chemical_list: 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