Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature.
We characterized the effect of potent vascular endothelial growth factor (VEGF) blockade on early-stage Wilms tumor xenograft growth, vasculature and metastasis. VEGF is a key mediator of both physiologic and tumor angiogenesis. We recently described that potent VEGF blockade induces regression of established Wilms tumor xenografts and vessels, also reducing the size but not the incidence of pre-existing metastases. In these studies, we examined the effects of potent VEGF blockade on earlier stages of experimental Wilms tumors, focusing on tumor growth, vasculature and metastasis. Athymic mice received intrarenal human Wilms tumor cell implants. Biweekly treatment with vehicle or the VEGF-Trap, a high-affinity soluble decoy receptor incorporating regions of VEGFR1 and VEGFR2, was begun 1 week later (100 or 500 micrograms/dose, n=20 in each group). Mice were euthanized at week 6 to examine tumor weight, incidence of lung metastases, vascularity and expression of angiogenic factors. A cohort of mice was examined 2 weeks after cessation of treatment. Compared to controls, VEGF-Trap treated tumors were significantly smaller (100 micrograms/dose: 92.7% smaller, p=0.0017; 500 micro g/dose: 99.0% smaller, p=0.0009). The incidence of lung metastasis also decreased significantly (p<0.0055). VEGF-Trap nearly eradicated tumor vasculature. Rare persisting vessels were characterized by large caliber, quiescence (lacking proliferation/apoptosis) and arterialization (both phenotypic and molecular). Potent VEGF blockade caused near-arrest of experimental Wilms tumor growth, resulted in nearly avascular tumors, and also decreased the incidence and size of metastases. Persistent vessels in tumors treated with VEGF-Trap displayed specific morphologic and molecular features, suggestive of arterialization. Future strategies that target these persisting vessels may enhance the efficacy of VEGF blockade therapy.
Division of Pediatric Surgery, College of Physicians and Surgeons, Columbia University, Children's Hospital of New York-Presbyterian, New York, NY, USA.
Jason S
JS
Frischer
Jianzhong
J
Huang
Anna
A
Serur
Angela
A
Kadenhe-Chiweshe
Kimberly W
KW
McCrudden
Kathleen
K
O'Toole
Jocelyn
J
Holash
George D
GD
Yancopoulos
Darrell J
DJ
Yamashiro
Jessica J
JJ
Kandel
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D009396:Wilms Tumor / Q000098:blood supply / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D011993:Recombinant Fusion Proteins; C475927:VEGF-Trap fusion protein, recombinant; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor