Resistance of a VEGF-producing tumor to anti-VEGF antibody: unimpeded growth of human rhabdoid tumor xenografts.
OBJECTIVE
Rhabdoid tumor of the kidney (RTK) is a lethal malignancy of childhood for which there currently are no effective therapies. Because vascular endothelial growth factor (VEGF) is nearly ubiquitous in human tumors, the authors hypothesized that a xenograft model of RTK would (1) express VEGF and (2) respond to anti-VEGF intervention.


METHODS
A total of 2 x 10(6) cultured RTK cells were implanted intrarenally (G-401) in athymic mice. Control/treated animals received either vehicle (phosphate-buffered saline, PBS) or anti-VEGF antibody (anti-VEGF) for 5 weeks (n = 20, 17, respectively). Vasculature was mapped by angiography and immunostaining. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL) assay, VEGF expression examined by reverse transcription polymerase chain reaction, and tumor weights compared by Kruskal-Wallis analysis.


RESULTS
Mean tumor weights were not altered significantly by anti-VEGF (0.78-g, controls v 0.56-g treated tumors; P value, not significant). Grossly, xenografts grew in a novel manner, encasing rather than invading the kidney, and did not metastasize. PECAM-1 immunostaining and fluorescein angiography showed similar vascularity in control and treated xenografts. Both apoptosis and VEGF expression were unchanged in treated specimens.


CONCLUSIONS
Unexpectedly, growth of RTK xenografts was not inhibited by specific anti-VEGF antibody, although these tumors express significant amounts of VEGF. In addition, RTK vasculature, apoptosis, and VEGF expression were not substantially altered by anti-VEGF antibody. These results suggest that tumor-derived VEGF is of highly variable importance in different malignancies.
Soffer
Samuel Z
SZ
Division of Pediatric Surgery, Department of Pathology, College of Physicians and Surgeons, Columbia University, NY, USA.
Kim
Eugene
E
Huang
Jianzhong
J
McCrudden
Kimberly
K
Yokoi
Akiko
A
Moore
James T
JT
Manley
Christina
C
O'Toole
Kathleen
K
Middlesworth
William
W
Stolar
Charles
C
Yamashiro
Darrell J
DJ
Kandel
Jessica J
JJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D016612:Paraffin Embedding; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014183:Transplantation, Heterologous / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors