Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases

BACKGROUND Recent studies have suggested that vascular endothelial growth factor (VEGF), in addition to its proangiogenic properties, also functions as a survival factor for endothelial cells. The authors hypothesized that inhibition of VEGF activity by blockade of VEGF receptor‐2 (R‐2) function pre...

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Published in:Cancer 2000-08, Vol.89 (3), p.488-499
Main Authors: Bruns, Christiane J., Liu, Wenbiao, Davis, Darren W., Shaheen, Raymond M., McConkey, David J., Wilson, Michael R., Bucana, Corazon D., Hicklin, Daniel J., Ellis, Lee M.
Format: Article
Language:English
Subjects:
angiogenesis
Angiogenesis Inhibitors - pharmacology
Angiogenesis Inhibitors - therapeutic use
Animals
antibodies
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
apoptosis
Apoptosis - drug effects
Biological and medical sciences
Cell Survival - drug effects
Colon and Rectum
colon carcinoma
Colonic Neoplasms - blood supply
Colonic Neoplasms - drug therapy
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
endothelial cells
Endothelial Growth Factors - antagonists & inhibitors
Endothelial Growth Factors - metabolism
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Fluorescent Antibody Technique
Gastroenterology. Liver. Pancreas. Abdomen
Humans
Immunohistochemistry
Liver Neoplasms - blood supply
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - secondary
Lymphokines - antagonists & inhibitors
Lymphokines - metabolism
Male
Medical sciences
metastasis
Mice
Mice, Nude
Neoplasm Transplantation
Neovascularization, Pathologic
Platelet Endothelial Cell Adhesion Molecule-1 - metabolism
Proliferating Cell Nuclear Antigen - metabolism
receptor
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptors, Growth Factor - antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor
Signal Transduction
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumor Cells, Cultured
Tumors
vascular endothelial growth factor
Vascular Endothelial Growth Factor A
vascular endothelial growth factor receptor‐2
Vascular Endothelial Growth Factors
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Summary:BACKGROUND Recent studies have suggested that vascular endothelial growth factor (VEGF), in addition to its proangiogenic properties, also functions as a survival factor for endothelial cells. The authors hypothesized that inhibition of VEGF activity by blockade of VEGF receptor‐2 (R‐2) function prevents angiogenesis and decreases tumor growth in colon carcinoma liver metastases. METHODS Spleens of mice were injected with human colon carcinoma cells producing liver metastases. After 7 days of tumor growth, groups of mice received either antibody to VEGFR‐2 (DC101) or phosphate‐buffered saline (control). In a follow‐up experiment, a similar treatment regimen was followed except that mice were sacrificed at 1‐week intervals to assess the time course of endothelial cell and tumor cell apoptosis. RESULTS After 21 days of therapy, the authors observed a significant decrease in vessel counts in liver metastases from human colon carcinoma in nude mice after therapy with VEGFR‐2 antibody. Tumor cell apoptosis was increased significantly in the tumors of mice receiving DC101. Temporal studies with immunofluorescent double staining for the microvasculature and apoptotic cells revealed an increase in endothelial cell apoptosis that preceded an increase in tumor cell apoptosis. In vitro, treatment of human umbilical vein endothelial cells with antibody to VEGFR‐2 produced a > 2.5‐fold increase in endothelial cell apoptosis. CONCLUSIONS Therapy targeting the VEGFR‐2 inhibited tumor growth in a murine model of colon carcinoma liver metastasis. Surprisingly, this therapy did not only inhibit angiogenesis but also led to endothelial cell death. These findings suggest that VEGF, via VEGFR‐2 signaling, functions as a survival factor for tumor endothelial cells in liver metastases from colon carcinoma. Cancer 2000;89:488–99. © 2000 American Cancer Society. In an experimental model of colon carcinoma liver metastases, antibodies to the vascular endothelial growth factor (VEGF) receptor led to a decrease in tumor growth and the number of vessels. Anti‐VEGF therapy led to endothelial cell apoptosis that preceded a wave of tumor cell apoptosis, suggesting that VEGF is an essential in vivo survival factor for hepatic tumor endothelium.
ISSN:0008-543X
1097-0142
DOI:10.1002/1097-0142(20000801)89:3<488::AID-CNCR3>3.0.CO;2-X