Inhibition of VEGF-A Prevents the Angiogenic Switch and Results in Increased Survival of$Apc^{+/\text{min}}$Mice

Anti-VEGF-A monoclonal antibodies, in combination with chemotherapy, result in a survival benefit in patients with metastatic colorectal and non-small cell lung cancer, but little is known regarding the impact of anti-VEGF-A therapy on benign or premalignant tumors. The$Apc^{+/\text{min}}$mice have...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-06, Vol.104 (25), p.10625-10630
Main Authors: Korsisaari, Nina, Kasman, Ian M., Forrest, William F., Pal, Navneet, Bai, Wei, Fuh, Germaine, Peale, Franklin V., Smits, Ron, Ferrara, Napoleone
Format: Article
Language:English
Subjects:
Adenoma
Angiogenesis
Animal physiology
Antibodies
Cell growth
Epithelial cells
Mice
Spleen
Tumor burden
Tumors
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Summary:Anti-VEGF-A monoclonal antibodies, in combination with chemotherapy, result in a survival benefit in patients with metastatic colorectal and non-small cell lung cancer, but little is known regarding the impact of anti-VEGF-A therapy on benign or premalignant tumors. The$Apc^{+/\text{min}}$mice have been widely used as a model recapitulating early intestinal adenoma formation. To investigate whether tumor growth in$Apc^{+/\text{min}}$mice is mediated by VEGF-A-dependent angiogenesis, we used two independent approaches to inhibit VEGF-A: monotherapy with a monoclonal antibody (Mab) targeting VEGF-A and genetic deletion of VEGF-A selectively in intestinal epithelial cells. Short-term (3 or 6 weeks) treatment with anti-VEGF-A Mab G6-31 resulted in a nearly complete suppression of adenoma growth throughout the small intestine. Growth inhibition by Mab G6-31 was associated with a decrease in vascular density. Long-term (up to 52 weeks) treatment with Mab G6-31 led to a substantial increase in median survival. Deletion of VEGF-A in intestinal epithelial cells of$Apc^{+/\text{min}}$mice yielded a significant inhibition of tumor growth, albeit of lesser magnitude than that resulting from Mab G6-31 administration. These results establish that inhibition of VEGF-A signaling is sufficient for tumor growth cessation and confers a long-term survival benefit in an intestinal adenoma model. Therefore, VEGF-A inhibition may be a previously uncharacterized strategy for the prevention of the angiogenic switch and growth in intestinal adenomas.
ISSN:0027-8424
DOI:10.1073/pnas.0704213104