Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice.

Abstract

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+/min mice have been widely used as a model recapitulating early intestinal adenoma formation. To investigate whether tumor growth in Apc+/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+/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.

• Authors: Nina Korsisaari, Ian M Kasman, William F Forrest, Navneet Pal, Wei Bai, Germaine Fuh, Franklin V Peale, Ron Smits, Napoleone Ferrara
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 25 Pg. 10625-30 (Jun 19 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17553957 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Vascular Endothelial Growth Factor A

Topics

• Adenoma (blood supply, genetics, immunology, therapy)
• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Gene Deletion
• Genes, APC (physiology)
• In Situ Hybridization
• Intestinal Neoplasms (blood supply, genetics, immunology, therapy)
• Mice
• Mice, Inbred C57BL
• Signal Transduction (immunology)
• Survival Analysis
• Time Factors
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)