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

• 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 - blood supply; Adenoma - genetics; Adenoma - immunology; Adenoma - therapy; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Biological Sciences; Gene Deletion; Genes, APC - physiology; In Situ Hybridization; Intestinal Neoplasms - blood supply; Intestinal Neoplasms - genetics; Intestinal Neoplasms - immunology; Intestinal Neoplasms - therapy; Mice; Mice, Inbred C57BL; Signal Transduction - immunology; Survival Analysis; Time Factors; Vascular Endothelial Growth Factor A - antagonists & inhibitors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704213104

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.