Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/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+/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.
Korsisaari
Nina
N
Genentech, Inc., South San Francisco, CA 94080, USA.
Kasman
Ian M
IM
Forrest
William F
WF
Pal
Navneet
N
Bai
Wei
W
Fuh
Germaine
G
Peale
Franklin V
FV
Smits
Ron
R
Ferrara
Napoleone
N
D000236:Adenoma / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017353:Gene Deletion; D017491:Genes, APC / Q000502:physiology*; D017403:In Situ Hybridization; D007414:Intestinal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D016019:Survival Analysis; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A