Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice
- Nina Korsisaari,
- Ian M. Kasman,
- William F. Forrest,
- Navneet Pal,
- Wei Bai*,
- Germaine Fuh,
- Franklin V. Peale,
- Ron Smits†, and
- Napoleone Ferrara‡
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Contributed by Napoleone Ferrara, May 6, 2007 (received for review February 9, 2007)
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.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: nf{at}gene.com
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Author contributions: N.K. and N.F. designed research; N.K., I.M.K., N.P., W.B., F.V.P., and R.S. performed research; G.F. and R.S. contributed new reagents/analytic tools; N.K., I.M.K., W.F.F., and F.V.P. analyzed data; and N.K. and N.F. wrote the paper.
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↵*Present address: Department of Medicine, New York Downtown Hospital, New York, NY 10038.
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↵ †Present address: Department of Experimental Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Dr. Molewaterplein 50, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
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Conflict of interest statement: The authors are employees and shareholders of Genentech, Inc.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0704213104/DC1.
- Abbreviations:
- EMH,
- extramedullary hematopoiesis;
- FAP,
- Familial Adenomatous Polyposis;
- RTK,
- receptor tyrosine kinase.
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Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
