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Carcinogenesis Advance Access originally published online on June 16, 2006
Carcinogenesis 2006 27(10):2133-2139; doi:10.1093/carcin/bgl113
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commerical License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Inhibiting vascular endothelial growth factor receptor-2 signaling reduces tumor burden in the ApcMin/+ mouse model of early intestinal cancer

R.A. Goodlad1,3,*, A.J. Ryan2, S.R. Wedge2, I.T. Pyrah2, D. Alferez1,3, R. Poulsom1, N.R. Smith2, N. Mandir1, A.J. Watkins1 and R.W. Wilkinson2

1 Histopathology Unit, London Research Institute, Cancer Research UK 44 Lincoln's Inn Fields, London WC2A 3PX, UK
2 Department of Cancer and Department of Infection Research and Safety Assessment, AstraZeneca Pharmaceuticals Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
3 Department of Histopathology, Division of Investigative Science, Imperial College, Hammersmith Hospital London W12 0NN, UK

*To whom correspondence should be addressed. Tel: +44 (0) 207 269 3086; Fax: +44 (0) 207 269 3491; Email: r.goodlad{at}cancer.org.uk

The ApcMin/+ mouse model is a clinically relevant model of early intestinal cancer. We used AZD2171, an oral, highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor, to investigate the role of VEGF receptor-2 (VEGFR-2) signaling in adenoma development and growth in ApcMin/+ mice. AZD2171 (5 mg/kg body wt/day) was administered once daily for 28 days to 6-week-old (early-intervention) or 10-week-old (late intervention) mice. In the early-intervention study, AZD2171 reduced the number of macroscopic polyps in the small bowel and colon. Macropolyp diameter was lower in the small bowel, but remained unchanged in the colon. In animals receiving AZD2171, microscopic evaluation of the small intestine showed a significant reduction in the number of larger lesions. In the late-intervention study, AZD2171 treatment reduced macropolyp diameter (but not number) in the small intestine. Microscopic analysis revealed that AZD2171 significantly reduced the number of larger micropolyps in the small bowel, with no large micropolyps present in the colon. AZD2171 treatment had no effect on microvessel density or localization of ß-catenin staining in adenomas or non-tumor intestinal tissue, but significantly reduced the number of cells expressing VEGFR-2 mRNA. In conclusion, the effects of AZD2171 in the small intestine of ApcMin/+ mice are consistent with an antiangiogenic mechanism of action, limiting growth of adenomas to ≤1 mm. These data also suggest that an early step in adenoma development may depend on VEGFR-2 signaling. Together, these results indicate that VEGFR-2 signaling may play key roles in the development and progression of intestinal adenomas.


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