© 2005 Oxford University Press
ARTICLE |
Role of Human Cripto-1 in Tumor Angiogenesis
Affiliations of authors: Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory (CB, LS, CC, YS, NK, MH, BW-J), Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory (EG, BKV), Extracellular Matrix Section, Laboratory of Pathology (LG, RS, WGS-S), Experimental Transplantation and Immunology Branch (GT), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Gynecology, Charite Campus Benjamin Franklin, Berlin, Germany (AE); Department of Molecular and Cellular Biology, University of Michigan, Ann Arbor, MI (AR); Division of Haematological Oncology and Department of Experimental Oncology, ITN-Fondazione Pascale, Naples, Italy (NN); Upper Austrian Research GmbH Zentrum, Linz, Austria (CW); Biogen-Idec Inc., Cambridge, MA (MS)
Correspondence to: David S. Salomon, PhD, Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg. 10, Rm. 5B39, Bethesda, MD 20892 (e-mail: salomond{at}mail.nih.gov)
Background: Human cripto-1 (CR-1) promotes cell transformation and increases migration and invasion of various mouse and human epithelial cell lines. We investigated whether CR-1 also stimulates angiogenesis. Methods: We used human umbilical vein endothelial cells (HUVECs) to measure in vitro migration with fibronectin-coated Boyden chambers, invasion with Matrigel-coated Boyden chambers, proliferation with a tetrazolium salt, and differentiation with an in vitro Matrigel assay. We investigated new blood vessel formation in vivo by use of Matrigel-filled silicone cylinders implanted under the skin of nude mice and by use of a breast cancer xenograft model with CR-1-transfected or control Neo-transfected MCF-7 human breast cancer cells. We also used a blocking anti-CR-1 monoclonal antibody to investigate the role of CR-1 in angiogenesis in vivo and in vitro. All statistical tests were two-sided. Results: CR-1 stimulated HUVEC proliferation, migration, and invasion and induced HUVEC differentiation into vascular-like structures on Matrigel. In vivo, recombinant CR-1 protein induced microvessel formation in Matrigel-filled silicone cylinders, and microvessel formation was statistically significantly inhibited with a blocking anti-CR-1 monoclonal antibody (CR-1 and antibody = 127% of microvessel formation compared with that in untreated control cylinders and CR-1 alone = 259%; difference = 132%, 95% confidence interval [CI] = 123% to 140%; P<.001). Tumors formed by CR-1-transfected MCF-7 cells in the cleared mammary fat pad of nude mice had higher microvessel density than tumors formed by control Neo-transfected MCF-7 cells (CR-1-transfected cells = 4.66 vessels per field and Neo-transfected cells = 2.33 vessels per field; difference = 2.33 vessels per field, 95% CI = 1.2 to 2.8; P = .004). Conclusion: CR-1 appears to have an important role in the multistep process of angiogenesis.
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