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- Title
Role of Human Cripto-1 in Tumor Angiogenesis.
- Authors
Bianco, Caterina; Strizzi, Luigi; Ebert, Andreas; Chang, Cindy; Rehman, Aasia; Normano, Nicola; Guedez, Liliana; Salloum, Rita; Ginsburg, Erika; Youping Sun; Khan, Nadia; Hirota, Morihisa; Wallace -Jones, Brenda; Wechselberger, Christian; Vonderhaar, Barbara K.; Tosato, Giovanna; Stetler-Stevenson, William G.; Sanicola, Michele; Salomon, David S.
- Abstract
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-I 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 [I] = 123% to 140%; P<.001). Tumors formed by CR-1-transfected MCF-7 cells in the cleared mammary tat 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.
- Subjects
CELL transformation; NEOVASCULARIZATION; EPITHELIAL cells; CELL lines; TUMOR growth; CARCINOGENESIS; BREAST cancer
- Publication
JNCI: Journal of the National Cancer Institute, 2005, Vol 97, Issue 2, p132
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/dji011