Role of human cripto-1 in tumor angiogenesis

Caterina Bianco, Luigi Strizzi, Andreas Ebert, Cindy Chang, Aasia Rehman, Nicola Normanno, Liliana Guedez, Rita Salloum, Erika Ginsburg, Youping Sun, Nadia Khan, Morihisa Hirota, Brenda Wallace-Jones, Christian Wechselberger, Barbara K. Vonderhaar, Giovanna Tosato, William G. Stetler-Stevenson, Michele Sanicola, David S. Salomon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)132-141
Number of pages10
JournalJournal of the National Cancer Institute
Issue number2
StatePublished - Jan 19 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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