Role of Human Cripto-1 in Tumor Angiogenesis

Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 02/2005; 97(2):132-41. DOI: 10.1093/jnci/dji011
Source: PubMed


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.
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.
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).
CR-1 appears to have an important role in the multistep process of angiogenesis.

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Available from: Morihisa Hirota
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    • "We believe that our findings could underscore the specific roles of trophoblast cells at the maternal-fetal interface. CRIPTO-1 signaling within tumor cells has previously been demonstrated to modulate cellular growth, survival, and invasion in several human cancers [30, 32, 33], and this could be especially relevant to the biology of trophoblast cells. In particular, extravillous cytotrophoblast cells are nonproliferative and exhibit a low apoptotic index during the late stages of gestation, which suggests the hypothesis that CRIPTO-1 contributes to trophoblast invasiveness or cell survival mechanisms [34]. "
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