Cripto molecule on cells inhibits tumor-suppressant Activin B

Overexpression of the cell surface-associated molecule Cripto inhibits the tumor suppressing effects of Activin B, according to a report in the August issue of The Journal of Clinical Investigation.

Cripto, which belongs to the EGF-CFC family of growth factors, is overexpressed in many human solid tumors and exhibits properties of an oncogene, the authors explain, but how it promotes cell transformation is unclear. Dr. Michele Sanicola from Biogen Inc. in Cambridge, Massachusetts and colleagues studied Cripto’s role in modulating signaling by the transforming growth factor (TGF)-beta family of ligands in cancer cells. They also investigated whether functional blockade of Cripto could inhibit tumor cell growth in xenograft models of testicular and colon cancer. Cripto-dependent signaling by Nodal (a TGF-beta ligand) was inhibited by antibodies to EGF and the CFC domains of Cripto, the authors report. After demonstrating that Cripto disrupts Activin-induced growth suppression of T47D breast cancer cells by preventing Activin B signaling, the researchers went on to show that only antibody specific to the CFC domain of Cripto was able to restore the growth suppression of Activin B. In animal models of human testicular and colon carcinoma, the investigators confirmed that anti-CFC antibody, which targets both the Nodal and Activin B pathways, is more effective in inhibiting tumor growth than anti-EGF antibody, which targets only the Nodal pathway. “Both Nodal and Activin B are available to the tumor in vivo,” the researchers note, “so we cannot at this time distinguish between the relative contributions of these ligands to tumor growth.” They conclude, “The ability of Cripto antibodies to inhibit tumor growth defines Cripto as an important oncogene and blocking of anti-CFC Cripto monoclonal antibodies as an important new therapeutic approach for treatment of human solid tumors.” In a related commentary, Dr. Michael M. Shen from Robert Wood Johnson Medical School in Piscataway, New Jersey writes: “The exciting finding that antibody blockade of Cripto has a strong effect in xenograft models indicates that Cripto functions in a central pathway for cell proliferation and/or maintenance of the transformed state.”While much more analysis is needed, he writes, this research “provides a glimmer of understanding as to the functions of this enigmatic protein in tumorigenesis.” (Source: J Clin Invest 2003;112:575-587,500-502: Reuters Health: August 29, 2003: Oncolink)