Decrypting the role of Cripto in tumor growth

The cell-surface associated molecule Cripto is overexpressed in a wide range of epithelial cancers, yet little is known about the potential mechanisms by which Cripto expression might enhance tumor growth. A new study by Michele Sanicola and colleagues at Biogen Inc. in the August 15 issue of the Journal of Clinical Investigation reveals that binding of Cripto to the TGFbeta ligand Activin B can block Activin B-mediated suppression of cell proliferation. Furthermore, this study also demonstrates that antibody blockade of Cripto function may prove useful in the inhibition of tumorigenesis.

Cripto was first discovered 15 years ago and was suitably named for its mysterious lack of relationship to known proteins and signaling pathways. Since then Cripto has been shown to play an essential role in embryonic development. It has also been shown to act as a coreceptor for Nodal, a member of the TGFbeta family. Cripto appears to recruit Nodal to the Activin receptor complex to mediate transcriptional responses. However there remains no explanation for the widespread overexpression of Cripto in human epithelial cancers. In attempting to determine whether Cripto activity is essential for tumor growth and/or maintenance, and what role, if any, that Nodal plays in this interaction, Sanicola and colleagues have revealed that Activin signaling can be blocked by Cripto overexpression in many cell types. They go on demonstrate that monoclonal antibodies specific for Cripto are capable of inhibiting tumor cell growth in models of testicular and colon cancer, and that this correlates with the ability to inhibit Activin signaling.

The study suggests that Cripto overexpression may play an early role in cancer progression through the inhibition of the tumor supressing effects of Activin. In an accompanying commentary, Michael Shen from the University of Medicine and Dentistry in Piscataway, New Jersey, discusses some of the proposed mechanisms of this inhibition. “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 to decode the molecular mechanisms of Cripto function, the work now provides a glimmer of understanding as to the functions of this enigmatic protein in tumorigenesis”.