The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep ), mouse cripto (Cr-1) and cryptic and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the embryonic anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right asymmetry. In the mouse cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of a human CR-1 transgene in the mouse mammary gland using an MMTV orWAP promoter results in the appearance of ductal hyperplasias in the mammary gland and papillary amd histologically mixed subtypes of adenocarcinomas in multiparous female mice. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mouse mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in beta-catenin adherens function and an increase in vimentin expression. Expression of CR-1 is increased several-fold in human colon, gastric, pancreatic, cervical, ovarian and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase in cripto-1 expression can first be detected in premalignant lesions in some of these tissues such as in the breast ( hyperplasias and DCIS ), colon ( adenomas ) and stomach ( intestinal metaplasias ). We have recently identied the Activin ALK4 type 1 receptor as a co-receptor for CR-1 which presents Nodal to ALK4 and thereby can stimulate Smad-2 phosphorylation and transcription through an SBE-luciferase reporter construct.In addition, CR-1 can function through a Nodal and ALK4-independent signaling pathway and activate MAPK, PI-3 kinase and Akt by binding to the GPI-linked heparan sulphate-containing proteoglycan, glypican-1 which can then activate c-src. Activation of MAPK, PI-3 kinase, GSK-3beta and Akt in mammary epithelial cells by CR-1 are required for the ability of CR-1 to stimulate epithelial to mesenchymal transition, cell migration and cell invasion which is invovled in metastasis and angiogenesis. The invasive effects of CR-1 can be antagonized by the neural guidance protein Netrin-1 through the UNC5b receptor in mammary epithelial cells. CR-1 is also invovled in maintaing embryonic stem cell pluripotentiality and may perform a similar function in adult stem cells in the mammary gland and colon. CR-1 can be found at significant levels in the plasma of breast and colon cancer paptients and may therefore represent a novel marker to detect the onset or progression of these diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Klauzinska, Malgorzata; Castro, Nadia P; Rangel, Maria Cristina et al. (2014) The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Semin Cancer Biol 29:51-8
Bianco, Caterina; Rangel, Maria Cristina; Castro, Nadia P et al. (2010) Role of Cripto-1 in stem cell maintenance and malignant progression. Am J Pathol 177:532-40
Bianco, Caterina; Salomon, David S (2010) Targeting the embryonic gene Cripto-1 in cancer and beyond. Expert Opin Ther Pat 20:1739-49
Watanabe, Kazuhide; Meyer, Matthew J; Strizzi, Luigi et al. (2010) Cripto-1 is a cell surface marker for a tumorigenic, undifferentiated subpopulation in human embryonal carcinoma cells. Stem Cells 28:1303-14
Watanabe, Kazuhide; Salomon, David S (2010) Intercellular transfer regulation of the paracrine activity of GPI-anchored Cripto-1 as a Nodal co-receptor. Biochem Biophys Res Commun 403:108-13
de Castro, Nadia Pereira; Rangel, Maria Cristina; Nagaoka, Tadahiro et al. (2010) Cripto-1: an embryonic gene that promotes tumorigenesis. Future Oncol 6:1127-42
di Bari, M G; Ginsburg, E; Plant, J et al. (2009) Msx2 induces epithelial-mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto-1. J Cell Physiol 219:659-66
Mancino, Mario; Esposito, Claudia; Watanabe, Kazuhide et al. (2009) Neuronal guidance protein Netrin-1 induces differentiation in human embryonal carcinoma cells. Cancer Res 69:1717-21
Strizzi, Luigi; Abbott, Daniel E; Salomon, David S et al. (2008) Potential for cripto-1 in defining stem cell-like characteristics in human malignant melanoma. Cell Cycle 7:1931-5
Hirota, Morihisa; Watanabe, Kazuhide; Hamada, Shin et al. (2008) Smad2 functions as a co-activator of canonical Wnt/beta-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300. Cell Signal 20:1632-41

Showing the most recent 10 out of 16 publications