Cripto-1: an oncofetal gene with many faces.
Human Cripto-1 (CR-1), a member of the epidermal growth factor (EGF)-CFC family, has been implicated in embryogenesis and in carcinogenesis. During early vertebrate development, CR-1 functions as a co-receptor for Nodal, a transforming growth factor beta (TGFbeta) family member and is essential for mesoderm and endoderm formation and anterior-posterior and left-right axis establishment. In adult tissues, CR-1 is expressed at a low level in all stages of mammary gland development and expression increases during pregnancy and lactation. Overexpression of CR-1 in mouse mammary epithelial cells leads to their transformation in vitro and, when injected into mammary glands, produces ductal hyperplasias. CR-1 can also enhance migration, invasion, branching morphogenesis and epithelial to mesenchymal transition (EMT) of several mouse mammary epithelial cell lines. Furthermore, transgenic mouse studies have shown that overexpression of a human CR-1 transgene in the mammary gland under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter results in mammary hyperplasias and papillary adenocarcinomas. Finally, CR-1 is expressed at high levels in approximately 50 to 80% of different types of human carcinomas, including breast, cervix, colon, stomach, pancreas, lung, ovary, and testis. In conclusion, EGF-CFC proteins play dual roles as embryonic pattern formation genes and as oncogenes. While during embryogenesis EGF-CFC proteins perform specific and regulatory functions related to cell and tissue patterning, inappropriate expression of these molecules in adult tissues can lead to cellular proliferation and transformation and therefore may be important in the etiology and/or progression of cancer.
Bianco
Caterina
C
Tumor Growth Factor Section, Mammary Biology & Tumorigenesis Laboratory Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Strizzi
Luigi
L
Normanno
Nicola
N
Khan
Nadia
N
Salomon
David S
DS
D004815:Epidermal Growth Factor / Q000502:physiology*; D058851:GPI-Linked Proteins; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism*
D058851:GPI-Linked Proteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; D004815:Epidermal Growth Factor