Cripto-1: an oncofetal gene with many faces
Caterina Bianco1, Luigi Strizzi, Nicola Normanno
1Tumor Growth Factor Section, Mammary Biology & Tumorigenesis Laboratory Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
Human Cripto-1 (CR-1) is vital for embryonic development and acts as an oncogene in adult tissues. Its overexpression drives mammary gland tumors and is found in many human carcinomas, highlighting its dual role.
Area of Science:
- Developmental Biology
- Cancer Biology
- Molecular Oncology
Background:
- Human Cripto-1 (CR-1), an epidermal growth factor (EGF)-CFC family member, is crucial for early vertebrate development, acting as a co-receptor for Nodal.
- CR-1 is essential for mesoderm/endoderm formation and establishing embryonic axes.
- In adult tissues, CR-1 expression is low but increases during pregnancy and lactation.
Purpose of the Study:
- To investigate the dual role of CR-1 in embryogenesis and carcinogenesis.
- To explore CR-1's function in mammary gland development and cancer progression.
- To assess CR-1 expression in various human carcinomas.
Main Methods:
- Studied CR-1's role in embryogenesis using Nodal co-receptor function.
- Investigated CR-1's effects on mouse mammary epithelial cells in vitro (transformation, migration, invasion, EMT).
- Utilized transgenic mouse models with CR-1 overexpression under MMTV promoter.
- Analyzed CR-1 expression levels in human carcinoma tissues.
Main Results:
- CR-1 overexpression in mouse mammary epithelial cells induced transformation, hyperplasia, and enhanced migration/invasion.
- Transgenic mice overexpressing CR-1 developed mammary hyperplasias and papillary adenocarcinomas.
- High CR-1 levels (50-80%) were observed in multiple human carcinomas (breast, cervix, colon, etc.).
Conclusions:
- EGF-CFC proteins, including CR-1, function as both embryonic pattern formation genes and oncogenes.
- Aberrant CR-1 expression in adult tissues promotes cellular proliferation and transformation.
- CR-1 is implicated in the etiology and progression of various cancers.
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