Cripto: a tumor growth factor and more.
Cripto, a growth factor with an EGF-like domain, and the first member of the EGF-CFC family of genes to be sequenced and characterized, contributes to deregulated growth of cancer cells. A role for Cripto in tumor development has been described in the human and the mouse. Members of the EGF-CFC family are found only in vertebrates: CFC proteins in zebrafish, Xenopus, chick, mouse and human have been characterized and indicate some common general functions in development. Cripto expression was first found in human and mouse embryonal carcinoma cells and male teratocarcinomas, and was demonstrated to be over-expressed in breast, cervical, ovarian, gastric, lung, colon, and pancreatic carcinomas in contrast to normal tissues where Cripto expression was invariably low or absent. Cripto may play a role in mammary tumorigenesis, since in vitro, Cripto induces mammary cell proliferation, reduces apoptosis, increases cell migration, and inhibits milk protein expression. This prediction is strengthened by observations of Cripto expression in 80% of human and mouse mammary tumors. At least three important roles for Cripto in development have created considerable interest, and each activity may be distinct in its mechanism of receptor signaling. One role is in the patterning of the anterior-posterior axis of the early embryo, a second is a crucial role in the development of the heart, and a third is in potentiating branching morphogenesis and modulating differentiation in the developing mammary gland. Whether these properties are functions of different forms of Cripto, different Cripto receptors or the distinct domains within this 15-38 kDa glycoprotein are examined here, but much remains to be revealed about this evolutionarily conserved gene product. Since all Cripto receptors have not yet been determined with certainty, future possible uses as therapeutic targets remain to be developed. Cripto is released or shed from expressing cells and may serve as an accessible marker gene in the early to mid-progressive stages of breast and other cancers. Meanwhile some speculations on possible receptor complexes for Cripto signaling in mammary cells are offered here as a spur to further discoveries.
Adamson
Eileen D
ED
La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA. eadamson@burnham.org
Minchiotti
Gabriella
G
Salomon
David S
DS
D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D004815:Epidermal Growth Factor; D005346:Fibroblast Growth Factors / Q000502:physiology; D058851:GPI-Linked Proteins; D015870:Gene Expression; D006133:Growth Substances / Q000502:physiology; D018398:Homeodomain Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D029867:Xenopus Proteins; D029961:Zebrafish Proteins
D058851:GPI-Linked Proteins; D006133:Growth Substances; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D014157:Transcription Factors; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C110484:tdgf1 protein, zebrafish; C096788:tdgf1.3 protein, Xenopus; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor