title: Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors.
abstract: Type II germ cell tumors arise after puberty from a germ cell that was incorrectly programmed during fetal life. Failure of testicular germ cells to properly differentiate can lead to the formation of germ cell neoplasia in situ of the testis; this precursor cell invariably gives rise to germ cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal germ cell development and is ectopically expressed in non-seminomas that arise from germ cell neoplasia in situ, suggesting that its aberrant expression may underlie germ cell dysregulation and hence germ cell cancer. Here we investigated methylation of the Cripto promoter in mouse germ cells and human germ cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal germ cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in germ cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of germ cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with germ cell neoplasia in situ cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during germ cell cancer management.
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Cassy M
authors.initials: CM
authors.lastname: Spiller
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Center, Rotterdam, 3015, The Netherlands.
authors.forename: Ad J M
authors.initials: AJ
authors.lastname: Gillis
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Departement de Biologie, Ecole Normale Superieure de Cachan, Cachan, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Burnet
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Center, Rotterdam, 3015, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Stoop
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Josephine
authors.initials: J
authors.lastname: Bowles
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Center, Rotterdam, 3015, The Netherlands. Electronic address: l.looijenga@erasmusmc.nl.
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000818:Animals; D018236:Carcinoma, Embryonal / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics; D044127:Epigenesis, Genetic; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D013736:Testicular Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D004815:Epidermal Growth Factor
keywords: Cripto; Diagnostic; Methylation; Testicular germ cell cancer