Abstract
Germ cell tumors (GCTs) are malignant cancers that arise from embryonic precursors known as Primordial Germ Cells. GCTs occur in neonates, children, adolescents and young adults and can occur in the testis, the ovary or extragonadal sites. Because GCTs arise from pluripotent cells, the tumors can exhibit a wide range of different histologies. Current cisplatin-based combination therapies cures most patients, however at the cost of significant toxicity to normal tissues. While GWAS studies and genomic analysis of human GCTs have uncovered somatic mutations and loci that might confer tumor susceptibility, little is still known about the exact mechanisms that drive tumor development, and animal models that faithfully recapitulate all the different GCT subtypes are lacking. Here, we summarize current understanding of germline development in humans and zebrafish, describe the biology of human germ cell tumors, and discuss progress and prospects for zebrafish GCT models that may contribute to better understanding of human GCTs.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Houston DW, King ML (2000) Germ plasm and molecular determinants of germ cell fate. Curr Top Dev Biol 50:155–181
Kosaka K et al (2007) Spatiotemporal localization of germ plasm RNAs during zebrafish oogenesis. Mech Dev 124(4):279–289
Raz E (2003) Primordial germ-cell development: the zebrafish perspective. Nat Rev Genet 4(9):690–700
Saffman EE, Lasko P (1999) Germline development in vertebrates and invertebrates. Cell Mol Life Sci 55(8–9):1141–1163
Koprunner M et al (2001) A zebrafish nanos-related gene is essential for the development of primordial germ cells. Genes Dev 15(21):2877–2885
Lai F, King ML (2013) Repressive translational control in germ cells. Mol Reprod Dev 80(8):665–676
Braat AK et al (1999) Characterization of zebrafish primordial germ cells: morphology and early distribution of vasa RNA. Dev Dyn 216(2):153–167
Knaut H et al (2000) Zebrafish vasa RNA but not its protein is a component of the germ plasm and segregates asymmetrically before germline specification. J Cell Biol 149(4):875–888
Olsen LC, Aasland R, Fjose A (1997) A vasa-like gene in zebrafish identifies putative primordial germ cells. Mech Dev 66(1–2):95–105
Yoon C, Kawakami K, Hopkins N (1997) Zebrafish vasa homologue RNA is localized to the cleavage planes of 2- and 4-cell-stage embryos and is expressed in the primordial germ cells. Development 124(16):3157–3165
Gruidl ME et al (1996) Multiple potential germ-line helicases are components of the germ-line-specific P granules of Caenorhabditis elegans. Proc Natl Acad Sci U S A 93(24): 13837–13842
Hay B, Jan LY, Jan YN (1988) A protein component of Drosophila polar granules is encoded by vasa and has extensive sequence similarity to ATP-dependent helicases. Cell 55(4):577–587
Komiya T et al (1994) Isolation and characterization of a novel gene of the DEAD box protein family which is specifically expressed in germ cells of Xenopus laevis. Dev Biol 162(2):354–363
Liang L, Diehl-Jones W, Lasko P (1994) Localization of vasa protein to the Drosophila pole plasm is independent of its RNA-binding and helicase activities. Development 120(5): 1201–1211
Weidinger G et al (1999) Identification of tissues and patterning events required for distinct steps in early migration of zebrafish primordial germ cells. Development 126(23):5295–5307
Kierszenbaum AL, Tres LL (2001) Primordial germ cell-somatic cell partnership: a balancing cell signaling act. Mol Reprod Dev 60(3):277–280
Ying Y, Qi X, Zhao GQ (2002) Induction of primordial germ cells from pluripotent epiblast. Sci World J 2:801–810
de Sousa Lopes SM et al (2004) BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev 18(15):1838–1849
Lacham-Kaplan O (2004) In vivo and in vitro differentiation of male germ cells in the mouse. Reproduction 128(2):147–152
Saitou M, Barton SC, Surani MA (2002) A molecular programme for the specification of germ cell fate in mice. Nature 418(6895):293–300
Tanaka SS et al (2004) Regulation of expression of mouse interferon-induced transmembrane protein like gene-3, Ifitm3 (mil-1, fragilis), in germ cells. Dev Dyn 230(4):651–659
Lawson KA et al (1999) Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev 13(4):424–436
Ying Y, Qi X, Zhao GQ (2001) Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc Natl Acad Sci U S A 98(14):7858–7862
Ying Y, Zhao GQ (2001) Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse. Dev Biol 232(2):484–492
Lange UC et al (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1
Tanaka SS et al (2005) IFITM/Mil/fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion. Dev Cell 9(6):745–756
Ohinata Y et al (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436(7048):207–213
Scholer HR et al (1990) Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J 9(7):2185–2195
Hansis C, Grifo JA, Krey LC (2000) Oct-4 expression in inner cell mass and trophectoderm of human blastocysts. Mol Hum Reprod 6(11):999–1004
Pesce M, Scholer HR (2000) Oct-4: control of totipotency and germline determination. Mol Reprod Dev 55(4):452–457
Pesce M, Scholer HR (2001) Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19(4):271–278
Rajpert-De Meyts E et al (2004) Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads. Hum Reprod 19(6):1338–1344
Hatano SY et al (2005) Pluripotential competence of cells associated with Nanog activity. Mech Dev 122(1):67–79
Yamaguchi S et al (2005) Nanog expression in mouse germ cell development. Gene Expr Patterns 5(5):639–646
Payer B et al (2006) Generation of stella-GFP transgenic mice: a novel tool to study germ cell development. Genesis 44(2):75–83
Buitrago W, Roop DR (2007) Oct-4: the almighty POUripotent regulator? J Invest Dermatol 127(2):260–262
Molyneaux KA et al (2001) Time-lapse analysis of living mouse germ cell migration. Dev Biol 240(2):488–498
Molyneaux K, Wylie C (2004) Primordial germ cell migration. Int J Dev Biol 48(5–6):537–544
Wylie C (2000) Germ cells. Curr Opin Genet Dev 10(4):410–413
Kunwar PS, Siekhaus DE, Lehmann R (2006) In vivo migration: a germ cell perspective. Annu Rev Cell Dev Biol 22:237–265
Weidinger G et al (2002) Regulation of zebrafish primordial germ cell migration by attraction towards an intermediate target. Development 129(1):25–36
Doitsidou M et al (2002) Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111(5):647–659
Knaut H et al (2003) A zebrafish homologue of the chemokine receptor Cxcr4 is a germ-cell guidance receptor. Nature 421(6920):279–282
Boldajipour B, Raz E (2007) What is left behind–quality control in germ cell migration. Sci STKE 2007(383):pe16
Anderson R et al (2000) The onset of germ cell migration in the mouse embryo. Mech Dev 91(1–2):61–68
Richardson BE, Lehmann R (2010) Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nat Rev Mol Cell Biol 11(1):37–49
Gu Y et al (2009) Steel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration. Development 136(8):1295–1303
Runyan C et al (2006) Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development 133(24):4861–4869
McCoshen JA, McCallion DJ (1975) A study of the primordial germ cells during their migratory phase in Steel mutant mice. Experientia 31(5):589–590
Buehr M et al (1993) Proliferation and migration of primordial germ cells in We/We mouse embryos. Dev Dyn 198(3):182–189
Takahashi H (1977) Juvenile hermaphroditism in the zebrafish, Brachydanio rerio. Bull Fac Fish Hokkaid Univ 28:57–65
Uchida D et al (2002) Oocyte apoptosis during the transition from ovary-like tissue to testes during sex differentiation of juvenile zebrafish. J Exp Biol 205(Pt 6):711–718
Rodriguez-Mari A et al (2005) Characterization and expression pattern of zebrafish Anti-Mullerian hormone (Amh) relative to sox9a, sox9b, and cyp19a1a, during gonad development. Gene Expr Patterns 5(5):655–667
von Hofsten J, Larsson A, Olsson PE (2005) Novel steroidogenic factor-1 homolog (ff1d) is coexpressed with anti-Mullerian hormone (AMH) in zebrafish. Dev Dyn 233(2):595–604
Wang XG, Orban L (2007) Anti-Mullerian hormone and 11 beta-hydroxylase show reciprocal expression to that of aromatase in the transforming gonad of zebrafish males. Dev Dyn 236(5):1329–1338
Sun D et al (2013) Sox9-related signaling controls zebrafish juvenile ovary-testis transformation. Cell Death Dis 4, e930
Siegfried KR, Nusslein-Volhard C (2008) Germ line control of female sex determination in zebrafish. Dev Biol 324(2):277–287
Dranow DB, Tucker RP, Draper BW (2013) Germ cells are required to maintain a stable sexual phenotype in adult zebrafish. Dev Biol 376(1):43–50
Weidinger G et al (2003) dead end, a novel vertebrate germ plasm component, is required for zebrafish primordial germ cell migration and survival. Curr Biol 13(16):1429–1434
Slanchev K et al (2005) Development without germ cells: the role of the germ line in zebrafish sex differentiation. Proc Natl Acad Sci U S A 102(11):4074–4079
Tzung KW et al (2015) Early depletion of primordial germ cells in zebrafish promotes testis formation. Stem Cell Rep 4(1):61–73
Houwing S et al (2007) A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell 129(1):69–82
Gill ME et al (2011) Licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells. Proc Natl Acad Sci U S A 108(18):7443–7448
Lin Y et al (2008) Germ cell-intrinsic and -extrinsic factors govern meiotic initiation in mouse embryos. Science 322(5908):1685–1687
Hajkova P et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117(1–2):15–23
Bullejos M, Koopman P (2001) Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn 221(2):201–205
Hacker A et al (1995) Expression of Sry, the mouse sex determining gene. Development 121(6):1603–1614
Jeske YW et al (1995) Expression of a linear Sry transcript in the mouse genital ridge. Nat Genet 10(4):480–482
Houston CS et al (1983) The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al in 1971. Am J Med Genet 15(1):3–28
Barrionuevo F et al (2006) Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol Reprod 74(1):195–201
Chaboissier MC et al (2004) Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development 131(9):1891–1901
Anderson EL et al (2008) Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A 105(39):14976–14980
Koubova J et al (2006) Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A 103(8):2474–2479
Bowles J et al (2006) Retinoid signaling determines germ cell fate in mice. Science 312(5773):596–600
Kim S, Bardwell VJ, Zarkower D (2007) Cell type-autonomous and non-autonomous requirements for Dmrt1 in postnatal testis differentiation. Dev Biol 307(2):314–327
Raymond CS et al (2000) Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev 14(20):2587–2595
Matson CK et al (2011) DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476(7358):101–104
Lindeman RE et al (2015) Sexual cell-fate reprogramming in the ovary by DMRT1. Curr Biol 25(6):764–771
Frazier AL, Amatruda JF (2009) Germ cell tumors. In: Fisher DE, Nathan D, Look AT (eds) Nathan and Oski’s textbook of pediatric hematology-oncology. Elsevier, London
Oosterhuis JW, Looijenga LH (2005) Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer 5(3):210–222
Poynter JN, Amatruda JF, Ross JA (2010) Trends in incidence and survival of pediatric and adolescent patients with germ cell tumors in the United States, 1975 to 2006. Cancer 116(20):4882–4891
Trabert B et al (2015) International patterns and trends in testicular cancer incidence, overall and by histologic subtype, 1973–2007. Andrology 3(1):4–12
Jacobsen R et al (2006) Trends in testicular cancer incidence in the Nordic countries, focusing on the recent decrease in Denmark. Int J Androl 29(1):199–204
Ross JA et al (1999) Genomic imprinting of H19 and insulin-like growth factor-2 in pediatric germ cell tumors. Cancer 85(6):1389–1394
Schneider DT et al (2001) Multipoint imprinting analysis indicates a common precursor cell for gonadal and nongonadal pediatric germ cell tumors. Cancer Res 61(19):7268–7276
Palmer RD et al (2008) Pediatric malignant germ cell tumors show characteristic transcriptome profiles. Cancer Res 68(11):4239–4247
Williams SD et al (1987) Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316(23):1435–1440
Einhorn LH, Donohue JP (1977) Improved chemotherapy in disseminated testicular cancer. J Urol 117(1):65–69
Einhorn LH (2002) Chemotherapeutic and surgical strategies for germ cell tumors. Chest Surg Clin N Am 12(4):695–706
Osanto S et al (1992) Long-term effects of chemotherapy in patients with testicular cancer. J Clin Oncol Off J Am Soc Clin Oncol 10(4):574–579
Bokemeyer C et al (1996) Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol Off J Am Soc Clin Oncol 14(11):2923–2932
Bosl GJ et al (1986) Increased plasma renin and aldosterone in patients treated with cisplatin-based chemotherapy for metastatic germ-cell tumors. J Clin Oncol Off J Am Soc Clin Oncol 4(11):1684–1689
Hansen SW et al (1988) Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol Off J Am Soc Clin Oncol 6(11):1728–1731
Hansen PV, Hansen SW (1993) Gonadal function in men with testicular germ cell cancer: the influence of cisplatin-based chemotherapy. Eur Urol 23(1):153–156
Hansen SW, Berthelsen JG, von der Maase H (1990) Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance. J Clin Oncol Off J Am Soc Clin Oncol 8(10):1695–1698
Huddart RA et al (2003) Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol Off J Am Soc Clin Oncol 21(8):1513–1523
Strumberg D et al (2002) Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO 13(2):229–236
Berger CC et al (1996) Endocrinological late effects after chemotherapy for testicular cancer. Br J Cancer 73(9):1108–1114
Bissett D et al (1990) Long-term sequelae of treatment for testicular germ cell tumours. Br J Cancer 62(4):655–659
Gietema JA et al (1992) Long-term follow-up of cardiovascular risk factors in patients given chemotherapy for disseminated nonseminomatous testicular cancer. Ann Intern Med 116(9):709–715
Teutsch C, Lipton A, Harvey HA (1977) Raynaud’s phenomenon as a side effect of chemotherapy with vinblastine and bleomycin for testicular carcinoma. Cancer Treat Rep 61(5):925–926
Vogelzang NJ et al (1981) Raynaud's phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med 95(3):288–292
Boyer M et al (1990) Lack of late toxicity in patients treated with cisplatin-containing combination chemotherapy for metastatic testicular cancer. J Clin Oncol Off J Am Soc Clin Oncol 8(1):21–26
Siviero-Miachon AA, Spinola-Castro AM, Guerra-Junior G (2009) Adiposity in childhood cancer survivors: insights into obesity physiopathology. Arq Bras Endocrinol Metabol 53(2):190–200
Siviero-Miachon AA, Spinola-Castro AM, Guerra-Junior G (2008) Detection of metabolic syndrome features among childhood cancer survivors: a target to prevent disease. Vasc Health Risk Manag 4(4):825–836
Glendenning JL et al (2010) Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer. Cancer 116(10):2322–2331
Travis LB et al (1997) Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89(19):1429–1439
Travis LB et al (2005) Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 97(18):1354–1365
van Echten J et al (1995) No recurrent structural abnormalities apart from i(12p) in primary germ cell tumors of the adult testis. Genes Chromosomes Cancer 14(2):133–144
Tian Q et al (1999) Activating c-kit gene mutations in human germ cell tumors. Am J Pathol 154(6):1643–1647
Looijenga LH et al (2003) Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors. Cancer Res 63(22):7674–7678
Kemmer K et al (2004) KIT mutations are common in testicular seminomas. Am J Pathol 164(1):305–313
Hoei-Hansen CE et al (2007) Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol Cancer 6:12
Coffey J et al (2008) Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes Chromosomes Cancer 47(1):34–42
Hersmus R et al (2012) Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas. PLoS One 7(8), e43952
Ganguly S et al (1990) Detection of preferential NRAS mutations in human male germ cell tumors by the polymerase chain reaction. Genes Chromosomes Cancer 1(3):228–232
Mulder MP, et al. (1991) Frequent occurrence of activated ras oncogenes in seminomas but not in nonseminomatous germ cell tumors. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 123, pp 125–31
Moul JW, Theune SM, Chang EH (1992) Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization. Genes Chromosomes Cancer 5(2):109–118
Olie RA et al (1995) N- and KRAS mutations in primary testicular germ cell tumors: incidence and possible biological implications. Genes Chromosomes Cancer 12(2):110–116
Wang L et al (2014) Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511(7508):241–245
Honecker F et al (2009) Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J Clin Oncol Off J Am Soc Clin Oncol 27(13):2129–2136
Brabrand S et al (2015) Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages. Neoplasia 17(2):167–174
Litchfield K et al (2015) Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat Commun 6:5973
Kanetsky PA et al (2009) Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet 41(7):811–815
Rapley EA et al (2009) A genome-wide association study of testicular germ cell tumor. Nat Genet 41(7):807–810
Turnbull C et al (2010) Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet 42(7):604–607
Kratz CP et al (2011) Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour. J Med Genet 48(7):473–476
Lessel D et al (2012) Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population. Carcinogenesis 33(8):1548–1552
Karlsson R et al (2013) Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4. Hum Mol Genet 22(16):3373–3380
Chung CC et al (2013) Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 45(6):680–685
Ruark E et al (2013) Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet 45(6):686–689
Stevens LC (1970) Experimental production of testicular teratomas in mice of strains 129, A/He, and their F1 hybrids. J Natl Cancer Inst 44(4):923–929
Youngren KK et al (2005) The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435(7040):360–364
Krentz AD et al (2013) Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line. Dev Biol 377(1):67–78
Krentz AD et al (2009) The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A 106(52):22323–22328
Morinaga C et al (2007) The hotei mutation of medaka in the anti-Mullerian hormone receptor causes the dysregulation of germ cell and sexual development. Proc Natl Acad Sci U S A 104(23):9691–9696
Neumann JC et al (2009) Identification of a heritable model of testicular germ cell tumor in the zebrafish. Zebrafish 6(4):319–327
Neumann JC et al (2011) Mutation in the type IB bone morphogenetic protein receptor Alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. Proc Natl Acad Sci U S A 108(32):13153–13158
Fustino N et al (2011) Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours. Int J Androl 34(4 Pt 2):e218–e233
Gill JA et al (2010) Enforced expression of Simian virus 40 large T-antigen leads to testicular germ cell tumors in zebrafish. Zebrafish 7(4):333–341
van Rooijen E et al (2008) LRRC50, a conserved ciliary protein implicated in polycystic kidney disease. J Am Soc Nephrol 19(6):1128–1138
Basten SG et al (2013) Mutations in LRRC50 predispose zebrafish and humans to seminomas. PLoS Genet 9(4), e1003384
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Sanchez, A., Amatruda, J.F. (2016). Zebrafish Germ Cell Tumors. In: Langenau, D. (eds) Cancer and Zebrafish. Advances in Experimental Medicine and Biology, vol 916. Springer, Cham. https://doi.org/10.1007/978-3-319-30654-4_21
Download citation
DOI: https://doi.org/10.1007/978-3-319-30654-4_21
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-30652-0
Online ISBN: 978-3-319-30654-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)