New Insights into Germ Cell Tumor Formation

Abstract

Recent years have witnessed a number of new findings with significant implications for our understanding of the development of germ cell tumors. This communication reviews some of these recent insights with an emphasis on mechanisms that may convert a germ cell into a tumor cell. Three aspects are discussed in this review: (1) the early origin of germ cell tumors from primordial germ cells through an aberrant mitosis-to-meiosis switch; (2) errors during meiosis, which promote tumorigenic transformation of germ cells; and (3) the role of small RNAs such as oncomirs (miRNAs) and oncopirs (piRNAs) in germ cell tumor formation. Since much has been learned using a variety of organismal models, data obtained in experiments with mice, nematodes, fruit flies, and human data will be considered. Only exemplary references are included.

Notch - microRNAs - meiotic genes - germ cell tumors

References

• 1 Raz E. Germ cells: sex and repression in mice.  Curr Biol. 2005;  15 R600-R603
• 2 Pepling ME. From primordial germ cell to primordial follicle: mammalian female germ cell development.  Genesis. 2006;  44 622-632
• 3 Aflatoonian B, Moore H. Germ cells from mouse and human embryonic stem cells.  Reproduction. 2006;  132 699-707
• 4 Lacham-Kaplan O. In vivo and in vitro differentiation of male germ cells in the mouse.  Reproduction. 2004;  128 147-152
• 5 Zhao G-Q, Garbers DL. Male germ cell specification and differentiation.  Developmental Cell. 2002;  2 537-547
• 6 Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues.  Mod Pathol. 2005;  18 ((Suppl 2)) S61-S79
• 7 Almstrup K, Sonne SB, Hoei-Hansen CE. et al . From embryonic stem cells to testicular germ cell cancer - should we be concerned?.  Int J Androl. 2006;  29 211-218
• 8 Berry LW, Westlund B, Schedl T. Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors.  Development. 1997;  124 925-936
• 9 Adamah DJ, Gokhale PJ, Eastwood DJ. et al . Dysfunction of the mitotic:meiotic switch as a potential cause of neoplastic conversion of primordial germ cells.  Int J Androl. 2006;  29 219-227
• 10 Rapley EA, Crockford GP, Easton DF, Stratton MR, Bishop DT. Localisation of susceptibility genes for familial testicular germ cell tumour.  APMIS. 2003;  111 128-135
• 11 Crockford GP, Linger R, Hockley S. et al . Genome-wide linkage screen for testicular germ cell tumour susceptibility loci.  Hum Mol Genet. 2006;  15 443-451
• 12 Hayashi T, Yamada T, Kageyama Y, Kihara K. Expression failure of the notch signaling system is associated with the pathogenesis of testicular germ cell tumor.  Tumour Biol. 2004;  25 99-105
• 13 Hansen D, Schedl T, Gerald PS. The regulatory network controlling the proliferation-meiotic entry decision in the Caenorhabditis elegans germ line. In: Current Topics in Developmental Biology. New York: Academic Press 2006: 185
• 14 Chung SS, Wolgemuth DJ. Role of retinoid signaling in the regulation of spermatogenesis.  Cytogenet Genome Res. 2004;  105 189-202
• 15 Bowles J, Koopman P. Retinoic acid, meiosis and germ cell fate in mammals.  Development. 2007;  134 3401-3411
• 16 Vernet N, Dennefeld C, Rochette-Egly C. et al . Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis.  Endocrinology. 2006;  147 96-110
• 17 Lufkin T, Lohnes D, Mark M. et al . High postnatal lethality and testis degeneration in retinoic acid receptor {alpha} mutant mice.  Proc Natl Acad Sci USA. 1993;  90 7225-7229
• 18 Oulad-Abdelghani M, Bouillet P, Decimo D. et al . Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene.  J Cell Biol. 1996;  135 469-477
• 19 Subramaniam K, Seydoux G. Dedifferentiation of primary spermatocytes into germ cell tumors in C. elegans lacking the pumilio-like protein PUF-8.  Curr Biol. 2003;  13 134-139
• 20 Bachorik JL, Kimble J. Redundant control of the Caenorhabditis elegans sperm/oocyte switch by PUF-8 and FBF-1, two distinct PUF RNA-binding proteins.  Proc Natl Acad Sci USA. 2005;  102 10893-10897
• 21 Eckmann CR, Kraemer B, Wickens M, Kimble J. GLD-3, a bicaudal-C homolog that inhibits FBF to control germline sex determination in C. elegans.  Dev Cell. 2002;  3 697-710
• 22 Costa Y, Cooke H. Dissecting the mammalian synaptonemal complex using targeted mutations.  Chromosome Res. 2007;  15 579-589
• 23 Boer E de, Heyting C. The diverse roles of transverse filaments of synaptonemal complexes in meiosis.  Chromosoma. 2006;  115 220-234
• 24 Revenkova E, Eijpe M, Heyting C. et al . Cohesin SMC1 beta is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination.  Nat Cell Biol. 2004;  6 555-562
• 25 Hodges CA, Revenkova E, Jessberger R, Hassold TJ, Hunt PA. SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction.  Nat Genet. 2005;  37 1351-1355
• 26 Kalejs M, Ivanov A, Plakhins G. et al . Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe.  BMC Cancer. 2006;  6 6
• 27 Looijenga LHJ, Hersmus R, Gillis AJM. et al . Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene.  Cancer Res. 2006;  66 290-302
• 28 Thomson T, Lasko P. Tudor and its domains: germ cell formation from a Tudor perspective.  Cell Res. 2005;  15 281-291
• 29 Ponting CP. Tudor domains in proteins that interact with RNA.  Trends Biochem Sci. 1997;  22 51-52
• 30 Maurer-Stroh S, Dickens NJ, Hughes-Davies L. et al . The Tudor domain “Royal Family’: Tudor, plant Agenet, Chromo, PWWP and MBT domains.  Trends Biochem Sci. 2003;  28 69-74
• 31 Huyen Y, Zgheib O, DiTullio Jr RA. et al . Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks.  Nature. 2004;  432 406-411
• 32 Hosokawa M, Shoji M, Kitamura K. et al . Tudor-related proteins TDRD1/MTR-1, TDRD6 and TDRD7/TRAP: domain composition, intracellular localization, and function in male germ cells in mice.  Dev Biol. 2007;  301 38-52
• 33 Scanlan MJ, Welt S, Gordon CM. et al . Cancer-related serological recognition of human colon cancer: identification of potential diagnostic and immunotherapeutic targets.  Cancer Res. 2002;  62 4041-4047
• 34 Kotaja N, Bhattacharyya SN, Jaskiewicz L. et al . The chromatoid body of male germ cells: similarity with processing bodies and presence of Dicer and microRNA pathway components.  Proc Natl Acad Sci USA. 2006;  103 2647-2652
• 35 Calin GA, Croce CM. MicroRNA signatures in human cancers.  Nat Rev Cancer. 2006;  6 857-866
• 36 Esquela-Kerscher A, Slack FJ. Oncomirs [mdash] microRNAs with a role in cancer.  Nat Rev Cancer. 2006;  6 259-269
• 37 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.  Cell. 1993;  75 843-854
• 38 Peters L, Meister G. Argonaute proteins: mediators of RNA silencing.  Mol Cell. 2007;  26 611-623
• 39 Lin H. piRNAs in the Germ Line.  Science. 2007;  316 397
• 40 Klattenhoff C, Theurkauf W. Biogenesis and germline functions of piRNAs.  Development. 2008;  135 3-9
• 41 Carmell MA, Girard A, Kant HJ van de. et al . MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline.  Dev Cell. 2007;  12 503-514
• 42 Kuramochi-Miyagawa S, Kimura T, Ijiri TW. et al . Mili, a mammalian member of piwi family gene, is essential for spermatogenesis.  Development. 2004;  131 839-849
• 43 Deng W, Lin H. miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis.  Dev Cell. 2002;  2 819-830
• 44 Qiao D, Zeeman AM, Deng W, Looijenga LH, Lin H. Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas.  Oncogene. 2002;  21 3988-3999
• 45 Taubert H, Greither T, Kaushal D. et al . Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma.  Oncogene. 2007;  26 1098-1100
• 46 Almeida MQ, Latronico AC. The molecular pathogenesis of childhood adrenocortical tumors.  Horm Metab Res. 2007;  39 461-466
• 47 Voorhoeve PM, Sage C le, Schrier M. et al . A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.  Cell. 2006;  124 1169-1181
• 48 Krutzfeldt J, Rajewsky N, Braich R. et al . Silencing of microRNAs in vivo with “antagomirs”.  Nature. 2005;  438 685-689
• 49 Orom UA, Kauppinen S, Lund AH. LNA-modified oligonucleotides mediate specific inhibition of microRNA function.  Gene. 2006;  372 137-141

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