The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets

Skye C McIver, Shaun D Roman, Brett Nixon, Kate L Loveland, Eileen A McLaughlin
2013 F1000Research  
No Comments Yet 2 1 REVIEW The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets [v1; ref status: indexed, Abstract Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including hypospadias, undescended testes and type II testicular germ cell tumours
more » ... cell tumours (TGCTs). The increase in TGCTs cannot be accounted for by genetic changes in the population. Therefore exposure to environmental toxicants appears to be a major contributor to the aetiology of TGCTs and men with a genetic predisposition are particularly vulnerable. In particular, Type II TGCTs have been identified to arise from a precursor lesion Carcinoma (CIS), identified as a dysfunctional gonocyte; however, the in situ exact triggers for CIS development are currently unknown. Therefore the transition from gonocytes into spermatogonia is key to those studying TGCTs. Recently we have identified seven miRNA molecules (including members of the miR-290 family and miR-136, 463* and 743a) to be significantly changed over this transition period. These miRNA molecules are predicted to have targets within the CXCR4, PTEN, DHH, RAC and PDGF pathways, all of which have important roles in germ cell migration, proliferation and homing to the spermatogonial stem cell niche. Given the plethora of potential targets affected by each miRNA molecule, subtle changes in miRNA expression could have significant consequences e.g. tumourigenesis. The role of non-traditional oncogenes and tumour suppressors such as miRNA in TGCT is highlighted by the fact that the majority of these tumours express wild type p53, a pivotal tumour suppressor usually inactivated in cancer. While treatment of TGCTs is highly successful, the impact of these treatments on fertility means that identification of exact triggers, earlier diagnosis and alternate treatments are essential. This review examines the genetic factors and possible triggers of type II TGCT to highlight target areas for potential new treatments. How to cite this article: et al. The rise of testicular germ cell tumours: the search for causes, risk 2013, :55 (doi: factors and novel therapeutic targets [v1; ref status: indexed, ] http://f1000r.es/md F1000Research 2 ) PubMed Abstract | Publisher Full Text 4. Kristensen DM, Sonne SB, Ottesen AM, et al.: Origin of pluripotent germ cell tumours: the role of microenvironment during embryonic development. Mol Cell Endocrinol. 2008; 288(1-2): 111-118. PubMed Abstract | Publisher Full Text 5. Baade P, Carriere P, Fritschi L: Trends in testicular germ cell cancer incidence in Australia. Cancer Causes Control. 2008; 19(10): 1043-1049. PubMed Abstract | Publisher Full Text 6. Skakkebaek NE, Rajpert-De Meyts E, Jorgensen N, et al.: Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations. Int J Androl. 2007; 30(4): 198-204. PubMed Abstract | Publisher Full Text 7. Walschaerts M, Huyghe E, Muller A, et al.: Doubling of testicular cancer incidence rate over the last 20 years in southern France. Cancer Causes Control. 2008; 19(2): 155-161. PubMed Abstract | Publisher Full Text 8. Richiardi L, Pettersson A, Akre O: Genetic and environmental risk factors for testicular cancer. Int J Androl. 2007; 30(4): 230-240. PubMed Abstract | Publisher Full Text 9. Matin A, Nadeau JH: Search for testicular cancer gene hits dead-end. Cell Cycle. 2005; 4(9): 1136-1138. PubMed Abstract | Publisher Full Text 10. Ferlin A, Pengo M, Pizzol D, et al.: Variants in KITLG predispose to testicular germ cell cancer independently from spermatogenic function. Endocr Relat Cancer. 2012; 19(1): 101-108. PubMed Abstract | Publisher Full Text 11. Goddard NC, McIntyre A, Summersgill B, et al.: KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature. Int J Androl. 2007; 30(4): 337-348. PubMed Abstract | Publisher Full Text 12. Kanetsky PA, Mitra N, Vardhanabhuti S, et al.: Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet. 2009; 41(7): 811-815. PubMed Abstract | Publisher Full Text | Free Full Text 13. Kemmer K, Corless CL, Fletcher JA, et al.: KIT mutations are common in testicular seminomas. Am J Pathol. 2004; 164(1): 305-313. PubMed Abstract | Publisher Full Text | Free Full Text 14. Aschim EL, Haugen TB, Tretli S, et al.: Subfertility among parents of men diagnosed with testicular cancer. Int J Androl. 2008; 31(6): 588-594. PubMed Abstract | Publisher Full Text 15. Paduch DA: Testicular cancer and male infertility. Curr Opin Urol. 2006; 16(6): 419-427. PubMed Abstract | Publisher Full Text 16. Sonne SB, Almstrup K, Dalgaard M, et al.: Analysis of gene expression profiles of microdissected cell populations indicates that testicular carcinoma in situ is an arrested gonocyte. Cancer Res. 2009; 69(12): 5241-5250. PubMed Abstract | Publisher Full Text | Free Full Text 17. Western P: Foetal germ cells: striking the balance between pluripotency and differentiation. Int J Dev Biol. 2009; 53(2-3): 393-409. PubMed Abstract | Publisher Full Text 18. Lange UC, Adams DJ, Lee C, et al.: Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Mol Cell Biol. 2008; 28(15): 4688-4696. PubMed Abstract | Publisher Full Text | Free Full Text 19. Tarbashevich K, Raz E: The nuts and bolts of germ-cell migration. Curr Opin Cell Biol. 2010; 22(6): 715-721. PubMed Abstract | Publisher Full Text 20. Aeckerle N, Eildermann K, Drummer C, et al.: The pluripotency factor LIN28 in monkey and human testes: a marker for spermatogonial stem cells? Mol Hum Reprod. 2012; 18(10): 477-488. PubMed Abstract | Publisher Full Text | Free Full Text PubMed Abstract | Publisher Full Text 22. McLaren A, Lawson KA: How is the mouse germ-cell lineage established? Differentiation. 2005; 73(9-10): 435-437. PubMed Abstract | Publisher Full Text 23. Saga Y: Mouse germ cell development during embryogenesis. Curr Opin Genet Dev. 2008; 18(4): 337-341. PubMed Abstract | Publisher Full Text 24. Ohinata Y, Payer B, O'Carroll D, et al.: Blimp1 is a critical determinant of the germ cell lineage in mice. Nature. 2005; 436(7048): 207-213. PubMed Abstract | Publisher Full Text 25. De Felici M: Nuclear reprogramming in mouse primordial germ cells: epigenetic contribution. Stem Cells Int. 2011; 2011: 425863. PubMed Abstract | Publisher Full Text | Free Full Text 26. Pirouz M, Klimke A, Kessel M: The reciprocal relationship between primordial germ cells and pluripotent stem cells. J Mol Med (Berl). 2012; 90(7): 753-761. PubMed Abstract | Publisher Full Text 27. Yabuta Y, Kurimoto K, Ohinata Y, et al.: Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol Reprod. 2006; 75(5): 705-716. PubMed Abstract | Publisher Full Text 28. Kehler J, Tolkunova E, Koschorz B, et al.: Oct4 is required for primordial germ cell survival. EMBO Rep. 2004; 5(11): 1078-1083. PubMed Abstract | Publisher Full Text | Free Full Text 29. Maldonado-Saldivia J, van den Bergen J, Krouskos M, et al.: Dppa2 and Dppa4 are closely linked SAP motif genes restricted to pluripotent cells and the germ line. Stem Cells. 2007; 25(1): 19-28. PubMed Abstract | Publisher Full Text 30. Chambers I, Silva J, Colby D, et al.: Nanog safeguards pluripotency and mediates germline development. Nature. 2007; 450(7173): 1230-1234. PubMed Abstract | Publisher Full Text 31. Gillis AJ, Stoop H, Biermann K, et al.: Expression and interdependencies of pluripotency factors LIN28, OCT 3/4, NANOG and SOX2 in human testicular germ cells and tumours of the testis. Int J Androl. 2011; 34(4 pt 2): e160-e174. PubMed Abstract | Publisher Full Text 32. Eildermann K, Aeckerle N, Debowski K, et al.: Developmental expression of the pluripotency factor sal-like protein 4 in the monkey, human and mouse testis: restriction to premeiotic germ cells. Cells Tissues Organs. 2012; 196(3): 206-220. PubMed Abstract | Publisher Full Text 33. Hobbs RM, Fagoonee S, Papa A, et al.: Functional antagonism between Sall4 and Plzf defines germline progenitors. Cell Stem Cell. 2012; 10(3): 284-298. PubMed Abstract | Publisher Full Text | Free Full Text 34. Nagamatsu G, Kosaka T, Saito S, et al.: Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice. Biol Reprod. 2012; 86(6): 182. PubMed Abstract | Publisher Full Text 35. Culty M: Gonocytes, the forgotten cells of the germ cell lineage. Birth Defects Res C Embryo Today. 2009; 87(1): 1-26. PubMed Abstract | Publisher Full Text 36. van de Geijn GJ, Hersmus R, Looijenga LH: Recent developments in testicular germ cell tumor research. Birth Defects Res C Embryo Today. 2009; 87(1): 96-113. PubMed Abstract | Publisher Full Text 37. Richardson BE, Lehmann R: Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nat Rev Mol Cell Biol. 2010; 11(1): 37-49. PubMed Abstract | Publisher Full Text 38. Bendel-Stenzel M, Anderson R, Heasman J, et al.: The origin and migration of primordial germ cells in the mouse. Semin Cell Dev Biol. 1998; 9(4): 393-400. PubMed Abstract | Publisher Full Text 39. Farini D, La Sala G, Tedesco M, et al.: Chemoattractant action and molecular signaling pathways of Kit ligand on mouse primordial germ cells. Dev Biol. 2007; 306(2): 572-583. PubMed Abstract | Publisher Full Text 40. Gu Y, Runyan C, Shoemaker A, et al.: 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. 2009; 136(8): 1295-1303. PubMed Abstract | Publisher Full Text 41. Molyneaux KA, Zinszner H, Kunwar PS, et al.: The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development. 2003; 130(18): 4279-4286. PubMed Abstract | Publisher Full Text 42. Mansour AA, Gafni O, Weinberger L, et al.: The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature. 2012; 488(7411): 409-413. PubMed Abstract | Publisher Full Text 43. De Felici M: Regulation of primordial germ cell development in the mouse. Int J Dev Biol. 2000; 44(6): 575-580. PubMed Abstract 44. Sekido R: SRY: A transcriptional activator of mammalian testis determination. Int J Biochem Cell Biol. 2010; 42(3): 417-420. PubMed Abstract | Publisher Full Text 45. Kashimada K, Koopman P: Sry: the master switch in mammalian sex determination. Development. 2010; 137(23): 3921-3930. PubMed Abstract | Publisher Full Text 46. Barsoum I, Yao HH: The road to maleness: from testis to Wolffian duct. Trends Endocrinol Metab. 2006; 17(6): 223-228. PubMed Abstract | Publisher Full Text 47. Kanai Y, Hiramatsu R, Matoba S, et al.: From SRY to SOX9: mammalian testis differentiation. J Biochem. 2005; 138(1): 13-19. PubMed Abstract | Publisher Full Text 48. Kocer A, Reichmann J, Best D, et al.: Germ cell sex determination in mammals. Mol Hum Reprod. 2009; 15(4): 205-213. PubMed Abstract | Publisher Full Text | Free Full Text 49. Kierszenbaum AL, Tres LL: Primordial germ cell-somatic cell partnership: a balancing cell signaling act. Mol Reprod Dev. 2001; 60(3): 277-280. PubMed Abstract | Publisher Full Text 50. Bowles J, Koopman P: Retinoic acid, meiosis and germ cell fate in mammals. Development. 2007; 134(19): 3401-3411. PubMed Abstract | Publisher Full Text 51. Saga Y: Sexual development of mouse germ cells: Nanos2 promotes the male germ cell fate by suppressing the female pathway. Dev Growth Differ. 2008; 50(Suppl 1): S141-S147. PubMed Abstract | Publisher Full Text 52. Oatley JM, Brinster RL: Spermatogonial stem cells. Methods Enzymol. 2006; 419: 259-282. PubMed Abstract | Publisher Full Text 53. Reuter VE: Origins and molecular biology of testicular germ cell tumors. Mod Pathol. 2005; 18(Suppl 2): S51-S60. PubMed Abstract | Publisher Full Text 54. Giwercman A, Giwercman YL: Environmental factors and testicular function. Best Pract Res Clin Endocrinol Metab. 2011; 25(2): 391-402. PubMed Abstract | Publisher Full Text 55. Cools M, Looijenga LH, Wolffenbuttel KP, et al.: Disorders of sex development: update on the genetic background, terminology and risk for the development of germ cell tumors. World J Pediatr. 2009; 5(2): 93-102. PubMed Abstract | Publisher Full Text 56. Krausz C, Looijenga LH: Genetic aspects of testicular germ cell tumors. Cell Cycle. 2008; 7(22): 3519-3524. PubMed Abstract | Publisher Full Text 57. Rajpert-de Meyts E, Hoei-Hansen CE: From gonocytes to testicular cancer: the role of impaired gonadal development. Ann N Y Acad Sci. 2007; 1120: 168-180. PubMed Abstract | Publisher Full Text 58. Gilbert D, Rapley E, Shipley J: Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nat Rev Cancer. 2011; 11(4): 278-288. PubMed Abstract | Publisher Full Text 59. Hussain SA, Ma YT, Palmer DH, et al.: Biology of testicular germ cell tumors. Expert Rev Anticancer Ther. 2008; 8(10): 1659-1673. PubMed Abstract | Publisher Full Text 60. Rapley EA, Turnbull C, Al Olama AA, et al.: A genome-wide association study of testicular germ cell tumor. Nat Genet. 2009; 41(7): 807-810. PubMed Abstract | Publisher Full Text | Free Full Text 61. Jessberger R: New insights into germ cell tumor formation. Horm Metab Res. 2008; 40(5): 342-346. PubMed Abstract | Publisher Full Text 62. Rapley EA, Crockford GP, Easton DF, et al.: Localisation of susceptibility genes for familial testicular germ cell tumour. APMIS. 2003; 111(1): 128-133. PubMed Abstract | Publisher Full Text 63. Liu L, Ishihara K, Ichimura T, et al.: MCAF1/AM is involved in Sp1-mediated maintenance of cancer-associated telomerase activity. J Biol Chem. 2009; 284(8): 5165-5174. PubMed Abstract | Publisher Full Text 64. Lessel D, Gamulin M, Kulis T, et al.: Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population. Carcinogenesis. 2012; 33(8): 1548-1552. PubMed Abstract | Publisher Full Text 65. Joffe M: What has happened to human fertility? Hum Reprod. 2010; 25(2): 295-307. PubMed Abstract | Publisher Full Text 66. Bray F, Ferlay J, Devesa SS, et al.: Interpreting the international trends in testicular seminoma and nonseminoma incidence. Nat Clin Pract Urol. 2006; 3(10): 532-543. PubMed Abstract | Publisher Full Text 67. Looijenga LH, Oosterhuis JW: Pathogenesis of testicular germ cell tumours. Rev Reprod. 1999; 4(2): 90-100. PubMed Abstract | Publisher Full Text 68. Okamoto K, Kawakami T: Epigenetic profile of testicular germ cell tumours. Int J Androl. 2007; 30(4): 385-392. PubMed Abstract | Publisher Full Text 69. Looijenga LH: Human testicular (non)seminomatous germ cell tumours: the PubMed Abstract | Publisher Full Text | Free Full Text 78. Di Vizio D, Cito L, Boccia A, et al.: Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene. 2005; 24(11): 1882-1894. PubMed Abstract | Publisher Full Text 79. Gilbert DC, McIntyre A, Summersgill B, et al.: Minimum regions of genomic imbalance in stage I testicular embryonal carcinoma and association of 22q loss with relapse. Gene Chromosomes Cancer. 2011; 50(3): 186-195. PubMed Abstract | Publisher Full Text 80. Freemantle SJ, Vaseva AV, Ewings KE, et al.: Repression of cyclin D1 as a target for germ cell tumors. Int J Oncol. 2007; 30(2): 333-340. PubMed Abstract 81. Orom UA, Lund AH: Isolation of microRNA targets using biotinylated synthetic microRNAs. Methods. 2007; 43(2): 162-165. PubMed Abstract | Publisher Full Text 82. Basciani S, De Luca G, Dolci S, et al.: Platelet-derived growth factor receptor beta-subtype regulates proliferation and migration of gonocytes. Endocrinology. 2008; 149(12): 6226-6235. PubMed Abstract | Publisher Full Text 83. Takashima S, Kanatsu-Shinohara M, Tanaka T, et al.: Rac mediates mouse spermatogonial stem cell homing to germline niches by regulating transmigration through the blood-testis barrier. Cell Stem Cell. 2011; 9(5): 463-475. PubMed Abstract | Publisher Full Text 84. Thuillier R, Mazer M, Manku G, et al.: Interdependence of platelet-derived growth factor and estrogen-signaling pathways in inducing neonatal rat testicular gonocytes proliferation. Biol Reprod. 2010; 82(5): 825-836. PubMed Abstract | Publisher Full Text | Free Full Text 85. Jiang W, Xiang C, Cazacu S, et al.: Insulin-like growth factor binding protein 7 mediates glioma cell growth and migration. Neoplasia. 2008; 10(12): 1335-1342. PubMed Abstract | Free Full Text 86. Amemiya Y, Yang W, Benatar T, et al.: Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors. Breast Cancer Res Treat. 2011; 126(2): 373-384. PubMed Abstract | Publisher Full Text 87. Chen D, Yoo BK, Santhekadur PK, et al.: Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma. Clin Cancer Res. 2011; 17(21): 6693-6701. PubMed Abstract | Publisher Full Text | Free Full Text 88. Medeiros LA, Dennis LM, Gill ME, et al.: mir-290-295 deficiency in mice results in partially penetrant embryonic lethality and germ cell defects. PubMed Abstract | Publisher Full Text | Free Full Text 89. Zheng GX, Ravi A, Calabrese JM, et al.: A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells. PLoS Genet. 2011; 7(5): e1002054. PubMed Abstract | Publisher Full Text | Free Full Text 90. Zovoilis A, Pantazi A, Smorag L, et al.: Embryonic stem cell-related miRNAs are involved in differentiation of pluripotent cells originating from the germ line. Mol Hum Reprod. 2010; 16(11): 793-803. PubMed Abstract | Publisher Full Text 91. Yang Y, Wu J, Guan H, et al.: MiR-136 promotes apoptosis of glioma cells by targeting AEG-1 and Bcl-2. FEBS Lett. 2012; 586(20): 3608-3612. PubMed Abstract | Publisher Full Text 92. Shi Q, Gibson GE: Up-regulation of the mitochondrial malate dehydrogenase by oxidative stress is mediated by miR-743a. J Neurochem. 2011; 118(3): 440-448. PubMed Abstract | Publisher Full Text | Free Full Text 93. Rajpert-De Meyts E: Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update. 2006; 12(3): 303-323. PubMed Abstract | Publisher Full Text
doi:10.3410/f1000research.2-55.v1 fatcat:mkb2r7yh6vgrzcs32q6hu6e3re