Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(9):1191–1198. doi: 10.1038/bjc.1997.532

Human testicular germ cell tumours express inhibin subunits, activin receptors and follistatin mRNAs.

R H van Schaik 1, C D Wierikx 1, L H Looijenga 1, J W Oosterhuis 1, F H de Jong 1
PMCID: PMC2228115  PMID: 9365168

Abstract

Germ cell development is influenced by activin and inhibin, which are produced by Sertoli cells. Activin also affects differentiation of mouse embryonal carcinoma cells, which, to a certain extent, resemble the embryonal carcinoma component of germ cell tumours. Therefore, the expression of inhibin/activin subunits, of activin receptors and of the activin-binding protein follistatin was studied in testicular germ cell tumours, using RNAase protection assays. Testicular germ cell tumours of adolescents and adults (TGCTs) and spermatocytic seminomas expressed activin type I and type II receptors (ActRI and ActRII respectively). Seminomas expressed significantly lower levels of ActRIIA (P<0.05, Mann-Whitney U-test) and higher levels of ActRIA (P<0.05) and ActRIB (P<0.05) compared with non-seminomas. All tumours expressed inhibin beta-subunit transcripts, which are a prerequisite for activin synthesis. Non-seminomas contained significantly higher levels of the inhibin betaA subunit (P<0.001) compared with seminomas. No activin betaC subunit transcripts could be demonstrated by RNAase protection. Inhibin alpha-subunit expression was absent in the spermatocytic seminomas, in six out of nine seminomas and in 10 out of 11 non-seminomas. Follistatin was expressed predominantly in non-seminomas and spermatocytic seminomas. This expression of activin type I and type II receptors in combination with expression of inhibin beta-subunits indicates that activin may act as a para- or autocrine factor in the regulation of growth and differentiation of tumours of human germ cells.

Full text

PDF
1191

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albano R. M., Groome N., Smith J. C. Activins are expressed in preimplantation mouse embryos and in ES and EC cells and are regulated on their differentiation. Development. 1993 Feb;117(2):711–723. doi: 10.1242/dev.117.2.711. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. W. Human teratocarcinomas. Biochim Biophys Acta. 1988 Aug 3;948(1):17–36. doi: 10.1016/0304-419x(88)90003-0. [DOI] [PubMed] [Google Scholar]
  3. Attisano L., Wrana J. L., Cheifetz S., Massagué J. Novel activin receptors: distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors. Cell. 1992 Jan 10;68(1):97–108. doi: 10.1016/0092-8674(92)90209-u. [DOI] [PubMed] [Google Scholar]
  4. Bilezikjian L. M., Corrigan A. Z., Vaughan J. M., Vale W. M. Activin-A regulates follistatin secretion from cultured rat anterior pituitary cells. Endocrinology. 1993 Dec;133(6):2554–2560. doi: 10.1210/endo.133.6.8243277. [DOI] [PubMed] [Google Scholar]
  5. Cameron V. A., Nishimura E., Mathews L. S., Lewis K. A., Sawchenko P. E., Vale W. W. Hybridization histochemical localization of activin receptor subtypes in rat brain, pituitary, ovary, and testis. Endocrinology. 1994 Feb;134(2):799–808. doi: 10.1210/endo.134.2.8299574. [DOI] [PubMed] [Google Scholar]
  6. Cárcamo J., Weis F. M., Ventura F., Wieser R., Wrana J. L., Attisano L., Massagué J. Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin. Mol Cell Biol. 1994 Jun;14(6):3810–3821. doi: 10.1128/mcb.14.6.3810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Jong F. H., Grootenhuis A. J., Steenbergen J., van Sluijs F. J., Foekens J. A., ten Kate F. J., Oosterhuis J. W., Lamberts S. W., Klijn J. G. Inhibin immunoreactivity in gonadal and non-gonadal tumors. J Steroid Biochem Mol Biol. 1990 Dec 20;37(6):863–866. doi: 10.1016/0960-0760(90)90433-l. [DOI] [PubMed] [Google Scholar]
  8. De Jong F. H. Inhibin. Physiol Rev. 1988 Apr;68(2):555–607. doi: 10.1152/physrev.1988.68.2.555. [DOI] [PubMed] [Google Scholar]
  9. De Jong F. H., Sharpe R. M. Evidence for inhibin-like activity in bovine follicular fluid. Nature. 1976 Sep 2;263(5572):71–72. doi: 10.1038/263071a0. [DOI] [PubMed] [Google Scholar]
  10. DePaolo L. V., Mercado M., Guo Y., Ling N. Increased follistatin (activin-binding protein) gene expression in rat anterior pituitary tissue after ovariectomy may be mediated by pituitary activin. Endocrinology. 1993 May;132(5):2221–2228. doi: 10.1210/endo.132.5.8477666. [DOI] [PubMed] [Google Scholar]
  11. Donaldson C. J., Mathews L. S., Vale W. W. Molecular cloning and binding properties of the human type II activin receptor. Biochem Biophys Res Commun. 1992 Apr 15;184(1):310–316. doi: 10.1016/0006-291x(92)91194-u. [DOI] [PubMed] [Google Scholar]
  12. Eble J. N. Spermatocytic seminoma. Hum Pathol. 1994 Oct;25(10):1035–1042. doi: 10.1016/0046-8177(94)90062-0. [DOI] [PubMed] [Google Scholar]
  13. Erba H. P., Gunning P., Kedes L. Nucleotide sequence of the human gamma cytoskeletal actin mRNA: anomalous evolution of vertebrate non-muscle actin genes. Nucleic Acids Res. 1986 Jul 11;14(13):5275–5294. doi: 10.1093/nar/14.13.5275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Esch F. S., Shimasaki S., Cooksey K., Mercado M., Mason A. J., Ying S. Y., Ueno N., Ling N. Complementary deoxyribonucleic acid (cDNA) cloning and DNA sequence analysis of rat ovarian inhibins. Mol Endocrinol. 1987 May;1(5):388–396. doi: 10.1210/mend-1-5-388. [DOI] [PubMed] [Google Scholar]
  15. Feijen A., Goumans M. J., van den Eijnden-van Raaij A. J. Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins. Development. 1994 Dec;120(12):3621–3637. doi: 10.1242/dev.120.12.3621. [DOI] [PubMed] [Google Scholar]
  16. Feng Z. M., Madigan M. B., Chen C. L. Expression of type II activin receptor genes in the male and female reproductive tissues of the rat. Endocrinology. 1993 Jun;132(6):2593–2600. doi: 10.1210/endo.132.6.7916681. [DOI] [PubMed] [Google Scholar]
  17. Forman D., Møller H. Testicular cancer. Cancer Surv. 1994;19-20:323–341. [PubMed] [Google Scholar]
  18. Giwercman A., Skakkebaek N. E. Carcinoma in situ of the testis: biology, screening and management. Eur Urol. 1993;23 (Suppl 2):19–21. doi: 10.1159/000474694. [DOI] [PubMed] [Google Scholar]
  19. H tten G., Neidhardt H., Schneider C., Pohl J. Cloning of a new member of the TGF-beta family: a putative new activin beta C chain. Biochem Biophys Res Commun. 1995 Jan 17;206(2):608–613. doi: 10.1006/bbrc.1995.1086. [DOI] [PubMed] [Google Scholar]
  20. Hashimoto M., Kondo S., Sakurai T., Etoh Y., Shibai H., Muramatsu M. Activin/EDF as an inhibitor of neural differentiation. Biochem Biophys Res Commun. 1990 Nov 30;173(1):193–200. doi: 10.1016/s0006-291x(05)81040-x. [DOI] [PubMed] [Google Scholar]
  21. Hildén K., Tuuri T., Erämaa M., Ritvos O. Expression of type II activin receptor genes during differentiation of human K562 cells and cDNA cloning of the human type IIB activin receptor. Blood. 1994 Apr 15;83(8):2163–2170. [PubMed] [Google Scholar]
  22. Hino M., Nishizawa Y., Tatsumi N., Tojo A., Morii H. Down-modulation of c-kit mRNA and protein expression by erythroid differentiation factor/activin A. FEBS Lett. 1995 Oct 23;374(1):69–71. doi: 10.1016/0014-5793(95)01078-s. [DOI] [PubMed] [Google Scholar]
  23. Kaipia A., Parvinen M., Shimasaki S., Ling N., Toppari J. Stage-specific cellular regulation of inhibin alpha-subunit mRNA expression in the rat seminiferous epithelium. Mol Cell Endocrinol. 1991 Dec;82(2-3):165–173. doi: 10.1016/0303-7207(91)90028-q. [DOI] [PubMed] [Google Scholar]
  24. Kaipia A., Parvinen M., Toppari J. Localization of activin receptor (ActR-IIB2) mRNA in the rat seminiferous epithelium. Endocrinology. 1993 Jan;132(1):477–479. doi: 10.1210/endo.132.1.8380387. [DOI] [PubMed] [Google Scholar]
  25. Lau A. L., Nishimori K., Matzuk M. M. Structural analysis of the mouse activin beta C gene. Biochim Biophys Acta. 1996 Jun 7;1307(2):145–148. doi: 10.1016/0167-4781(96)00061-9. [DOI] [PubMed] [Google Scholar]
  26. Ling N., Ying S. Y., Ueno N., Shimasaki S., Esch F., Hotta M., Guillemin R. Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature. 1986 Jun 19;321(6072):779–782. doi: 10.1038/321779a0. [DOI] [PubMed] [Google Scholar]
  27. Loveland K. L., McFarlane J. R., de Kretser D. M. Expression of activin beta C subunit mRNA in reproductive tissues. J Mol Endocrinol. 1996 Aug;17(1):61–65. doi: 10.1677/jme.0.0170061. [DOI] [PubMed] [Google Scholar]
  28. Martens J. W., de Winter J. P., Timmerman M. A., McLuskey A., van Schaik R. H., Themmen A. P., de Jong F. H. Inhibin interferes with activin signaling at the level of the activin receptor complex in Chinese hamster ovary cells. Endocrinology. 1997 Jul;138(7):2928–2936. doi: 10.1210/endo.138.7.5250. [DOI] [PubMed] [Google Scholar]
  29. Mason A. J., Hayflick J. S., Ling N., Esch F., Ueno N., Ying S. Y., Guillemin R., Niall H., Seeburg P. H. Complementary DNA sequences of ovarian follicular fluid inhibin show precursor structure and homology with transforming growth factor-beta. Nature. 1985 Dec 19;318(6047):659–663. doi: 10.1038/318659a0. [DOI] [PubMed] [Google Scholar]
  30. Mason A. J., Niall H. D., Seeburg P. H. Structure of two human ovarian inhibins. Biochem Biophys Res Commun. 1986 Mar 28;135(3):957–964. doi: 10.1016/0006-291x(86)91021-1. [DOI] [PubMed] [Google Scholar]
  31. Mather J. P., Attie K. M., Woodruff T. K., Rice G. C., Phillips D. M. Activin stimulates spermatogonial proliferation in germ-Sertoli cell cocultures from immature rat testis. Endocrinology. 1990 Dec;127(6):3206–3214. doi: 10.1210/endo-127-6-3206. [DOI] [PubMed] [Google Scholar]
  32. Mather J. P., Woodruff T. K., Krummen L. A. Paracrine regulation of reproductive function by inhibin and activin. Proc Soc Exp Biol Med. 1992 Oct;201(1):1–15. doi: 10.3181/00379727-201-43473. [DOI] [PubMed] [Google Scholar]
  33. Mathews L. S. Activin receptors and cellular signaling by the receptor serine kinase family. Endocr Rev. 1994 Jun;15(3):310–325. doi: 10.1210/edrv-15-3-310. [DOI] [PubMed] [Google Scholar]
  34. Mayo K. E., Cerelli G. M., Spiess J., Rivier J., Rosenfeld M. G., Evans R. M., Vale W. Inhibin A-subunit cDNAs from porcine ovary and human placenta. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5849–5853. doi: 10.1073/pnas.83.16.5849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Michel U., Farnworth P., Findlay J. K. Follistatins: more than follicle-stimulating hormone suppressing proteins. Mol Cell Endocrinol. 1993 Feb;91(1-2):1–11. doi: 10.1016/0303-7207(93)90248-i. [DOI] [PubMed] [Google Scholar]
  36. Mostofi F. K. Pathology of germ cell tumors of testis: a progress report. Cancer. 1980 Apr 15;45(7 Suppl):1735–1754. [PubMed] [Google Scholar]
  37. Mostofi F. K., Sesterhenn I. A., Davis C. J., Jr Immunopathology of germ cell tumors of the testis. Semin Diagn Pathol. 1987 Nov;4(4):320–341. [PubMed] [Google Scholar]
  38. Moul J. W., McCarthy W. F., Fernandez E. B., Sesterhenn I. A. Percentage of embryonal carcinoma and of vascular invasion predicts pathological stage in clinical stage I nonseminomatous testicular cancer. Cancer Res. 1994 Jan 15;54(2):362–364. [PubMed] [Google Scholar]
  39. Müller J., Skakkebaek N. E., Parkinson M. C. The spermatocytic seminoma: views on pathogenesis. Int J Androl. 1987 Feb;10(1):147–156. doi: 10.1111/j.1365-2605.1987.tb00176.x. [DOI] [PubMed] [Google Scholar]
  40. Oosterhuis J. W., Castedo S. M., de Jong B., Cornelisse C. J., Dam A., Sleijfer D. T., Schraffordt Koops H. Ploidy of primary germ cell tumors of the testis. Pathogenetic and clinical relevance. Lab Invest. 1989 Jan;60(1):14–21. [PubMed] [Google Scholar]
  41. Oosterhuis J. W., Looijenga L. H. The biology of human germ cell tumours: retrospective speculations and new prospectives. Eur Urol. 1993;23(1):245–250. doi: 10.1159/000474601. [DOI] [PubMed] [Google Scholar]
  42. Qu J., Thomas K. Inhibin and activin production in human placenta. Endocr Rev. 1995 Aug;16(4):485–507. doi: 10.1210/edrv-16-4-485. [DOI] [PubMed] [Google Scholar]
  43. Skakkebaek N. E., Berthelsen J. G., Giwercman A., Müller J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl. 1987 Feb;10(1):19–28. doi: 10.1111/j.1365-2605.1987.tb00161.x. [DOI] [PubMed] [Google Scholar]
  44. Strohmeyer T., Peter S., Hartmann M., Munemitsu S., Ackermann R., Ullrich A., Slamon D. J. Expression of the hst-1 and c-kit protooncogenes in human testicular germ cell tumors. Cancer Res. 1991 Apr 1;51(7):1811–1816. [PubMed] [Google Scholar]
  45. Talerman A. Spermatocytic seminoma: clinicopathological study of 22 cases. Cancer. 1980 Apr 15;45(8):2169–2176. doi: 10.1002/1097-0142(19800415)45:8<2169::aid-cncr2820450827>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  46. Ulbright T. M. Germ cell neoplasms of the testis. Am J Surg Pathol. 1993 Nov;17(11):1075–1091. doi: 10.1097/00000478-199311000-00001. [DOI] [PubMed] [Google Scholar]
  47. Vale W., Rivier J., Vaughan J., McClintock R., Corrigan A., Woo W., Karr D., Spiess J. Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature. 1986 Jun 19;321(6072):776–779. doi: 10.1038/321776a0. [DOI] [PubMed] [Google Scholar]
  48. Woodruff T. K., Borree J., Attie K. M., Cox E. T., Rice G. C., Mather J. P. Stage-specific binding of inhibin and activin to subpopulations of rat germ cells. Endocrinology. 1992 Feb;130(2):871–881. doi: 10.1210/endo.130.2.1310280. [DOI] [PubMed] [Google Scholar]
  49. Wrana J. L., Tran H., Attisano L., Arora K., Childs S. R., Massagué J., O'Connor M. B. Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol Cell Biol. 1994 Feb;14(2):944–950. doi: 10.1128/mcb.14.2.944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. de Jong F. H., de Winter J. P., Wesseling J. G., Timmerman M. A., van Genesen S., van den Eijnden-van Raaij A. J., van Zoelen E. J. Inhibin subunits, follistatin and activin receptors in the human teratocarcinoma cell line Tera-2. Biochem Biophys Res Commun. 1993 May 14;192(3):1334–1339. doi: 10.1006/bbrc.1993.1562. [DOI] [PubMed] [Google Scholar]
  51. de Winter J. P., Vanderstichele H. M., Timmerman M. A., Blok L. J., Themmen A. P., de Jong F. H. Activin is produced by rat Sertoli cells in vitro and can act as an autocrine regulator of Sertoli cell function. Endocrinology. 1993 Mar;132(3):975–982. doi: 10.1210/endo.132.3.7679985. [DOI] [PubMed] [Google Scholar]
  52. de Winter J. P., Vanderstichele H. M., Verhoeven G., Timmerman M. A., Wesseling J. G., de Jong F. H. Peritubular myoid cells from immature rat testes secrete activin-A and express activin receptor type II in vitro. Endocrinology. 1994 Aug;135(2):759–767. doi: 10.1210/endo.135.2.8033824. [DOI] [PubMed] [Google Scholar]
  53. ten Dijke P., Ichijo H., Franzén P., Schulz P., Saras J., Toyoshima H., Heldin C. H., Miyazono K. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene. 1993 Oct;8(10):2879–2887. [PubMed] [Google Scholar]
  54. van Dissel-Emiliani F. M., Grootenhuis A. J., de Jong F. H., de Rooij D. G. Inhibin reduces spermatogonial numbers in testes of adult mice and Chinese hamsters. Endocrinology. 1989 Oct;125(4):1899–1903. doi: 10.1210/endo-125-4-1898. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES