Clinical and Experimental Reproductive Medicine

The Korean Society for Reproductive Medicine (대한생식의학회)
권호 표지
DOI QR코드

DOI QR Code

Insights into granulosa cell tumors using spontaneous or genetically engineered mouse models

  • Kim, So-Youn (Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University)
  • Received : 2016.01.25
  • Accepted : 2016.03.04
  • Published : 2016.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Granulosa cell tumors (GCTs) are rare sex cord-stromal tumors that have been studied for decades. However, their infrequency has delayed efforts to research their etiology. Recently, mutations in human GCTs have been discovered, which has led to further research aimed at determining the molecular mechanisms underlying the disease. Mouse models have been important tools for studying GCTs, and have provided means to develop and improve diagnostics and therapeutics. Thus far, several genetically modified mouse models, along with one spontaneous mouse model, have been reported. This review summarizes the phenotypes of these mouse models and their applicability in elucidating the mechanisms of granulosa cell tumor development.

Keywords

References

  1. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21:1180-9. https://doi.org/10.1200/JCO.2003.10.019
  2. Jamieson S, Fuller PJ. Molecular pathogenesis of granulosa cell tumors of the ovary. Endocr Rev 2012;33:109-44. https://doi.org/10.1210/er.2011-0014
  3. Dilworth JP, Farrow GM, Oesterling JE. Non-germ cell tumors of testis. Urology 1991;37:399-417. https://doi.org/10.1016/0090-4295(91)80100-L
  4. Richards JS, Fan HY, Liu Z, Tsoi M, Lague MN, Boyer A, et al. Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis. Oncogene 2012;31:1504-20. https://doi.org/10.1038/onc.2011.341
  5. Sehouli J, Drescher FS, Mustea A, Elling D, Friedmann W, Kuhn W, et al. Granulosa cell tumor of the ovary: 10 years follow-up data of 65 patients. Anticancer Res 2004;24:1223-9.
  6. Colombo N, Parma G, Zanagnolo V, Insinga A. Management of ovarian stromal cell tumors. J Clin Oncol 2007;25:2944-51. https://doi.org/10.1200/JCO.2007.11.1005
  7. Young RH, Dickersin GR, Scully RE. Juvenile granulosa cell tumor of the ovary: a clinicopathological analysis of 125 cases. Am J Surg Pathol 1984;8:575-96. https://doi.org/10.1097/00000478-198408000-00002
  8. Fox H. Sex cord-stromal tumours of the ovary. J Pathol 1985;145:127-48. https://doi.org/10.1002/path.1711450202
  9. Lappohn RE, Burger HG, Bouma J, Bangah M, Krans M, de Bruijn HW. Inhibin as a marker for granulosa-cell tumors. N Engl J Med 1989;321:790-3. https://doi.org/10.1056/NEJM198909213211204
  10. Jobling T, Mamers P, Healy DL, MacLachlan V, Burger HG, Quinn M, et al. A prospective study of inhibin in granulosa cell tumors of the ovary. Gynecol Oncol 1994;55:285-9. https://doi.org/10.1006/gyno.1994.1291
  11. Petraglia F, Luisi S, Pautier P, Sabourin JC, Rey R, Lhomme C, et al. Inhibin B is the major form of inhibin/activin family secreted by granulosa cell tumors. J Clin Endocrinol Malpb 1998;83:1029-32. https://doi.org/10.1210/jcem.83.3.4800
  12. Bjorkholm E, Silfversward C. Prognostic factors in granulosa-cell tumors. Gynecol Oncol 1981;11:261-74. https://doi.org/10.1016/0090-8258(81)90040-8
  13. Zaloudek C, Norris HJ. Granulosa tumors of the ovary in children: a clinical and pathologic study of 32 cases. Am J Surg Pathol 1982;6:503-12. https://doi.org/10.1097/00000478-198209000-00002
  14. Shah SP, Kobel M, Senz J, Morin RD, Clarke BA, Wiegand KC, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009;360:2719-29. https://doi.org/10.1056/NEJMoa0902542
  15. Jamieson S, Butzow R, Andersson N, Alexiadis M, Unkila-Kallio L, Heikinheimo M, et al. The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary. Mod Pathol 2010;23:1477-85. https://doi.org/10.1038/modpathol.2010.145
  16. Kalfa N, Philibert P, Patte C, Ecochard A, Duvillard P, Baldet P, et al. Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children. Fertil Steril 2007;87:896-901. https://doi.org/10.1016/j.fertnstert.2006.11.016
  17. Kim JH, Yoon S, Park M, Park HO, Ko JJ, Lee K, et al. Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W). Oncogene 2011;30:1653-63. https://doi.org/10.1038/onc.2010.541
  18. Fleming NI, Knower KC, Lazarus KA, Fuller PJ, Simpson ER, Clyne CD. Aromatase is a direct target of FOXL2: C134W in granulosa cell tumors via a single highly conserved binding site in the ovarian specific promoter. PLoS One 2010;5:e14389. https://doi.org/10.1371/journal.pone.0014389
  19. Beysen D, Moumne L, Veitia R, Peters H, Leroy BP, De Paepe A, et al. Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation. Hum Mol Genet 2008;17:2030-8. https://doi.org/10.1093/hmg/ddn100
  20. Benayoun BA, Caburet S, Dipietromaria A, Georges A, D'Haene B, Pandaranayaka PJ, et al. Functional exploration of the adult ovarian granulosa cell tumor-associated somatic FOXL2 mutation p.Cys134Trp (c.402C>G). PLoS One 2010;5:e8789. https://doi.org/10.1371/journal.pone.0008789
  21. Kim JH, Kim YH, Kim HM, Park HO, Ha NC, Kim TH, et al. FOXL2 posttranslational modifications mediated by $GSK3{\beta}$ determine the growth of granulosa cell tumours. Nat Commun 2014;5:2936. https://doi.org/10.1038/ncomms3936
  22. Kalfa N, Ecochard A, Patte C, Duvillard P, Audran F, Pienkowski C, et al. Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab 2006;91:1842-7. https://doi.org/10.1210/jc.2005-2710
  23. Auguste A, Bessiere L, Todeschini AL, Caburet S, Sarnacki S, Prat J, et al. Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads. Hum Mol Genet 2015;24:6687-98. https://doi.org/10.1093/hmg/ddv373
  24. Zhang H, Vollmer M, De Geyter M, Litzistorf Y, Ladewig A, Durrenberger M, et al. Characterization of an immortalized human granulosa cell line (COV434). Mol Hum Reprod 2000;6:146-53. https://doi.org/10.1093/molehr/6.2.146
  25. Nishi Y, Yanase T, Mu Y, Oba K, Ichino I, Saito M, et al. Establishment and characterization of a steroidogenic human granulosalike tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology 2001;142:437-45. https://doi.org/10.1210/endo.142.1.7862
  26. Alexiadis M, Eriksson N, Jamieson S, Davis M, Drummond AE, Chu S, et al. Nuclear receptor profiling of ovarian granulosa cell tumors. Horm Cancer 2011;2:157-69. https://doi.org/10.1007/s12672-011-0069-3
  27. Beamer WG, Hoppe PC, Whitten WK. Spontaneous malignant granulosa cell tumors in ovaries of young SWR mice. Cancer Res 1985;45(11 Pt 2):5575-81.
  28. Dorward AM, Yaskowiak ES, Smith KN, Stanford KR, Shultz KL, Beamer WG. Chromosome X loci and spontaneous granulosa cell tumor development in SWR mice: epigenetics and epistasis at work for an ovarian phenotype. Epigenetics 2013;8:184-91. https://doi.org/10.4161/epi.23399
  29. Beamer WG, Shultz KL, Tennent BJ. Induction of ovarian granulosa cell tumors in SWXJ-9 mice with dehydroepiandrosterone. Cancer Res 1988;48:2788-92.
  30. Smith KN, Halfyard SJ, Yaskowiak ES, Shultz KL, Beamer WG, Dorward AM. Fine map of the Gct1 spontaneous ovarian granulosa cell tumor locus. Mamm Genome 2013;24:63-71. https://doi.org/10.1007/s00335-012-9439-6
  31. Beamer WG. Gonadotropin, steroid, and thyroid hormone milieu of young SWR mice bearing spontaneous granulosa cell tumors. J Natl Cancer Inst 1986;77:1117-23.
  32. Meunier H, Rivier C, Evans RM, Vale W. Gonadal and extragonadal expression of inhibin alpha, beta A, and beta B subunits in various tissues predicts diverse functions. Proc Natl Acad Sci U S A 1988;85:247-51. https://doi.org/10.1073/pnas.85.1.247
  33. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 1994;8:133-46. https://doi.org/10.1101/gad.8.2.133
  34. Matzuk MM, Finegold MJ, Su JG, Hsueh AJ, Bradley A. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 1992;360:313-9. https://doi.org/10.1038/360313a0
  35. Kumar TR, Wang Y, Matzuk MM. Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice. Endocrinology 1996;137:4210-6. https://doi.org/10.1210/endo.137.10.8828479
  36. Danilovich N, Roy I, Sairam MR. Ovarian pathology and high incidence of sex cord tumors in follitropin receptor knockout (FORKO) mice. Endocrinology 2001;142:3673-84. https://doi.org/10.1210/endo.142.8.8320
  37. Cipriano SC, Chen L, Kumar TR, Matzuk MM. Follistatin is a modulator of gonadal tumor progression and the activin-induced wasting syndrome in inhibin-deficient mice. Endocrinology 2000;141:2319-27. https://doi.org/10.1210/endo.141.7.7535
  38. Looyenga BD, Hammer GD. Genetic removal of Smad3 from inhibin-null mice attenuates tumor progression by uncoupling extracellular mitogenic signals from the cell cycle machinery. Mol Endocrinol 2007;21:2440-57. https://doi.org/10.1210/me.2006-0402
  39. Li Q, Graff JM, O’Connor AE, Loveland KL, Matzuk MM. SMAD3 regulates gonadal tumorigenesis. Mol Endocrinol 2007;21:2472-86. https://doi.org/10.1210/me.2007-0147
  40. Rajanahally S, Agno JE, Nalam RL, Weinstein MB, Loveland KL, Matzuk MM, et al. Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice. Reprod Biol Endocrinol 2010;8:69. https://doi.org/10.1186/1477-7827-8-69
  41. Fuller PJ, Chu S. Signalling pathways in the molecular pathogenesis of ovarian granulosa cell tumours. Trends Endocrinol Metab 2004;15:122-8. https://doi.org/10.1016/j.tem.2004.02.005
  42. Robertson DM, Burger HG, Fuller PJ. Inhibin/activin and ovarian cancer. Endocr Relat Cancer 2004;11:35-49. https://doi.org/10.1677/erc.0.0110035
  43. Kananen K, Markkula M, Rainio E, Su JG, Hsueh AJ, Huhtaniemi IT. Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/simian virus T-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines. Mol Endocrinol 1995;9:616-27.
  44. Dutertre M, Gouedard L, Xavier F, Long WQ, di Clemente N, Picard JY, et al. Ovarian granulosa cell tumors express a functional membrane receptor for anti-Mullerian hormone in transgenic mice. Endocrinology 2001;142:4040-6. https://doi.org/10.1210/endo.142.9.8393
  45. Risma KA, Clay CM, Nett TM, Wagner T, Yun J, Nilson JH. Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci U S A 1995;92:1322-6. https://doi.org/10.1073/pnas.92.5.1322
  46. Keri RA, Lozada KL, Abdul-Karim FW, Nadeau JH, Nilson JH. Luteinizing hormone induction of ovarian tumors: oligogenic differences between mouse strains dictates tumor disposition. Proc Natl Acad Sci U S A 2000;97:383-7. https://doi.org/10.1073/pnas.97.1.383
  47. Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, et al. Crystal structure of human chorionic gonadotropin. Nature 1994;369:455-61. https://doi.org/10.1038/369455a0
  48. Nagaraja AK, Agno JE, Kumar TR, Matzuk MM. Luteinizing hormone promotes gonadal tumorigenesis in inhibin-deficient mice. Mol Cell Endocrinol 2008;294:19-28. https://doi.org/10.1016/j.mce.2008.06.019
  49. Mikola M, Kero J, Nilson JH, Keri RA, Poutanen M, Huhtaniemi I. High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-alpha-subunit promoter/Simian virus 40 T-antigen fusion gene. Oncogene 2003;22:3269-78. https://doi.org/10.1038/sj.onc.1206518
  50. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785-9. https://doi.org/10.1038/378785a0
  51. Boyer A, Goff AK, Boerboom D. WNT signaling in ovarian follicle biology and tumorigenesis. Trends Endocrinol Metab 2010;21:25-32. https://doi.org/10.1016/j.tem.2009.08.005
  52. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature 1999;397:405-9. https://doi.org/10.1038/17068
  53. Hsieh M, Boerboom D, Shimada M, Lo Y, Parlow AF, Luhmann UF, et al. Mice null for Frizzled4 (Fzd4-/-) are infertile and exhibit impaired corpora lutea formation and function. Biol Reprod 2005;73:1135-46. https://doi.org/10.1095/biolreprod.105.042739
  54. Abedini A, Zamberlam G, Lapointe E, Tourigny C, Boyer A, Paquet M, et al. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling. FASEB J 2015 Dec 14 [Epub]. http://dx.doi.org/10.1096/fj.15-280313.
  55. Lapointe E, Boerboom D. WNT signaling and the regulation of ovarian steroidogenesis. Front Biosci (Schol Ed) 2011;3:276-85.
  56. Boerboom D, Paquet M, Hsieh M, Liu J, Jamin SP, Behringer RR, et al. Misregulated Wnt/beta-catenin signaling leads to ovarian granulosa cell tumor development. Cancer Res 2005;65:9206-15. https://doi.org/10.1158/0008-5472.CAN-05-1024
  57. Boerboom D, White LD, Dalle S, Courty J, Richards JS. Dominantstable beta-catenin expression causes cell fate alterations and Wnt signaling antagonist expression in a murine granulosa cell tumor model. Cancer Res 2006;66:1964-73. https://doi.org/10.1158/0008-5472.CAN-05-3493
  58. Lague MN, Paquet M, Fan HY, Kaartinen MJ, Chu S, Jamin SP, et al. Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression. Carcinogenesis 2008;29:2062-72. https://doi.org/10.1093/carcin/bgn186
  59. Pangas SA, Li X, Umans L, Zwijsen A, Huylebroeck D, Gutierrez C, et al. Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice. Mol Cell Biol 2008;28:248-57. https://doi.org/10.1128/MCB.01404-07
  60. Middlebrook BS, Eldin K, Li X, Shivasankaran S, Pangas SA. Smad1-Smad5 ovarian conditional knockout mice develop a disease profile similar to the juvenile form of human granulosa cell tumors. Endocrinology 2009;150:5208-17. https://doi.org/10.1210/en.2009-0644
  61. Mansouri-Attia N, Tripurani SK, Gokul N, Piard H, Anderson ML, Eldin K, et al. $TGF{\beta}$ signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis. Mol Endocrinol 2014;28:1887-98. https://doi.org/10.1210/me.2014-1217
  62. Erickson GF, Shimasaki S. The spatiotemporal expression pattern of the bone morphogenetic protein family in rat ovary cell types during the estrous cycle. Reprod Biol Endocrinol 2003;1:9. https://doi.org/10.1186/1477-7827-1-9
  63. Edson MA, Nalam RL, Clementi C, Franco HL, Demayo FJ, Lyons KM, et al. Granulosa cell-expressed BMPR1A and BMPR1B have unique functions in regulating fertility but act redundantly to suppress ovarian tumor development. Mol Endocrinol 2010;24:1251-66. https://doi.org/10.1210/me.2009-0461
  64. Fan X, Gabbi C, Kim HJ, Cheng G, Andersson LC, Warner M, et al. Gonadotropin-positive pituitary tumors accompanied by ovarian tumors in aging female ERbeta-/- mice. Proc Natl Acad Sci U S A 2010;107:6453-8. https://doi.org/10.1073/pnas.1002029107
  65. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999;20:358-417. https://doi.org/10.1210/edrv.20.3.0370
  66. Burns KH, Agno JE, Chen L, Haupt B, Ogbonna SC, Korach KS, et al. Sexually dimorphic roles of steroid hormone receptor signaling in gonadal tumorigenesis. Mol Endocrinol 2003;17:2039-52. https://doi.org/10.1210/me.2003-0039
  67. Fan HY, Liu Z, Cahill N, Richards JS. Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Mol Endocrinol 2008;22:2128-40. https://doi.org/10.1210/me.2008-0095
  68. Liu Z, Ren YA, Pangas SA, Adams J, Zhou W, Castrillon DH, et al. FOXO1/3 and PTEN depletion in granulosa cells promotes ovarian granulosa cell tumor development. Mol Endocrinol 2015;29:1006-24. https://doi.org/10.1210/me.2015-1103
  69. Lan ZJ, Xu X, Cooney AJ. Differential oocyte-specific expression of Cre recombinase activity in GDF-9-iCre, Zp3cre, and Msx2Cre transgenic mice. Biol Reprod 2004;71:1469-74. https://doi.org/10.1095/biolreprod.104.031757
  70. Kim SY, Ebbert K, Cordeiro MH, Romero M, Zhu J, Serna VA, et al. Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles. Endocrinology 2015;156:1464-76. https://doi.org/10.1210/en.2014-1926
  71. Kim SY, Ebbert K, Cordeiro M, Romero M, Whelan KA, Woodruff TK, et al. Oocyte-driven granulosa cell tumorigenesis in mouse ovary. Proceedings of ENDO 2016; 2016 April 3; Boston, MA.

Cited by

  1. Ovarian Toxicity Induced by Aluminum Chloride: Alteration of Cyp19a1, Pcna, Puma, and Map1lc3b genes Expression vol.466, pp.None, 2022, https://doi.org/10.1016/j.tox.2021.153084