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Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice


Ovarian teratomas (OTs) are the most frequent germ cell tumors in adult women, but their origin and molecular etiology remains poorly defined. We found that conditional deletion of the tumor suppressor Rb1 in the oocyte leads to OT development in young adult female mice. Further analysis revealed disturbances in both recruitment and growth of follicles. Although oocytes from mutants did not exhibit an enhanced propensity for parthenogenetic activation–a proposed source of OTs–premature meiotic resumption was evident in oocytes of immature follicles. These findings, together with data from previous studies, suggest that a defect in oocyte-somatic cell communication leading to an uncoupling of coordinated growth and ultimately impaired sustainment of meiotic arrest is sufficient to drive OT development.


Vyšlo v časopise: Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005355
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005355

Souhrn

Ovarian teratomas (OTs) are the most frequent germ cell tumors in adult women, but their origin and molecular etiology remains poorly defined. We found that conditional deletion of the tumor suppressor Rb1 in the oocyte leads to OT development in young adult female mice. Further analysis revealed disturbances in both recruitment and growth of follicles. Although oocytes from mutants did not exhibit an enhanced propensity for parthenogenetic activation–a proposed source of OTs–premature meiotic resumption was evident in oocytes of immature follicles. These findings, together with data from previous studies, suggest that a defect in oocyte-somatic cell communication leading to an uncoupling of coordinated growth and ultimately impaired sustainment of meiotic arrest is sufficient to drive OT development.


Zdroje

1. dos Santos Silva I, Swerdlow AJ (1991) Ovarian germ cell malignancies in England: epidemiological parallels with testicular cancer. Br J Cancer 63: 814–818. 1645564

2. Smith HO, Berwick M, Verschraegen CF, Wiggins C, Lansing L, et al. (2006) Incidence and survival rates for female malignant germ cell tumors. Obstet Gynecol 107: 1075–1085. 16648414

3. Gershenson DM (1993) Update on malignant ovarian germ cell tumors. Cancer 71: 1581–1590. 8381708

4. Koshy M, Vijayananthan A, Vadiveloo V (2005) Malignant ovarian mixed germ cell tumour: a rare combination. Biomed Imaging Interv J 1: e10. doi: 10.2349/biij.1.2.e10 21625278

5. Outwater EK, Siegelman ES, Hunt JL (2001) Ovarian teratomas: tumor types and imaging characteristics. Radiographics 21: 475–490. 11259710

6. Surti U, Hoffner L, Chakravarti A, Ferrell RE (1990) Genetics and biology of human ovarian teratomas. I. Cytogenetic analysis and mechanism of origin. Am J Hum Genet 47: 635–643. 2220805

7. Takagi H, Ichigo S, Murase T, Ikeda T, Imai A (2012) Early diagnosis of malignant-transformed ovarian mature cystic teratoma: fat-suppressed MRI findings. J Gynecol Oncol 23: 125–128. doi: 10.3802/jgo.2012.23.2.125 22523630

8. Ginsburg M, Snow MH, McLaren A (1990) Primordial germ cells in the mouse embryo during gastrulation. Development 110: 521–528. 2133553

9. de Rooij DG, Russell LD (2000) All you wanted to know about spermatogonia but were afraid to ask. J Androl 21: 776–798. 11105904

10. Yang QE, Oatley JM (2014) Spermatogonial stem cell functions in physiological and pathological conditions. Curr Top Dev Biol 107: 235–267. doi: 10.1016/B978-0-12-416022-4.00009-3 24439809

11. Lin Y, Gill ME, Koubova J, Page DC (2008) Germ cell-intrinsic and-extrinsic factors govern meiotic initiation in mouse embryos. Science 322: 1685–1687. doi: 10.1126/science.1166340 19074348

12. McLaren A, Southee D (1997) Entry of mouse embryonic germ cells into meiosis. Dev Biol 187: 107–113. 9224678

13. Sarraj MA, Drummond AE (2012) Mammalian foetal ovarian development: consequences for health and disease. Reproduction 143: 151–163. doi: 10.1530/REP-11-0247 22106406

14. Yamaguchi S, Kimura H, Tada M, Nakatsuji N, Tada T (2005) Nanog expression in mouse germ cell development. Gene Expr Patterns 5: 639–646. 15939376

15. Leitch HG, Okamura D, Durcova-Hills G, Stewart CL, Gardner RL, et al. (2014) On the fate of primordial germ cells injected into early mouse embryos. Dev Biol 385: 155–159. doi: 10.1016/j.ydbio.2013.11.014 24269765

16. Kraggerud SM, Hoei-Hansen CE, Alagaratnam S, Skotheim RI, Abeler VM, et al. (2013) Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis. Endocr Rev 34: 339–376. doi: 10.1210/er.2012-1045 23575763

17. Linder D, McCaw BK, Hecht F (1975) Parthenogenic origin of benign ovarian teratomas. N Engl J Med 292: 63–66. 162806

18. Stanojevic B, Dzodic R, Saenko V, Milovanovic Z, Krstevski V, et al. (2012) Unilateral follicular variant of papillary thyroid carcinoma with unique KRAS mutation in struma ovarii in bilateral ovarian teratoma: a rare case report. BMC Cancer 12: 224. doi: 10.1186/1471-2407-12-224 22682753

19. Iwasa A, Oda Y, Kurihara S, Ohishi Y, Yasunaga M, et al. (2008) Malignant transformation of mature cystic teratoma to squamous cell carcinoma involves altered expression of p53- and p16/Rb-dependent cell cycle regulator proteins. Pathol Int 58: 757–764. doi: 10.1111/j.1440-1827.2008.02307.x 19067849

20. Tate G, Tajiri T, Suzuki T, Mitsuya T (2009) Mutations of the KIT gene and loss of heterozygosity of the PTEN region in a primary malignant melanoma arising from a mature cystic teratoma of the ovary. Cancer Genet Cytogenet 190: 15–20. doi: 10.1016/j.cancergencyto.2008.11.002 19264228

21. Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G, et al. (2013) Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature 495: 241–245. doi: 10.1038/nature11979 23467088

22. Szabova L, Yin C, Bupp S, Guerin TM, Schlomer JJ, et al. (2012) Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer. Cancer Res 72: 4141–4153. doi: 10.1158/0008-5472.CAN-11-3834 22617326

23. Schroder W (1991) Similar Histological Patterns in a Bilateral Malignant Teratoma of the Ovary and a Previous Retinoblastoma in a Girl. Onkologie 14: 437–439.

24. Hashimoto N, Watanabe N, Furuta Y, Tamemoto H, Sagata N, et al. (1994) Parthenogenetic activation of oocytes in c-mos-deficient mice. Nature 370: 68–71. 8015610

25. Youngson NA, Vickaryous N, van der Horst A, Epp T, Harten S, et al. (2011) A missense mutation in the transcription factor Foxo3a causes teratomas and oocyte abnormalities in mice. Mamm Genome 22: 235–248. doi: 10.1007/s00335-011-9317-7 21347845

26. Eppig JJ, Wigglesworth K, Varnum DS, Nadeau JH (1996) Genetic regulation of traits essential for spontaneous ovarian teratocarcinogenesis in strain LT/Sv mice: aberrant meiotic cell cycle, oocyte activation, and parthenogenetic development. Cancer Res 56: 5047–5054. 8895763

27. Hirao Y, Eppig JJ (1997) Parthenogenetic development of Mos-deficient mouse oocytes. Mol Reprod Dev 48: 391–396. 9322252

28. Balakrishnan A, Chaillet JR (2013) Role of the inositol polyphosphate-4-phosphatase type II Inpp4b in the generation of ovarian teratomas. Dev Biol 373: 118–129. doi: 10.1016/j.ydbio.2012.10.011 23078915

29. Spiller CM, Wilhelm D, Koopman P (2010) Retinoblastoma 1 protein modulates XY germ cell entry into G1/G0 arrest during fetal development in mice. Biol Reprod 82: 433–443. doi: 10.1095/biolreprod.109.078691 19864318

30. Guo J, Sheng G, Warner BW (2005) Epidermal growth factor-induced rapid retinoblastoma phosphorylation at Ser780 and Ser795 is mediated by ERK1/2 in small intestine epithelial cells. J Biol Chem 280: 35992–35998. 16126730

31. Gallardo T, Shirley L, John GB, Castrillon DH (2007) Generation of a germ cell-specific mouse transgenic Cre line, Vasa-Cre. Genesis 45: 413–417. 17551945

32. Ohinata Y, Payer B, O'Carroll D, Ancelin K, Ono Y, et al. (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436: 207–213. 15937476

33. Talerman A (1985) Germ cell tumours. Ann Pathol 5: 145–157. 3000396

34. Eppig JJ, Wigglesworth K, Pendola FL (2002) The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci U S A 99: 2890–2894. 11867735

35. Oliveira FG, Dozortsev D, Diamond MP, Fracasso A, Abdelmassih S, et al. (2004) Evidence of parthenogenetic origin of ovarian teratoma: case report. Hum Reprod 19: 1867–1870. 15192066

36. Racki WJ, Richter JD (2006) CPEB controls oocyte growth and follicle development in the mouse. Development 133: 4527–4537. 17050619

37. Parrington JM, West LF, Povey S (1984) The origin of ovarian teratomas. J Med Genet 21: 4–12. 6363699

38. Eppig JJ, Kozak LP, Eicher EM, Stevens LC (1977) Ovarian teratomas in mice are derived from oocytes that have completed the first meiotic division. Nature 269: 517–518. 909601

39. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270: 96–99. 7569956

40. Hsu SY, Lai RJ, Finegold M, Hsueh AJ (1996) Targeted overexpression of Bcl-2 in ovaries of transgenic mice leads to decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis. Endocrinology 137: 4837–4843. 8895354

41. Peltoketo H, Strauss L, Karjalainen R, Zhang M, Stamp GW, et al. (2010) Female mice expressing constitutively active mutants of FSH receptor present with a phenotype of premature follicle depletion and estrogen excess. Endocrinology 151: 1872–1883. doi: 10.1210/en.2009-0966 20172968

42. Vogel F (1979) Genetics of retinoblastoma. Hum Genet 52: 1–54. 393614

43. Hung CC, Lin SY, Lee CN, Chen CP, Lin SP, et al. (2011) Low penetrance of retinoblastoma for p.V654L mutation of the RB1 gene. BMC Med Genet 12: 76. doi: 10.1186/1471-2350-12-76 21615945

44. Furuta Y, Shigetani Y, Takeda N, Iwasaki K, Ikawa Y, et al. (1995) Ovarian teratomas in mice lacking the protooncogene c-mos. Jpn J Cancer Res 86: 540–545. 7622418

45. Mayer F, Mueller S, Malenke E, Kuczyk M, Hartmann JT, et al. (2005) Induction of apoptosis by flavopiridol unrelated to cell cycle arrest in germ cell tumour derived cell lines. Invest New Drugs 23: 205–211. 15868376

46. Andreu-Vieyra C, Chen R, Matzuk MM (2008) Conditional deletion of the retinoblastoma (Rb) gene in ovarian granulosa cells leads to premature ovarian failure. Mol Endocrinol 22: 2141–2161. doi: 10.1210/me.2008-0033 18599617

47. Yang QE, Gwost I, Oatley MJ, Oatley JM (2013) Retinoblastoma protein (RB1) controls fate determination in stem cells and progenitors of the mouse male germline. Biol Reprod 89: 113. doi: 10.1095/biolreprod.113.113159 24089198

48. Woods LM, Hodges CA, Baart E, Baker SM, Liskay M, et al. (1999) Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. J Cell Biol 145: 1395–1406. 10385520

49. Nagaoka SI, Hodges CA, Albertini DF, Hunt PA (2011) Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Curr Biol 21: 651–657. doi: 10.1016/j.cub.2011.03.003 21497085

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