Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1

English version České info

Germline mutations of the Liver Kinase b1 (LKB1/STK11) tumor suppressor gene have been linked to Peutz-Jeghers Syndrome (PJS), an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. We have conditionally deleted Lkb1 in Müllerian duct mesenchyme-derived cells of the female reproductive tract and observed expansion of the stromal compartment and hyperplasia and/or neoplasia of adjacent epithelial cells throughout the reproductive tract with paratubal cysts and adenomyomas in oviducts and, eventually, endometrial cancer. Examination of the proliferation marker phospho-histone H3 and mammalian Target Of Rapamycin Complex 1 (mTORC1) pathway members revealed increased proliferation and mTORC1 activation in stromal cells of both the oviduct and uterus. Treatment with rapamycin, an inhibitor of mTORC1 activity, decreased tumor burden in adult Lkb1 mutant mice. Deletion of the genes for Tuberous Sclerosis 1 (Tsc1) or Tsc2, regulators of mTORC1 that are downstream of LKB1 signaling, in the oviductal and uterine stroma phenocopies some of the defects observed in Lkb1 mutant mice, confirming that dysregulated mTORC1 activation in the Lkb1-deleted stroma contributes to the phenotype. Loss of PTEN, an upstream regulator of mTORC1 signaling, along with Lkb1 deletion significantly increased tumor burden in uteri and induced tumorigenesis in the cervix and vagina. These studies show that LKB1/TSC1/TSC2/mTORC1 signaling in mesenchymal cells is important for the maintenance of epithelial integrity and suppression of carcinogenesis in adjacent epithelial cells. Because similar changes in the stromal population are also observed in human oviductal/ovarian adenoma and endometrial adenocarcinoma patients, we predict that dysregulated mTORC1 activity by upstream mechanisms similar to those described in these model systems contributes to the pathogenesis of these human diseases.

Vyšlo v časopise: Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1. PLoS Genet 8(8): e32767. doi:10.1371/journal.pgen.1002906
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002906

Souhrn

Zdroje

1. KobayashiA, BehringerRR (2003) Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet 4: 969–980.

2. CunhaGR (1976) Stromal induction and specification of morphogenesis and cytodifferentiation of the epithelia of the Mullerian ducts and urogenital sinus during development of the uterus and vagina in mice. J Exp Zool 196: 361–370.

3. KuritaT, CookePS, CunhaGR (2001) Epithelial-stromal tissue interaction in paramesonephric (Mullerian) epithelial differentiation. Dev Biol 240: 194–211.

4. TanwarPS, ZhangL, RobertsDJ, TeixeiraJM (2011) Stromal deletion of the APC tumor suppressor in mice triggers development of endometrial cancer. Cancer Res 71: 1584–1596.

5. HezelAF, BardeesyN (2008) LKB1; linking cell structure and tumor suppression. Oncogene 27: 6908–6919.

6. Sanchez-CespedesM (2007) A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26: 7825–7832.

7. CarlingD (2004) The AMP-activated protein kinase cascade–a unifying system for energy control. Trends Biochem Sci 29: 18–24.

8. HezelAF, GurumurthyS, GranotZ, SwisaA, ChuGC, et al. (2008) Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol Cell Biol 28: 2414–2425.

9. ContrerasCM, GurumurthyS, HaynieJM, ShirleyLJ, AkbayEA, et al. (2008) Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res 68: 759–766.

10. WingoSN, GallardoTD, AkbayEA, LiangMC, ContrerasCM, et al. (2009) Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE 4: e5137 doi:10.1371/journal.pone.0005137.

11. KatajistoP, VaahtomeriK, EkmanN, VentelaE, RistimakiA, et al. (2008) LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet 40: 455–459.

12. ClementsA, RobisonK, GranaiC, SteinhoffMM, Scalia-WilburJ, et al. (2009) A case of Peutz-Jeghers syndrome with breast cancer, bilateral sex cord tumor with annular tubules, and adenoma malignum caused by STK11 gene mutation. Int J Gynecol Cancer 19: 1591–1594.

13. CondeE, Suarez-GauthierA, Garcia-GarciaE, Lopez-RiosF, Lopez-EncuentraA, et al. (2007) Specific pattern of LKB1 and phospho-acetyl-CoA carboxylase protein immunostaining in human normal tissues and lung carcinomas. Hum Pathol 38: 1351–1360.

14. SrivatsaPJ, KeeneyGL, PodratzKC (1994) Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz-Jeghers syndrome. Gynecol Oncol 53: 256–264.

15. ContrerasCM, AkbayEA, GallardoTD, HaynieJM, SharmaS, et al. (2010) Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. Dis Model Mech 3: 181–193.

16. JaminSP, ArangoNA, MishinaY, HanksMC, BehringerRR (2002) Requirement of Bmpr1a for Mullerian duct regression during male sexual development. Nat Genet 32: 408–410.

17. SeidmanJD (1994) Mucinous lesions of the fallopian tube. A report of seven cases. Am J Surg Pathol 18: 1205–1212.

18. GilksCB, YoungRH, AguirreP, DeLellisRA, ScullyRE (1989) Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol 13: 717–729.

19. BardeesyN, SinhaM, HezelAF, SignorettiS, HathawayNA, et al. (2002) Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419: 162–167.

20. GonzalezG, BehringerRR (2009) Dicer is required for female reproductive tract development and fertility in the mouse. Mol Reprod Dev 76: 678–688.

21. HongX, LuenseLJ, McGinnisLK, NothnickWB, ChristensonLK (2008) Dicer1 is essential for female fertility and normal development of the female reproductive system. Endocrinology 149: 6207–6212.

22. ArangoNA, SzotekPP, ManganaroTF, OlivaE, DonahoePK, et al. (2005) Conditional deletion of beta-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium. Dev Biol 288: 276–283.

23. NagarajaAK, Andreu-VieyraC, FrancoHL, MaL, ChenR, et al. (2008) Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Mol Endocrinol 22: 2336–2352.

24. NelsonWJ (2009) Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol 1: a000513.

25. WewerUM, DamjanovA, WeissJ, LiottaLA, DamjanovI (1986) Mouse endometrial stromal cells produce basement-membrane components. Differentiation 32: 49–58.

26. TanakaT, WangC, UmesakiN (2009) Remodeling of the human endometrial epithelium is regulated by laminin and type IV collagen. Int J Mol Med 23: 173–180.

27. FaberM, WewerUM, BerthelsenJG, LiottaLA, AlbrechtsenR (1986) Laminin production by human endometrial stromal cells relates to the cyclic and pathologic state of the endometrium. Am J Pathol 124: 384–391.

28. BullettiC, GalassiA, JasonniVM, MartinelliG, TabanelliS, et al. (1988) Basement membrane components in normal hyperplastic and neoplastic endometrium. Cancer 62: 142–149.

29. TorresM, Gomez-PardoE, DresslerGR, GrussP (1995) Pax-2 controls multiple steps of urogenital development. Development 121: 4057–4065.

30. PendeM, UmSH, MieuletV, StickerM, GossVL, et al. (2004) S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24: 3112–3124.

31. DeutscherE, Hung-Chang YaoH (2007) Essential roles of mesenchyme-derived beta-catenin in mouse Mullerian duct morphogenesis. Dev Biol 307: 227–236.

32. MorenA, RajaE, HeldinCH, MoustakasA (2011) Negative regulation of TGFbeta signaling by the kinase LKB1 and the scaffolding protein LIP1. J Biol Chem 286: 341–353.

33. WynnTA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214: 199–210.

34. BhowmickNA, ChytilA, PliethD, GorskaAE, DumontN, et al. (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303: 848–851.

35. BhowmickNA, NeilsonEG, MosesHL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432: 332–337.

36. HaramisAP, BegthelH, van den BornM, van EsJ, JonkheerS, et al. (2004) De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303: 1684–1686.

37. KwiatkowskiDJ (2003) Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol Ther 2: 471–476.

38. ParkHS, LeeSO, LeeJM, KangMJ, LeeDG, et al. (2003) Adenomyoma of the small intestine: report of two cases and review of the literature. Pathol Int 53: 111–114.

39. KisslerS, HamschoN, ZangosS, WiegratzI, SchlichterS, et al. (2006) Uterotubal transport disorder in adenomyosis and endometriosis–a cause for infertility. BJOG 113: 902–908.

40. TahlanA, NandaA, MohanH (2006) Uterine adenomyoma: a clinicopathologic review of 26 cases and a review of the literature. Int J Gynecol Pathol 25: 361–365.

41. ApiO, ErgenB, GulAE, ErgenC, UnalO, et al. (2009) Primary ovarian adenomyoma in a woman with endometrial polyp: a case report and review of the literature. Arch Gynecol Obstet 280: 445–448.

42. Teixeira J, Rueda BR, Pru JK (2008) Uterine stem cells. StemBook, ed. The Stem Cell Research Community, StemBook. doi:10.3824/stembook.1.16.1, http://www.stembook.org.

43. LuKH, WuW, DaveB, SlomovitzBM, BurkeTW, et al. (2008) Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res 14: 2543–2550.

44. FrielAM, GrowdonWB, McCannCK, OlawaiyeAB, MunroEG, et al. (2010) Mouse models of uterine corpus tumors: clinical significance and utility. Front Biosci (Elite Ed) 2: 882–905.

45. TanwarPS, ZhangL, Kaneko-TaruiT, CurleyMD, TaketoMM, et al. (2011) Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/beta-catenin and PTEN. PLoS ONE 6: e20715 doi:10.1371/journal.pone.0020715.

46. PattersonMJ, KernenJA (1985) Epithelioid leiomyosarcoma originating in a hamartomatous polyp from a patient with Peutz-Jeghers syndrome. Gastroenterology 88: 1060–1064.

47. GibaultL, FerreiraC, PerotG, AudebourgA, ChibonF, et al. (2012) From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas. Mod Pathol 25: 197–211.

48. CrabtreeJS, JelinskySA, HarrisHA, ChoeSE, CotreauMM, et al. (2009) Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway. Cancer Res 69: 6171–6178.

49. LagueMN, DetmarJ, PaquetM, BoyerA, RichardsJS, et al. (2010) Decidual PTEN expression is required for trophoblast invasion in the mouse. Am J Physiol Endocrinol Metab 299: E936–946.

50. DaikokuT, JacksonL, BesnardV, WhitsettJ, EllensonLH, et al. (2011) Cell-specific conditional deletion of Pten in the uterus results in differential phenotypes. Gynecol Oncol 122: 424–429.

51. ZhouJ, BrugarolasJ, ParadaLF (2009) Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1. Hum Mol Genet 18: 4428–4441.

52. JiJ, ZhengPS (2010) Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecol Oncol 117: 103–108.

53. HearleN, SchumacherV, MenkoFH, OlschwangS, BoardmanLA, et al. (2006) Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12: 3209–3215.

54. CorradettiMN, InokiK, BardeesyN, DePinhoRA, GuanKL (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18: 1533–1538.

55. ShawRJ, BardeesyN, ManningBD, LopezL, KosmatkaM, et al. (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6: 91–99.

56. AdhikariD, ZhengW, ShenY, GorreN, HamalainenT, et al. (2010) Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet 19: 397–410.

57. TanakaY, ParkJH, TanwarPS, Kaneko-TaruiT, MittalS, et al. (2012) Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility. Endocrinology 153: 404–416.

58. OllilaS, MakelaTP (2011) The tumor suppressor kinase LKB1: lessons from mouse models. J Mol Cell Biol 3: 330–340.

59. MalhowskiAJ, HiraH, BashiruddinS, WarburtonR, GotoJ, et al. (2011) Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin. Hum Mol Genet 20: 1290–1305.

60. IkushimaH, MiyazonoK (2010) TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 10: 415–424.

61. KuperwasserC, ChavarriaT, WuM, MagraneG, GrayJW, et al. (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A 101: 4966–4971.

62. EllenriederV, HendlerSF, RuhlandC, BoeckW, AdlerG, et al. (2001) TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer 93: 204–211.

63. FariedLS, FariedA, KanumaT, AokiH, SanoT, et al. (2008) Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: A potential biomarker and molecular target therapy. Mol Carcinog 47: 446–457.

64. Marignani PA, Sanchez-Cespedes M (2010) The tumour suppressor role of LKB1 in human cancer. In: Lazo PA, editor. Emerging Signaling Pathways in Tumor Biology. Kerala India: Transworld Research Network. pp. 71–94.

65. KwiatkowskiDJ, ZhangH, BanduraJL, HeibergerKM, GlogauerM, et al. (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11: 525–534.

66. HernandezO, WayS, McKennaJ3rd, GambelloMJ (2007) Generation of a conditional disruption of the Tsc2 gene. Genesis 45: 101–106.

67. LescheR, GroszerM, GaoJ, WangY, MessingA, et al. (2002) Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 32: 148–149.

68. TanwarPS, LeeHJ, ZhangL, ZukerbergLR, TaketoMM, et al. (2009) Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol Reprod 81: 545–552.