Endocrinol Metab.  2013 Dec;28(4):245-254. 10.3803/EnM.2013.28.4.245.

The Molecular Pathogenesis of Pituitary Adenomas: An Update

• Jiang X
• Zhang X

• KMID: 2169301
• DOI: http://doi.org/10.3803/EnM.2013.28.4.245

Abstract

Pituitary tumors represent the most common intracranial neoplasms accompanying serious morbidity through mass effects and inappropriate secretion of pituitary hormones. Understanding the etiology of pituitary tumorigenesis will facilitate the development of satisfactory treatment for pituitary adenomas. Although the pathogenesis of pituitary adenomas is largely unknown, considerable evidence indicates that the pituitary tumorigenesis is a complex process involving multiple factors, including genetic and epigenetic changes. This review summarized the recent progress in the study of pituitary tumorigenesis, focusing on the role of tumor suppressor genes, oncogenes and microRNAs.

Keyword

Pituitary neoplasms; Oncogenes; Tumor suppressors; Cell cycle; MicroRNAs

MeSH Terms

Brain Neoplasms
Cell Cycle
Cell Transformation, Neoplastic
Epigenomics
Genes, Tumor Suppressor
MicroRNAs
Oncogenes
Pituitary Hormones
Pituitary Neoplasms*
MicroRNAs
Pituitary Hormones

Reference

1. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004; 101:613–619.

2. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab. 2006; 91:4769–4775.

3. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf). 2010; 72:377–382.

4. Ezzat S, Asa SL. Mechanisms of disease: the pathogenesis of pituitary tumors. Nat Clin Pract Endocrinol Metab. 2006; 2:220–230.

5. Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol. 2011; 7:257–266.

6. Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold A, Klibanski A. Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest. 1990; 86:336–340.

7. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. 1990; 71:1427–1433.

8. Jacoby LB, Hedley-Whyte ET, Pulaski K, Seizinger BR, Martuza RL. Clonal origin of pituitary adenomas. J Neurosurg. 1990; 73:731–735.

9. Melmed S. Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Invest. 2003; 112:1603–1618.

10. Ezzat S. Epigenetic control in pituitary tumors. Endocr J. 2008; 55:951–957.

11. Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 2012; 48:R45–R53.

12. Shi X, Tao B, He H, Sun Q, Fan C, Bian L, Zhao W, Lu YC. MicroRNAs-based network: a novel therapeutic agent in pituitary adenoma. Med Hypotheses. 2012; 78:380–384.

13. Daly AF, Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA, Murat A, Emy P, Gimenez-Roqueplo AP, Tamburrano G, Raverot G, Barlier A, De Herder W, Penfornis A, Ciccarelli E, Estour B, Lecomte P, Gatta B, Chabre O, Sabate MI, Bertagna X, Garcia Basavilbaso N, Stalldecker G, Colao A, Ferolla P, Wemeau JL, Caron P, Sadoul JL, Oneto A, Archambeaud F, Calender A, Sinilnikova O, Montanana CF, Cavagnini F, Hana V, Solano A, Delettieres D, Luccio-Camelo DC, Basso A, Rohmer V, Brue T, Bours V, Teh BT, Beckers A. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab. 2007; 92:1891–1896.

14. Marko NF, Weil RJ. Pituitary gland: new pathways in the pathogenesis of pituitary adenomas. Nat Rev Endocrinol. 2012; 8:572–573.

15. Oriola J, Lucas T, Halperin I, Mora M, Perales MJ, Alvarez-Escola C, Paz de MN, Diaz Soto G, Salinas I, Julian MT, Olaizola I, Bernabeu I, Marazuela M, Puig-Domingo M. Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. Eur J Endocrinol. 2012; 168:9–13.

16. Tichomirowa MA, Barlier A, Daly AF, Jaffrain-Rea ML, Ronchi C, Yaneva M, Urban JD, Petrossians P, Elenkova A, Tabarin A, Desailloud R, Maiter D, Schürmeyer T, Cozzi R, Theodoropoulou M, Sievers C, Bernabeu I, Naves LA, Chabre O, Montanana CF, Hana V, Halaby G, Delemer B, Aizpun JI, Sonnet E, Longas AF, Hagelstein MT, Caron P, Stalla GK, Bours V, Zacharieva S, Spada A, Brue T, Beckers A. High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol. 2011; 165:509–515.

17. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab. 2010; 24:355–370.

18. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J, Atkinson MJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 2006; 103:15558–15563.

19. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab. 2009; 94:1826–1834.

20. Lania AG, Ferrero S, Pivonello R, Mantovani G, Peverelli E, Di Sarno A, Beck-Peccoz P, Spada A, Colao A. Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation. J Clin Endocrinol Metab. 2010; 95:13–17.

21. Freda PU, Chung WK, Matsuoka N, Walsh JE, Kanibir MN, Kleinman G, Wang Y, Bruce JN, Post KD. Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission. Pituitary. 2007; 10:275–282.

22. Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000; 26:89–92.

23. Kaltsas GA, Kola B, Borboli N, Morris DG, Gueorguiev M, Swords FM, Czirjak S, Kirschner LS, Stratakis CA, Korbonits M, Grossman AB. Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Clin Endocrinol (Oxf). 2002; 57:443–448.

24. Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL. Ras mutations in human pituitary tumors. J Clin Endocrinol Metab. 1992; 74:914–919.

25. Dudley KJ, Revill K, Clayton RN, Farrell WE. Pituitary tumours: all silent on the epigenetics front. J Mol Endocrinol. 2009; 42:461–468.

26. Farrell WE. Epigenetic mechanisms of tumorigenesis. Horm Metab Res. 2005; 37:361–368.

27. Bahar A, Bicknell JE, Simpson DJ, Clayton RN, Farrell WE. Loss of expression of the growth inhibitory gene GADD45gamma, in human pituitary adenomas, is associated with CpG island methylation. Oncogene. 2004; 23:936–944.

28. Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, Klibanski A. A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab. 2003; 88:5119–5126.

29. Zhao J, Dahle D, Zhou Y, Zhang X, Klibanski A. Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors. J Clin Endocrinol Metab. 2005; 90:2179–2186.

30. Zhao J, Zhang X, Zhou Y, Ansell PJ, Klibanski A. Cyclic AMP stimulates MEG3 gene expression in cells through a cAMP-response element (CRE) in the MEG3 proximal promoter region. Int J Biochem Cell Biol. 2006; 38:1808–1820.

31. Gejman R, Batista DL, Zhong Y, Zhou Y, Zhang X, Swearingen B, Stratakis CA, Hedley-Whyte ET, Klibanski A. Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 2008; 93:4119–4125.

32. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991; 325:1688–1695.

33. Vortmeyer AO, Glasker S, Mehta GU, Abu-Asab MS, Smith JH, Zhuang Z, Collins MT, Oldfield EH. Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome. J Clin Endocrinol Metab. 2012; 97:2404–2413.

34. Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol (Oxf). 2012; 76:96–102.

35. Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J. The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clin Endocrinol (Oxf). 2008; 68:458–465.

36. Musat M, Korbonits M, Kola B, Borboli N, Hanson MR, Nanzer AM, Grigson J, Jordan S, Morris DG, Gueorguiev M, Coculescu M, Basu S, Grossman AB. Enhanced protein kinase B/Akt signalling in pituitary tumours. Endocr Relat Cancer. 2005; 12:423–433.

37. Lin Y, Jiang X, Shen Y, Li M, Ma H, Xing M, Lu Y. Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocr Relat Cancer. 2009; 16:301–310.

38. Yu R, Melmed S. Pituitary tumor transforming gene: an update. Front Horm Res. 2004; 32:175–185.

39. Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B, Klibanski A. Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis. J Clin Endocrinol Metab. 2002; 87:1262–1267.

40. Michaelis KA, Knox AJ, Xu M, Kiseljak-Vassiliades K, Edwards MG, Geraci M, Kleinschmidt-DeMasters BK, Lillehei KO, Wierman ME. Identification of growth arrest and DNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor in pituitary gonadotrope tumors. Endocrinology. 2011; 152:3603–3613.

41. Vandeva S, Tichomirowa MA, Zacharieva S, Daly AF, Beckers A. Genetic factors in the development of pituitary adenomas. Endocr Dev. 2010; 17:121–133.

42. Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, Igreja SC, Chapple JP, Jordan S, Lupp A, Schulz S, Ansorge O, Karavitaki N, Carlsen E, Wass JA, Grossman AB, Korbonits M. Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J Clin Endocrinol Metab. 2012; 97:E1411–E1420.

43. Rostad S. Pituitary adenoma pathogenesis: an update. Curr Opin Endocrinol Diabetes Obes. 2012; 19:322–327.

44. Walls GV, Lemos MC, Javid M, Bazan-Peregrino M, Jeyabalan J, Reed AA, Harding B, Tyler DJ, Stuckey DJ, Piret S, Christie PT, Ansorge O, Clarke K, Seymour L, Thakker RV. MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas. Cancer Res. 2012; 72:5060–5068.

45. Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, Rene-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab. 2009; 94:2085–2091.

46. Yin Z, Williams-Simons L, Parlow AF, Asa S, Kirschner LS. Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Mol Endocrinol. 2008; 22:380–387.

47. Xu M, Knox AJ, Michaelis KA, Kiseljak-Vassiliades K, Kleinschmidt-DeMasters BK, Lillehei KO, Wierman ME. Reprimo (RPRM) is a novel tumor suppressor in pituitary tumors and regulates survival, proliferation, and tumorigenicity. Endocrinology. 2012; 153:2963–2973.

48. Lee EY, Cam H, Ziebold U, Rayman JB, Lees JA, Dynlacht BD. E2F4 loss suppresses tumorigenesis in Rb mutant mice. Cancer Cell. 2002; 2:463–472.

49. Georgitsi M. MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors [p27(Kip1) and p18(INK4C)] mutations. Best Pract Res Clin Endocrinol Metab. 2010; 24:425–437.

50. Bellodi C, Krasnykh O, Haynes N, Theodoropoulou M, Peng G, Montanaro L, Ruggero D. Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. Cancer Res. 2010; 70:6026–6035.

51. Cander S, Erturk E, Karkucak M, Oz Gul O, Gorukmez O, Yakut T, Unal OK, Ersoy C, Tuncel E, Imamoglu S. Effect of cycline D1 (CCND1) gene polymorphism on tumor formation and behavior in patients with prolactinoma. Gene. 2012; 509:158–163.

52. Fedele M, Palmieri D, Fusco A. HMGA2: a pituitary tumour subtype-specific oncogene? Mol Cell Endocrinol. 2010; 326:19–24.

53. Fedele M, Battista S, Kenyon L, Baldassarre G, Fidanza V, Klein-Szanto AJ, Parlow AF, Visone R, Pierantoni GM, Outwater E, Santoro M, Croce CM, Fusco A. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene. 2002; 21:3190–3198.

54. Fedele M, Visone R, De Martino I, Troncone G, Palmieri D, Battista S, Ciarmiello A, Pallante P, Arra C, Melillo RM, Helin K, Croce CM, Fusco A. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell. 2006; 9:459–471.

55. Fedele M, Pentimalli F, Baldassarre G, Battista S, Klein-Szanto AJ, Kenyon L, Visone R, De Martino I, Ciarmiello A, Arra C, Viglietto G, Croce CM, Fusco A. Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene. 2005; 24:3427–3435.

56. Palmieri D, Valentino T, De Martino I, Esposito F, Cappabianca P, Wierinckx A, Vitiello M, Lombardi G, Colao A, Trouillas J, Pierantoni GM, Fusco A, Fedele M. PIT1 upregulation by HMGA proteins has a role in pituitary tumorigenesis. Endocr Relat Cancer. 2012; 19:123–135.

57. Zhu X, Asa SL, Ezzat S. Fibroblast growth factor 2 and estrogen control the balance of histone 3 modifications targeting MAGE-A3 in pituitary neoplasia. Clin Cancer Res. 2008; 14:1984–1996.

58. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116:281–297.

59. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004; 101:2999–3004.

60. Mao ZG, He DS, Zhou J, Yao B, Xiao WW, Chen CH, Zhu YH, Wang HJ. Differential expression of microRNAs in GH-secreting pituitary adenomas. Diagn Pathol. 2010; 5:79.

61. Bottoni A, Zatelli MC, Ferracin M, Tagliati F, Piccin D, Vignali C, Calin GA, Negrini M, Croce CM, Degli Uberti EC. Identification of differentially expressed microRNAs by microarray: a possible role for microRNA genes in pituitary adenomas. J Cell Physiol. 2007; 210:370–377.

62. Bottoni A, Piccin D, Tagliati F, Luchin A, Zatelli MC, degli Uberti EC. miR-15a and miR-16-1 down-regulation in pituitary adenomas. J Cell Physiol. 2005; 204:280–285.

63. Amaral FC, Torres N, Saggioro F, Neder L, Machado HR, Silva WA Jr, Moreira AC, Castro M. MicroRNAs differentially expressed in ACTH-secreting pituitary tumors. J Clin Endocrinol Metab. 2009; 94:320–323.

64. Butz H, Liko I, Czirjak S, Igaz P, Khan MM, Zivkovic V, Balint K, Korbonits M, Racz K, Patocs A. Down-regulation of Wee1 kinase by a specific subset of microRNA in human sporadic pituitary adenomas. J Clin Endocrinol Metab. 2010; 95:E181–E191.

65. Stilling G, Sun Z, Zhang S, Jin L, Righi A, Kovacs G, Korbonits M, Scheithauer BW, Kovacs K, Lloyd RV. MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas. Endocrine. 2010; 38:67–75.

66. Trivellin G, Butz H, Delhove J, Igreja S, Chahal HS, Zivkovic V, McKay T, Patocs A, Grossman AB, Korbonits M. MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro. Am J Physiol Endocrinol Metab. 2012; 303:E708–E719.

67. Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I, Briasoulis E. The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cell Mol Life Sci. 2013; 70:795–814.

68. Cheunsuchon P, Zhou Y, Zhang X, Lee H, Chen W, Nakayama Y, Rice KA, Tessa Hedley-Whyte E, Swearingen B, Klibanski A. Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas. Am J Pathol. 2011; 179:2120–2130.

69. Finelli P, Giardino D, Rizzi N, Buiatiotis S, Virduci T, Franzin A, Losa M, Larizza L. Non-random trisomies of chromosomes 5, 8 and 12 in the prolactinoma sub-type of pituitary adenomas: conventional cytogenetics and interphase FISH study. Int J Cancer. 2000; 86:344–350.

70. D'Angelo D, Palmieri D, Mussnich P, Roche M, Wierinckx A, Raverot G, Fedele M, Croce CM, Trouillas J, Fusco A. Altered microRNA expression profile in human pituitary GH adenomas: down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1. J Clin Endocrinol Metab. 2012; 97:E1128–E1138.

71. Palmieri D, D'Angelo D, Valentino T, De Martino I, Ferraro A, Wierinckx A, Fedele M, Trouillas J, Fusco A. Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis. Oncogene. 2012; 31:3857–3865.

72. Zhang Z, Florez S, Gutierrez-Hartmann A, Martin JF, Amendt BA. MicroRNAs regulate pituitary development, and microRNA 26b specifically targets lymphoid enhancer factor 1 (Lef-1), which modulates pituitary transcription factor 1 (Pit-1) expression. J Biol Chem. 2010; 285:34718–34728.

73. Palumbo T, Faucz FR, Azevedo M, Xekouki P, Iliopoulos D, Stratakis CA. Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway. Oncogene. 2013; 32:1651–1659.

74. Zhang X, Zhou Y, Klibanski A. Isolation and characterization of novel pituitary tumor related genes: a cDNA representational difference approach. Mol Cell Endocrinol. 2010; 326:40–47.

75. Balik V, Srovnal J, Sulla I, Kalita O, Foltanova T, Vaverka M, Hrabalek L, Hajduch M. MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas. J Neurooncol. 2013; 112:1–8.