Skip to main content

Advertisement

SpringerLink
Log in

The molecular biology of pituitary tumors: a personal perspective

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Oncogenes and tumor suppressor genes involved in most common cancers are not involved in the great majority of pituitary adenomas. Similarly, there is little evidence to suggest that the mutations involved in genetic syndromes associated with pituitary tumors (such as the gsp, MEN1, PKAR1A or AIP mutations) are common in sporadic tumors. A novel pituitary tumor transforming gene (PTTG, securin) has been identified which is over-expressed in most tumors—but it is unclear as to its causal role in oncogenesis. Cell signaling abnormalities have been identified in pituitary tumors but their genetic basis is unknown. However, both the Akt pathway and the MAPK pathway are over-expressed in many pituitary tumors, which results in the inhibition of cell cycle inhibitors. These pathways share a common root in the tyrosine kinase receptor, and a change to these receptors or their relationship to membrane matrix-related proteins may be an early event in tumorigenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Spada A, Arosio M, Bochicchio D, Bazzoni N, Vallar L, Bassetti M et al (1990) Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 71(6):1421–1426

    Article  PubMed  CAS  Google Scholar 

  2. Lania A, Mantovani G, Spada A (2003) Genetics of pituitary tumors: focus on G-protein mutations. Exp Biol Med (Maywood) 228(9):1004–1017

    CAS  Google Scholar 

  3. Farrell WE, Simpson DJ, Bicknell J, Magnay JL, Kyrodimou E, Thakker RV et al (1999) Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours. Br J Cancer 80(1–2):44–50. doi:10.1038/sj.bjc.6690319

    Article  PubMed  CAS  Google Scholar 

  4. Georgitsi M, Raitila A, Karhu A, van der Luijt RB, Aalfs CM, Sane T et al (2007) Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 92(8):3321–3325. doi:10.1210/jc.2006-2843

    Article  PubMed  CAS  Google Scholar 

  5. Dahia PL, Aguiar RC, Honegger J, Fahlbush R, Jordan S, Lowe DG et al (1998) Mutation and expression analysis of the p27/kip1 gene in corticotrophin-secreting tumours. Oncogene 16(1):69–76. doi:10.1038/sj.onc.1201516

    Article  PubMed  CAS  Google Scholar 

  6. Kaltsas GA, Kola B, Borboli N, Morris DG, Gueorguiev M, Swords FM et al (2002) Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Clin Endocrinol (Oxf) 57(4):443–448. doi:10.1046/j.1365-2265.2002.01643.x

    Article  CAS  Google Scholar 

  7. Sandrini F, Kirschner LS, Bei T, Farmakidis C, Yasufuku-Takano J, Takano K et al (2002) PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely altered in pituitary tumours outside the Carney complex. J Med Genet 39(12):e78. doi:10.1136/jmg.39.12.e78

    Article  PubMed  CAS  Google Scholar 

  8. Gadelha MR, Une KN, Rohde K, Vaisman M, Kineman RD, Frohman LA (2000) Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12. J Clin Endocrinol Metab 85(2):707–714. doi:10.1210/jc.85.2.707

    Article  PubMed  CAS  Google Scholar 

  9. Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A et al (2006) Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312(5777):1228–1230. doi:10.1126/science.1126100

    Article  PubMed  CAS  Google Scholar 

  10. Marlowe JL, Puga A (2005) Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 96(6):1174–1184. doi:10.1002/jcb.20656

    Article  PubMed  CAS  Google Scholar 

  11. Leontiou CA, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S et al (2008) The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab 93(6):2390–2401. doi:10.1210/jc.2007-2611

    Article  PubMed  CAS  Google Scholar 

  12. Iwata T, Yamada S, Mizusawa N, Golam HM, Sano T, Yoshimoto K (2007) The aryl hydrocarbon receptor-interacting protein gene is rarely mutated in sporadic GH-secreting adenomas. Clin Endocrinol (Oxf) 66(4):499–502

    CAS  Google Scholar 

  13. Daly AF, Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA et al (2007) Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 92(5):1891–1896. doi:10.1210/jc.2006-2513

    Article  PubMed  CAS  Google Scholar 

  14. Toledo RA, Lourenco DM Jr, Liberman B, Cunha-Neto MB, Cavalcanti MG, Moyses CB et al (2007) Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma. J Clin Endocrinol Metab 92(5):1934–1937. doi:10.1210/jc.2006-2394

    Article  PubMed  CAS  Google Scholar 

  15. Dahia PL, Ahmed-Shuaib A, Jacobs RA, Chew SL, Honegger J, Fahlbusch R et al (1996) Vasopressin receptor expression and mutation analysis in corticotropin-secreting tumors. J Clin Endocrinol Metab 81(5):1768–1771. doi:10.1210/jc.81.5.1768

    Article  PubMed  CAS  Google Scholar 

  16. Dahia PL, Honegger J, Reincke M, Jacobs RA, Mirtella A, Fahlbusch R et al (1997) Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors. J Clin Endocrinol Metab 82(4):1088–1093. doi:10.1210/jc.82.4.1088

    Article  PubMed  CAS  Google Scholar 

  17. Morris DG, Kola B, Borboli N, Kaltsas GA, Gueorguiev M, McNicol AM et al (2003) Identification of adrenocorticotropin receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas. J Clin Endocrinol Metab 88(12):6080–6087. doi:10.1210/jc.2002-022048

    Article  PubMed  CAS  Google Scholar 

  18. Korbonits M, Bujalska I, Shimojo M, Nobes J, Jordan S, Grossman AB et al (2001) Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the human pituitary: induction of the type 2 enzyme in corticotropinomas and other pituitary tumors. J Clin Endocrinol Metab 86(6):2728–2733. doi:10.1210/jc.86.6.2728

    Article  PubMed  CAS  Google Scholar 

  19. Bilodeau S, Vallette-Kasic S, Gauthier Y, Figarella-Branger D, Brue T, Berthelet F et al (2006) Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev 20(20):2871–2886. doi:10.1101/gad.1444606

    Article  PubMed  CAS  Google Scholar 

  20. Kola B, Korbonits M, Diaz-Cano S, Kaltsas G, Morris DG, Jordan S et al (2003) Reduced expression of the growth hormone and type 1 insulin-like growth factor receptors in human somatotroph tumours and an analysis of possible mutations of the growth hormone receptor. Clin Endocrinol (Oxf) 59(3):328–338. doi:10.1046/j.1365-2265.2003.01851.x

    Article  CAS  Google Scholar 

  21. Asa SL, Digiovanni R, Jiang J, Ward ML, Loesch K, Yamada S et al (2007) A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors. Cancer Res 67(15):7505–7511. doi:10.1158/0008-5472.CAN-07-0219

    Article  PubMed  CAS  Google Scholar 

  22. Greenman Y, Prager D, Melmed S (1995) The IGF-I receptor sub-membrane domain is intact in GH-secreting pituitary tumours. Clin Endocrinol (Oxf) 42(2):169–172. doi:10.1111/j.1365-2265.1995.tb01858.x

    Article  CAS  Google Scholar 

  23. Lidhar K, Korbonits M, Jordan S, Khalimova Z, Kaltsas G, Lu X et al (1999) Low expression of the cell cycle inhibitor p27Kip1 in normal corticotroph cells, corticotroph tumors, and malignant pituitary tumors. J Clin Endocrinol Metab 84(10):3823–3830. doi:10.1210/jc.84.10.3823

    Article  PubMed  CAS  Google Scholar 

  24. Jin L, Qian X, Kulig E, Sanno N, Scheithauer BW, Kovacs K et al (1997) Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries. Am J Pathol 151(2):509–519

    PubMed  CAS  Google Scholar 

  25. Korbonits M, Chahal HS, Kaltsas G, Jordan S, Urmanova Y, Khalimova Z et al (2002) Expression of phosphorylated p27(Kip1) protein and Jun activation domain-binding protein 1 in human pituitary tumors. J Clin Endocrinol Metab 87(6):2635–2643. doi:10.1210/jc.87.6.2635

    Article  PubMed  CAS  Google Scholar 

  26. Musat M, Korbonits M, Kola B, Borboli N, Hanson MR, Nanzer AM et al (2005) Enhanced protein kinase B/Akt signalling in pituitary tumours. Endocr Relat Cancer 12(2):423–433. doi:10.1677/erc.1.00949

    Article  PubMed  CAS  Google Scholar 

  27. Farrell WE, Clayton RN (2003) Epigenetic change in pituitary tumorigenesis. Endocr Relat Cancer 10(2):323–330. doi:10.1677/erc.0.0100323

    Article  PubMed  CAS  Google Scholar 

  28. Chesnokova V, Zonis S, Rubinek T, Yu R, Ben-Shlomo A, Kovacs K et al (2007) Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. Cancer Res 67(21):10564–10572. doi:10.1158/0008-5472.CAN-07-0974

    Article  PubMed  CAS  Google Scholar 

  29. Gejman R, Batista DL, Zhong Y, Zhou Y, Zhang X, Swearingen B et al (2008) 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 93(10):4119–4125. doi:10.1210/jc.2007-2633

    Article  PubMed  CAS  Google Scholar 

  30. Ewing I, Pedder-Smith S, Franchi G, Ruscica M, Emery M, Vax V et al (2007) A mutation and expression analysis of the oncogene BRAF in pituitary adenomas. Clin Endocrinol (Oxf) 66(3):348–352. doi:10.1111/j.1365-2265.2006.02735.x

    Article  CAS  Google Scholar 

  31. Morris DG, Musat M, Czirjak S, Hanzely Z, Lillington DM, Korbonits M et al (2005) Differential gene expression in pituitary adenomas by oligonucleotide array analysis. Eur J Endocrinol 153(1):143–151. doi:10.1530/eje.1.01937

    Article  PubMed  CAS  Google Scholar 

  32. Dworakowska D et al (2008) Extracellular signal-regulated kinase (ERK 1/2) overactivation in pituitary adenomas. In: The endocrine society’s annual meeting, San Francisco, USA

  33. Vlotides G, Siegel E, Donangelo I, Gutman S, Ren SG, Melmed S (2008) Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands. Cancer Res 68(15):6377–6386. doi:10.1158/0008-5472.CAN-08-0508

    Article  PubMed  CAS  Google Scholar 

  34. Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD et al (1999) Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 84(2):761–767. doi:10.1210/jc.84.2.761

    Article  PubMed  CAS  Google Scholar 

  35. Filippella M, Galland F, Kujas M, Young J, Faggiano A, Lombardi G et al (2006) Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin Endocrinol (Oxf) 65(4):536–543. doi:10.1111/j.1365-2265.2006.02630.x

    Article  Google Scholar 

  36. Abbud RA, Takumi I, Barker EM, Ren SG, Chen DY, Wawrowsky K et al (2005) Early multipotential pituitary focal hyperplasia in the alpha-subunit of glycoprotein hormone-driven pituitary tumor-transforming gene transgenic mice. Mol Endocrinol 19(5):1383–1391. doi:10.1210/me.2004-0403

    Article  PubMed  CAS  Google Scholar 

  37. Vlotides G, Eigler T, Melmed S (2007) Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev 28(2):165–186. doi:10.1210/er.2006-0042

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I am grateful to all the co-workers in our laboratory, but particularly to Dr. Márta Korbonits. The author takes full responsibility for the content of the paper but thanks Martin Gilmour, PhD (supported by Ipsen) for editorial assistance in the preparation of the initial draft of the manuscript and its subsequent revision.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Centre for Endocrinology, St. Bartholomew’s Hospital, 5th Floor King George V Building, West Smithfield, London, EC1A 7BE, UK

    Ashley B. Grossman

Authors
  1. Ashley B. Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashley B. Grossman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grossman, A.B. The molecular biology of pituitary tumors: a personal perspective. Pituitary 12, 265–270 (2009). https://doi.org/10.1007/s11102-008-0158-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-008-0158-7

Keywords

Search

Navigation