Skip to main content

Advertisement

SpringerLink
Log in

mTOR is Frequently Active in GH-Secreting Pituitary Adenomas without Influencing their Morphopathological Features

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

Initiating factors and mechanisms of tumor formation are poorly understood in nonfamilial pituitary adenomas. Alteration of intracellular pathways is an underlying event in numerous neoplasms. Among them, excessive activation of mammalian target of rapamycin (mTOR) pathway and its two main regulators, Akt and Erk, has been detected frequently in solid tumors. This study tests the activation of mTOR pathway in pituitary adenomas and its influence on their morphopathological features. Fifty-three pituitary adenomas were fresh frozen after surgery and analyzed by western blotting using phospho-specific antibodies. The impact of Akt and Erk activation on mTOR pathway was assessed in five primary cultures derived from the excised adenomas using selective kinase inhibitors. Statistical correlations of size, volume, Ki-67 %, Knosp’s grading, and somatostatin receptor (SSTR) expression with the activation of mentioned kinases was performed. GHomas showed the highest frequency (71 %) and level of mTOR pathway activity comparing to other adenomas (33 %). No significant correlation was found between mTOR activation and any of the morphopathological features in the studied samples. mTOR kinase phosphorylation was independent of Erk and Akt in primary cultures. Erk activity was significant in all types of adenomas but was the highest in control samples. Its phosphorylation correlated inversely with the Knosp’s grading in nonfunctional pituitary adenomas and directly with somatostatin receptor subtype 2 A expression in GHomas. Presented data point to the noteworthy mTOR activity in GHomas. However, the lack of correlation with morphopathological features, its independence of Erk and Akt phosphorylation, and high level of Erk activity in control pituitary necessitate further research for clarifying the role of these pathways in pituitary adenomas.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF, Jr., Meyer FB, Kuroki T, Riehle DL, Laws ER, Jr. (2006) Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59 (2):341–353; discussion 341–353. doi:10.1227/01.NEU.0000223437.51435.6E

    Article  PubMed  Google Scholar 

  2. Salehi F, Kovacs K, Scheithauer BW, Cantelmi D, Horvath E, Lloyd RV, Cusimano M (2010) Immunohistochemical expression of pituitary tumor transforming gene (PTTG) in pituitary adenomas: a correlative study of tumor subtypes. Int J Surg Pathol 18 (1):5–13. doi:10.1177/1066896909356105

    Article  PubMed  Google Scholar 

  3. Lloyd RJ, Kovacs K, Young WFJ, Farrell WE, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E, Watson REJ, Lindell EP, Barkan AL, Saeger W, Nose´ V, Osamura RY, Ezzat S, Yamada S, Roncaroli F, Lopes MBS, Vidal Ruibal S (2004) Tumours of the pituitary in WHO Classification of Tumours. Pathology & Genetics. Tumours of Endocrine Organs. International Agency for Research and Cancer (IARC):9–48

  4. Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M (2009) Ki-67 in pituitary neoplasms: a review--part I. Neurosurgery 65 (3):429–437; discussion 437. doi:10.1227/01.NEU.0000349930.66434.82

    Article  PubMed  Google Scholar 

  5. Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D, Laws ER, Jr. (1996) Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38 (1):99–106; discussion 106–107

    Article  PubMed  CAS  Google Scholar 

  6. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE (2004) The prevalence of pituitary adenomas: a systematic review. Cancer 101 (3):613–619. doi:10.1002/cncr.20412

    Article  PubMed  Google Scholar 

  7. Beckers A, Daly AF (2007) The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 157 (4):371–382. doi:10.1530/EJE-07-0348

    Article  PubMed  CAS  Google Scholar 

  8. Karhu A, Aaltonen LA (2007) Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update. Hum Mol Genet 16 Spec No 1:R73-79. doi:10.1093/hmg/ddm036

    Article  PubMed  CAS  Google Scholar 

  9. Horvath A, Stratakis CA (2008) Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune-Albright syndrome, familial acromegaly and genetic defects in sporadic tumors. Rev Endocr Metab Disord 9 (1):1–11. doi:10.1007/s11154-007-9066-9

    Article  PubMed  CAS  Google Scholar 

  10. Dworakowska D, Grossman AB (2009) The pathophysiology of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 23 (5):525–541. doi:10.1016/j.beem.2009.05.004

    Article  PubMed  CAS  Google Scholar 

  11. Drakos E, Rassidakis GZ, Medeiros LJ (2008) Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas. Expert Rev Mol Med 10:e4. doi:10.1017/S1462399408000586

    Article  PubMed  Google Scholar 

  12. Bai X, Jiang Y (2010) Key factors in mTOR regulation. Cell Mol Life Sci 67 (2):239–253. doi:10.1007/s00018-009-0163-7

    Article  PubMed  CAS  Google Scholar 

  13. Dworakowska D, Wlodek E, Leontiou CA, Igreja S, Cakir M, Teng M, Prodromou N, Goth MI, Grozinsky-Glasberg S, Gueorguiev M, Kola B, Korbonits M, Grossman AB (2009) Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. Endocr Relat Cancer 16 (4):1329–1338. doi:10.1677/ERC-09-0101

    Article  PubMed  CAS  Google Scholar 

  14. 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 (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 

  15. Ewing I, Pedder-Smith S, Franchi G, Ruscica M, Emery M, Vax V, Garcia E, Czirjak S, Hanzely Z, Kola B, Korbonits M, Grossman AB (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 

  16. Noh TW, Jeong HJ, Lee MK, Kim TS, Kim SH, Lee EJ (2009) Predicting recurrence of nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 94 (11):4406–4413. doi:10.1210/jc.2009-0471

    Article  PubMed  CAS  Google Scholar 

  17. Adjei AA, Hidalgo M (2005) Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol 23 (23):5386–5403. doi:10.1200/JCO.2005.23.648

    Article  PubMed  CAS  Google Scholar 

  18. Friday BB, Adjei AA (2008) Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 14 (2):342–346. doi:10.1158/1078-0432.CCR-07-4790

    Article  PubMed  CAS  Google Scholar 

  19. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26 (22):3291–3310. doi:10.1038/sj.onc.1210422

    Article  PubMed  CAS  Google Scholar 

  20. Iwenofu OH, Lackman RD, Staddon AP, Goodwin DG, Haupt HM, Brooks JS (2008) Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy. Mod Pathol 21 (3):231–237. doi:10.1038/modpathol.3800995

    Article  PubMed  CAS  Google Scholar 

  21. Kim SH, Zukowski K, Novak RF (2009) Rapamycin effects on mTOR signaling in benign, premalignant and malignant human breast epithelial cells. Anticancer Res 29 (4):1143–1150. doi:29/4/1143

    PubMed  CAS  Google Scholar 

  22. Dieterlen MT, Bittner HB, Klein S, von Salisch S, Mittag A, Tarnok A, Dhein S, Mohr FW, Barten MJ (2011) Assay validation of phosphorylated S6 ribosomal protein for a pharmacodynamic monitoring of mTOR-inhibitors in peripheral human blood. Cytometry B Clin Cytom. doi:10.1002/cyto.b.21005

  23. O’Reilly KE, Warycha M, Davies MA, Rodrik V, Zhou XK, Yee H, Polsky D, Pavlick AC, Rosen N, Bhardwaj N, Mills G, Osman I (2009) Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res 15 (8):2872–2878. doi:10.1158/1078-0432.CCR-08-2336

    Article  PubMed  Google Scholar 

  24. Ronellenfitsch MW, Brucker DP, Burger MC, Wolking S, Tritschler F, Rieger J, Wick W, Weller M, Steinbach JP (2009) Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death. Brain 132 (Pt 6):1509–1522. doi:10.1093/brain/awp093

    Article  PubMed  Google Scholar 

  25. Abramoff MD, Magalhaes PJ, Ram SJ (2004) Image processing with ImageJ. Biophotonics Int 11(7): 36–42

    Google Scholar 

  26. Wlodarski P, Kasprzycka M, Liu X, Marzec M, Robertson ES, Slupianek A, Wasik MA (2005) Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, insulin growth factor-I, and serum. Cancer Res 65 (17):7800–7808. doi:10.1158/0008-5472.CAN-04-4180

    PubMed  CAS  Google Scholar 

  27. Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33 (4):610–617; discussion 617–618

    Article  PubMed  CAS  Google Scholar 

  28. Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN (2009) The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 35 (2):148–159. doi:10.1016/j.ctrv.2008.09.006

    Article  PubMed  CAS  Google Scholar 

  29. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364 (6):514–523. doi:10.1056/NEJMoa1009290

    Article  PubMed  CAS  Google Scholar 

  30. Zatelli MC, Minoia M, Filieri C, Tagliati F, Buratto M, Ambrosio MR, Lapparelli M, Scanarini M, Degli Uberti EC (2010) Effect of everolimus on cell viability in nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 95 (2):968–976. doi:10.1210/jc.2009-1641

    Article  PubMed  CAS  Google Scholar 

  31. Cerovac V, Monteserin-Garcia J, Rubinfeld H, Buchfelder M, Losa M, Florio T, Paez-Pereda M, Stalla GK, Theodoropoulou M (2010) The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells. Cancer Res 70 (2):666–674. doi:10.1158/0008-5472.CAN-09-2951

    Article  PubMed  CAS  Google Scholar 

  32. Gorshtein A, Rubinfeld H, Kendler E, Theodoropoulou M, Cerovac V, Stalla GK, Cohen ZR, Hadani M, Shimon I (2009) Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro. Endocr Relat Cancer 16 (3):1017–1027. doi:10.1677/ERC-08-0269

    Article  PubMed  CAS  Google Scholar 

  33. Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J (2002) Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol 4 (8):556–564. doi:10.1038/ncb822 ncb822

    PubMed  CAS  Google Scholar 

  34. Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, Cato AC (2001) Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 20 (24):7108–7116. doi:10.1093/emboj/20.24.7108

    Article  PubMed  CAS  Google Scholar 

  35. Kumamaru E, Numakawa T, Adachi N, Kunugi H (2011) Glucocorticoid suppresses BDNF-stimulated MAPK/ERK pathway via inhibiting interaction of Shp2 with TrkB. FEBS Lett 585 (20):3224–3228. doi:10.1016/j.febslet.2011.09.010

    Article  PubMed  CAS  Google Scholar 

  36. Sukumari-Ramesh S, Singh N, Dhandapani KM, Vender JR (2011) mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation. Surg Neurol Int 2:22. doi:10.4103/2152-7806.77029

    Article  PubMed  Google Scholar 

  37. Zeng J, See AP, Aziz K, Thiyagarajan S, Salih T, Gajula RP, Armour M, Phallen J, Terezakis S, Kleinberg L, Redmond K, Hales RK, Salvatori R, Quinones-Hinojosa A, Tran PT, Lim M (2011) Nelfinavir induces radiation sensitization in pituitary adenoma cells. Cancer Biol Ther 12 (7):657–663. doi:17172

    Article  PubMed  CAS  Google Scholar 

  38. Jouanneau E, Wierinckx A, Ducray F, Favrel V, Borson-Chazot F, Honnorat J, Trouillas J, Raverot G (2012) New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15 (1):37–43. doi:10.1007/s11102-011-0341-0

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Medical University of Warsaw grants 1M15/NM7/2010, 1M15/NK1W and 1M15/W1/2010. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

We would like to thank Professor Paweł Krajewski, Department of Forensic Medicine, Medical University of Warsaw for constructive cooperation.

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, Chałubińskiego 5, 02-004, Warszawa, Poland

    Emir Ahmed Sajjad, Łukasz Hutnik & Paweł Włodarski

  2. Department of Neurosurgery, Military Institute of Medicine, Szaserów 128, 04-141, Warszawa, Poland

    Grzegorz Zieliński

  3. Department of Internal Disease and Endocrinology, Medical University of Warsaw, Banacha 1A, 02-097, Warszawa, Poland

    Tomasz Bednarczuk

  4. Department of Pathology, Maria Skłodowska-Curie Institute of Oncology, Roentgena 5, 02-781, Warszawa, Poland

    Maria Maksymowicz

Authors
  1. Emir Ahmed Sajjad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grzegorz Zieliński
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Maksymowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Łukasz Hutnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomasz Bednarczuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paweł Włodarski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paweł Włodarski.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

PDF 193 kb

ESM 2

PDF 18,100 kb

ESM 3

PDF 173 kb

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sajjad, E.A., Zieliński, G., Maksymowicz, M. et al. mTOR is Frequently Active in GH-Secreting Pituitary Adenomas without Influencing their Morphopathological Features. Endocr Pathol 24, 11–19 (2013). https://doi.org/10.1007/s12022-012-9230-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-012-9230-y

Keywords

Search

Navigation