, Volume 20, Issue 3, pp 358–371 | Cite as

Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas

  • Mark GruppettaEmail author
  • Robert Formosa
  • Sharon Falzon
  • Sabrina Ariff Scicluna
  • Edward Falzon
  • James Degeatano
  • Josanne VassalloEmail author



The pathogenesis of pituitary adenomas (PA) is complex. Ki-67, pituitary tumour transforming gene (PTTG), vascular endothelial growth factor (VEGF), cyclin D1, c-MYC and pituitary adenylate cyclase-activating peptide (PACAP) protein expression were analysed and correlated with tumour and patient characteristics.


74 pituitary tumour samples (48 non-functional PA, 26 functional PAs); Immunohistochemical analysis of protein expression, retrospective analysis of MR images and in vitro analysis of octreotide treatment was carried out on GH3 cells.


PTTG expression was negatively associated with age and positively with PA size, regrowth and Ki-67 index. Cyclin D1 correlated with Ki-67 and tumour size. c-MYC negatively correlated with size of tumour and age; and correlated with PTTG expression. Somatostatin analogue treatment was associated with lower Ki-67, PTTG and Cyclin D1 expression while T2 hypointense PAs were associated with lower PTTG, cyclin D1, c-MYC and Ki-67. In vitro analyses confirmed the effect of somatostatin analogue treatment on Pttg and Cyclin D1 expression.


Interesting and novel observations on the differences in expression of tumour markers studied are reported. Correlation between Ki-67 expression, PTTG nuclear expression and recurrence/regrowth of PAs, emphasizes the role that Ki-67 and PTTG expression have as markers of increased proliferation. c-MYC and PTTG nuclear expression levels were correlated providing evidence that PTTG induces c-MYC expression in PAs and we propose that c-MYC might principally have a role in early pituitary tumorigenesis. Evidence is shown that the anti-proliferative effect of somatostatin analogue treatment in vivo occurs through regulation of the cell cycle.


Pituitary adenoma PTTG Ki67 Tumorigenesis Regrowth Somatostatin analogues 



The authors would like to acknowledge all the medical specialists and other healthcare staff at Mater Dei Hospital who gave invaluable support during this study.


This study was funded by two independent research funds awarded to JV (University of Malta Research Fund: MEDRP02-05 and the Dean’s Research Fund, Faculty of Medicine and Surgery: MDSIN08-22). RF is funded by the REACH HIGH Scholars Programme—Post-Doctoral Grant. The Research work disclosed in this publication is partially funded by the REACH HIGH Scholars Programme—Post Doctoral Grants. The grant is part-financed by the European Union, Operational Programme II—Cohesion Policy 2014–2020 “Investing in human capital to create more opportunities and promote the wellbeing of society”—European Social Fund.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11102_2017_803_MOESM1_ESM.docx (27 kb)
Supplementary material 1 (DOCX 27 KB)
11102_2017_803_MOESM2_ESM.docx (22 kb)
Supplementary material 2 (DOCX 21 KB)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Mark Gruppetta
    • 1
    • 2
    Email author
  • Robert Formosa
    • 1
  • Sharon Falzon
    • 3
  • Sabrina Ariff Scicluna
    • 3
  • Edward Falzon
    • 3
  • James Degeatano
    • 3
  • Josanne Vassallo
    • 1
    • 2
    Email author
  1. 1.Division of Endocrinology, Department of Medicine, Faculty of Medicine and Surgery, Mater Dei HospitalUniversity of MaltaMsidaMalta
  2. 2.Neuroendocrine Clinic, Department of MedicineMater Dei HospitalMsidaMalta
  3. 3.Immunohistochemistry Laboratory, Department of PathologyMater Dei HospitalMsidaMalta

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