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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

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.

Funding

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.

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Correspondence to Mark Gruppetta or Josanne Vassallo.

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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.

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

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Gruppetta, M., Formosa, R., Falzon, S. et al. Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas. Pituitary 20, 358–371 (2017). https://doi.org/10.1007/s11102-017-0803-0

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  • DOI: https://doi.org/10.1007/s11102-017-0803-0

Keywords

  • Pituitary adenoma
  • PTTG
  • Ki67
  • Tumorigenesis
  • Regrowth
  • Somatostatin analogues