Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas.
OBJECTIVE
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.
Division of Endocrinology, Department of Medicine, Faculty of Medicine and Surgery, Mater Dei Hospital, University of Malta, Msida, MSD2090, Malta. markgruppetta@gmail.com.|Neuroendocrine Clinic, Department of Medicine, Mater Dei Hospital, Msida, Malta. markgruppetta@gmail.com.
Mark
M
Gruppetta
Division of Endocrinology, Department of Medicine, Faculty of Medicine and Surgery, Mater Dei Hospital, University of Malta, Msida, MSD2090, Malta.
Robert
R
Formosa
Immunohistochemistry Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta.
Sharon
S
Falzon
Immunohistochemistry Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta.
Sabrina
S
Ariff Scicluna
Immunohistochemistry Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta.
Edward
E
Falzon
Immunohistochemistry Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta.
James
J
Degeatano
Division of Endocrinology, Department of Medicine, Faculty of Medicine and Surgery, Mater Dei Hospital, University of Malta, Msida, MSD2090, Malta. josanne.vassallo@um.edu.mt.|Neuroendocrine Clinic, Department of Medicine, Mater Dei Hospital, Msida, Malta. josanne.vassallo@um.edu.mt.
Josanne
J
Vassallo
D015415:Biomarkers / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000378:metabolism*; D012189:Retrospective Studies; D064249:Securin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015415:Biomarkers; D019394:Ki-67 Antigen; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D064249:Securin; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1
Ki67; PTTG; Pituitary adenoma; Regrowth; Somatostatin analogues; Tumorigenesis