Endocrine Abstracts (2004) 7 S5

Cycling into trouble

AB Grossman

Department of Endocrinology, Barts and the London School of Medicine, St. Bartholomew's Hospital, London EC1A 7BE, UK.

Pituitary tumours are usually benign and present early due to hormonal hypersecretion: the mean size of corticotroph adenomas is only 100mm3. Furthermore, of the 6 essential stages in carcinogenesis (activation of oncogenes, loss of tumour suppressor genes, inhibition of apoptosis, immortalisation, vascular invasion and metastasis), probably only the first 3 are relevant to these tumours: this renders them a valuable paradigm for the earliest stages of oncogenesis. Menin and PRKR1A, genes involved in familial endocrine disorders, are not generally dysregulated in sporadic tumours. In terms of normal regulatory pathways, the feedback receptors for GH and IGF-I in somatotrophinomas, and of the ACTH receptor in corticotrophinomas are down-regulated, while the enzyme 11 -HSD2 is over-expressed, but no mutations were recorded and it seem unlikely that these represent a primary derangement. In animal models changes in cell cycle regulators are potent inducers of neuroendocrine tumours, and indeed multiple changes in cell cycle regulators have been noted in pituitary tumours, particularly a fall in the cell cycle inhibitor p27 and a rise in cyclin E, many of these alterations occurring at the level of degradation. We have recently identified up-regulation of the mRNA for the serine/threonine kinase akt, and an increase in its active phosphorylated protein. Akt was shown to associate with p27 and sequester p27 in the cytoplasm thus enhancing its degradation. This may account for many, if not all, of the changes in cell cycle regulators. In addition, such enforced cycling can lead to impaired chromosomal segregation and abnormalities in securin (PTTG) function. Finally, akt hyperfunction can cause inhibition of apoptosis as well as enhanced proliferation. The cause of enhanced akt expression remains unclear. Further studies using AffymetrixTM cDNA microarray are currently being employed to identify putative upstream candidates involved in akt dysregulation.

I am grateful to Dr. Marta Korbonits for our on-going fruitful collaboration.

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