Cell Cycle Dysregulation in Pituitary Oncogenesis

The cell cycle is the process by which cells grow, replicate their genome and divide. The cell cycle control system is a cyclically-operating biochemical device constructed from a set of interacting proteins that induce and coordinate proper progression through the cycle, and includes cyclins, cyclin-dependent kinases (CDK) and their inhibitors (CDKI). There are mainly two families of CDKI, the INK family (INK4a/p16; INK4b/p15; INK4c/p18 and INK4d/p19) and the WAF/KIP family (WAF1/p21; KIP1/p27; KIP2/p57). Progression through the cell cycle is mainly dependent on fluctuations in the concentration of cyclins and CDKI achieved through the programmed degradation of these proteins by proteolysis within the ubiquitin-proteasome system. There is also a transcriptional regulation of cyclin expression, probably dependent on CDK phosphorylation. The p53 family--p53, p63 and p73--function as transcription factors that play a major role in regulating the response of mammalian cells to stressors and damage, in part through the transcriptional activation of genes involved in cell cycle control (e.g. p21), DNA repair, senescence, angiogenesis and apoptosis. Essential for the maintenance of euploidy during mitosis is human securin, identical to the product of the pituitary tumour-transforming gene (PTTG). Loss of regulation at the G1/S transition appears to be a common event among virtually all types of human tumours. Aberrations of one or more components of the pRb/p16/cyclin D1/CDK4 pathway seem to be a frequent event (80%) in pituitary tumours. The role of p27 is rather that of a haploinsufficient gene. p27-/- mice show an increased growth rate, due to increased cellularity, testicular and ovarian cell hyperplasia and infertility, and hyperplasia of the pituitary intermediate lobe with nearly 100% mortality caused by such a benign pituitary tumour. Although the p27 gene was not found to be mutated in human pituitary tumours and its mRNA expression was similar in tumour samples in comparison with normal pituitaries, the load of p27 protein expression in corticotroph adenomas and pituitary carcinomas was shown to be much lower than those in normal pituitary tissue or other types of pituitary adenoma, suggesting that post-translational processing of p27 accelerates its removal from the nucleus. In respect to p27 degradation and its cellular compartmentalization, several pathways have been explored. Malignant tumours are associated with increased nuclear immunostaining for Jun-activation binding protein-1 (Jab1) which is responsible for phosphorylated p27 export from the nucleus. Corticotrophinomas are characterized by massively increased phosphorylation of p27 on Thr187, but are not associated with changes in Jab1. Macrophage inhibitory factor (MIF), which binds and inactivates Jab1, was noted to be over-expressed in tumours with abundant Jab1, suggesting that it may be part of a compensatory mechanism to moderate Jab1 activity. Proteasomal degradation of p27 requires its ubiquitylation by the SCF ubiquitin ligase, with specific addressing by the F-box protein Skp2 and its co-factor Cks1. Pituitary tumours with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 immunostaining, suggesting that increased Skp2 could play at least a part in this process. No difference was observed in Cks1 mRNA levels between normal pituitaries and pituitary adenomas. The present data suggest that inhibition of growth and tumour development is sensitive not only to the absolute levels of p27 protein, but also to its cellular compartmentalization. Very recent findings from our group have established up-regulation of the serine-threonine kinase Akt in pituitary tumours compared to normal pituitary, which may cause phosphorylation of p27 on Thr157 and cytoplasmic retention of p27. PTTG protein is highly expressed in various human tumours, including pituitary tumours. While its mRNA levels are low in normal pituitary, increases in PTTG transcripts from more than 50% to more than 10-fold were recorded in the majority of a series of pituitary adenomas. Control of the cell cycle is a vital part of the cell's replication machinery. Disruption of this process is commonly seen in pituitary tumours and we are now beginning to identify regulatory elements which are likely to play a major role in pituitary oncogenesis

Pituitary prolactotropic function in patients with "inactive" pituitary adenoma

Pituitary prolactotropic function was retrospectively analyzed in 23 patients with "inactive" pituitary adenoma (8 oncocytomas and 15 zero-cell adenomas) verified by electron microscopy. Before surgery basal prolactin level, prolactin concentrations in tests with thyrotropin-releasing hormone (TRH) and Parlodel, and daily fluctuations in prolactin levels in the blood were measured in all the patients. Moderate hyperprolactinemia was detected in 11 (47.8%) patients, which was often associated with galactorrhea-amenorrhea in women and with sexual dysfunction in men and was related to disturbed hypothalamo-pituitary relationships in cases with large adenomas. Irrespective of the basal level of prolactin, its secretion in response to TRH was abnormal: the reaction was reduced, particularly in patients in whom the tumors were associated with hyperprolactinemia. Acute loading with Parlodel led to a reliable reduction of prolactin concentration in the blood both in controls and in patients with normo- and hyperprolactinemia. A reduction of prolactin level by more than half in patients with inactive pituitary adenomas and moderate hyperprolactinemia in response to Parlodel loading, similarly as in normal subjects, confirms the functional type of hyperprolactinemia in such patients. Daily fluctuations of prolactin level were revealed in patients with large or giant adenomas.</jats:p

The reproductive system and gonadotropic function of the pituitary gland in patients with "inactive" pituitary adenoma

The status of the sex system and pituitary gonadotropic function were retrospectively analyzed after diagnosis verification by electron microscopy in 28patients with "inactive"pituitary adenoma, using preoperative serum values of gonadotropins, testosterone, estradiol, and LH and FSH levels from the results of gonadotropin releasing hormone (GnRH). Two variants of the diseases course were distinguished in female (21%) and male (36%) patients with inactive pituitary adenoma involving no clinically manifest endocrine disorders: a) in women: the onset with oligo-opsomenorrhea type disorders of the cycle (57%) associated with the polycystic ovaries syndrome (88%); in men (37%): onset with a decrease of the libido caused by moderate hyperprolactinemia paralleled by an appreciable increase of adenoma with high (mostly FSH) or normal levels of gonadotropins and sex glands unchanged or enlarged; b) clinical and biochemical signs of secondary hypogonadism in women (22%) and men (27%). Two types of LH reactions to GnRH are observed, depending on the state of the sex glands: a) hyperergic reaction with increase of LH reserve in women with polycystic ovaries and in men with normal sex glands; b) hypo- ergic reaction of LH with a decrease of its reserve in the presence of secondary hypogonadism symptoms. A hypoergic reaction of FSH to GnRF and its low pituitary reserve were observed in both groups.</jats:p