Pituitary Tumor Progression Research Articles

Molecular pathology of pituitary adenomas.

A great deal of knowledge about anterior pituitary development, the pathogenesis of pituitary tumor and pituitary tumor progression has accumulated during the past decade. The role of multiple genes and gene products in pituitary development and the relationship of these genes to postnatal pituitary function and pituitary tumor development are being actively explored. Recent studies indicate that genes important in pituitary development do not contribute to pituitary tumorigenesis. However, mutations and other genetic alterations in these genes often lead to pituitary hypofunction. Many oncogenes and tumor suppressor genes that contribute to pituitary tumorigenesis have been described. There is a growing body of evidence showing that cellular and molecular changes in cyclins and cyclin-dependent kinase inhibitors contribute to pituitary tumorigenesis. Finally, recent comparative genomic hybridization studies show that many more genes that are important in pituitary tumorigenesis and tumor progression have yet to be discovered.

Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas.

Vascular endothelial growth factor (VEGF) is a key mediator of endothelial cell proliferation, angiogenesis, and vascular permeability. Little is known about its expression in human pituitary adenomas. We examined 148 human pituitary adenomas for VEGF protein expression by immunohistochemistry. The strongest immunoreactivity was present in GH adenomas, corticotroph, silent corticotroph. silent subtype 3, and nononcocytic null cell adenomas. GH adenomas treated with octreotide stained less intensely than did untreated tumors. Relatively weak staining was present in PRL, gonadotroph, thyrotroph, and oncocytic null cell adenomas in the same sections showed evidence of down-regulation of VEGE protein expression in adenomas. Pituitary carcinomas usually had stronger staining than adenomas. In situ hybridization studies with oligonucleotide probes showed positive staining in all groups with stronger staining in GH, ACTH, TSH, and gonadotroph adenomas and in pituitary carcinomas. These results indicate that VEGF expression is more prominent in certain adenoma subtypes, that decreased expression occurs in adenomas as compared to nontumorous pituitary and that carcinomas show increased VEGF expression relative to adenomas suggesting up-regulation of VEGF during pituitary tumor progression.

Molecular pathogenesis of acromegaly.

Acromegaly is generally caused by growth hormone (GH) hypersecretion from a benign, monoclonal pituitary adenoma. As in other neoplastic conditions, pituitary tumor formation and dysregulated hormone secretion are most likely the ultimate result of a series of genetic alterations. A number of molecular and biochemical defects have been associated with pituitary tumorigenesis. Molecular events such as tumor suppressor gene inactivation and oncogene activation involved in pituitary tumor progression are examined. The role of hypothalamic regulatory hormones and hereditary syndromes involving acromegaly are also discussed.

Molecular biology of human pituitary adenomas

While the majority of pituitary tumours will remain benign, a proportion will show invasive behaviour and a still smaller proportion will become malignant. Recent studies at both the biochemical and molecular level are now defining the changes associated with pituitary tumour initiation and progression. In particular, the use of microsatellite analysis in determining regions of gene deletion has considerably advanced our understanding of pituitary tumourigenenesis. Bringing together the data of several groups now allows a tentative map to be drawn showing loss of heterozygosity at several chromosomal loci to be associated with the transition to the invasive and malignant phenotype, while changes associated with chromosome 9p and silencing, through methylation, of the tumour suppressor gene pl6 appear to occur early in pituitary tumourigenesis. At the biochemical level, immunohistochemical studies have defined changes in key regulatory proteins along this multistep pathway. To determine whether these changes are truly predictive of tumour behaviour awaits carefully designed prospective studies. These future studies may well aid decision-making regarding management in a manner not possible using current histological assessment.

Molecular Genetics of Pituitary Tumours

The last several years have seen a significant increase in our understanding of the molecular and biochemical changes associated with pituitary tumour initiation and progression. The combined data, from several groups, now allow a tentative map to be drawn showing that reduction to hemizygosity at several chromosomal loci (10q, 11q13 and 13q) is associated with the transition to the invasive phenotype, while loss on chromosome 9p and methylation of the tumour suppressor gene p16 appear to occur early in pituitary tumorigenesis. Changes in the expression/status of several genes and/or proteins including p53, the cAMP response element-binding factor (CREB), growth hormone-releasing hormone (GHRH), nm23, p16 and p27 have also been identified along this multi-step pathway. Prospective studies will determine whether these markers are truly predictive of subsequent tumour behaviour and can be used to aid clinical management in a manner not possible when current histological criteria are used.

Anti-Tumor Action of Dietary Restriction Is Lesion-Dependent in Male Fischer 344 Rats

The effects of dietary restriction (DR) on spontaneous oncogenesis in male Fischer 344 rats were analyzed. Previously reported analyses of studies carried out in our laboratory demonstrated that DR reduces the incidence and delays the onset, but not the progression, of leukemia in male F344 rats. In this report, the influence of DR on pituitary tumors, adrenal pheochromocytoma, pancreatic islet cell tumors, and interstitial cell tumors of the testis was analyzed. DR reduced the relative incidence (relative onset rates) and delayed the onset of the four tumors. DR also retarded the progression (duration from onset to death) of pituitary tumors and pheochromocytoma. DR has delayed the onset of all tumors of the male F344 rat so far analyzed, but its effect on tumor progression appears to be lesion-dependent.

Effect of diet or reproductive status on the histology of spontaneous pituitary tumors in female Wistar rats.

Hypophyses of four groups of 50 female rats (F0--nulliparous, F0--multiparous, F1--standard diet, and F1--low protein) were examined by light microscopy and immunocytochemistry by the avidin-biotin complex method. In pituitary glands of rats fed a low protein diet, the incidence of neoplasms of the pars distalis, the number of multifocal tumors, and the degree of neoplastic cellular atypia were significantly reduced. Pituitary adenomata in rats fed a low protein diet also caused significantly less brain compression at the time of necropsy than in rats fed a standard diet. All but two neoplastic foci from the 83 tumors stained for prolactin, and 14 of these also stained for growth hormone. No differences were found in the frequency of hemorrhagic or solid patterns of tumor. These findings may reflect a reduction in pituitary tumor initiation, promotion, and/or progression in rats fed a low protein diet.