Pathogenesis Of Pituitary Tumors Research Articles

PTTG--a new pituitary tumour transforming gene.

The pathogenesis of sporadic pituitary tumours remains elusive. Recently, a new candidate gene has been described which is able to induce pituitary cell transformation, and the expression of which appears to be strongly correlated with pituitary tumorigenesis. The so-called pituitary tumour transforming gene (PTTG) encodes a 23 kDa, 202 amino acid protein, and is located on chromosome 5q33, a locus previously associated with recurrent lung cancer and acute myelogenous leukaemias. Although the precise function of PTTG protein is unknown, in vitro experiments have demonstrated that it is capable of inducing fibroblast growth factor (FGF) expression. Mutation of the two proline-rich domains of the PTTG protein has also been shown to abolish subsequent FGF induction. Furthermore, in patients with pituitary adenomas, serum FGF concentrations fall post-operatively after successful excision of the tumour.

Molecular pathogenesis of pituitary adenomas: a review.

Modern theory of tumorigenesis suggests that genetic alterations may play a role in the initiation and promotion of pituitary adenomas. Gsp and MEN-1 genes play a role in the initiation event, while p53, ras, Rb and nm23 genes play some role in the progression of the tumor. Gsp gene, that may play an important role in 40% of GH-producing tumor, activation of 10% of non-functioning tumors and 6% of corticotroph adenomas, produces cAMP, which stimulates cyclin D1 and D3 which later produce cdk2 and cdk4 respectively, and stimulates cell progression from G1 to S phase. cAMP also induces ras gene, which inhibits binding of pRb with E2F that is necessary to prevent action of E2F in accelerating cell cycle. MEN-1 gene, although found in some sporadic tumors, is more likely associated with familial adenoma. p53, Ras, Rb, nm23 and c-myc genes play some role in the promotion of tumors especially toward their aggressive variant. p53 gene, which is found in up to 60% of ACTH producing adenomas, through action of p21 inhibits progression of cell cycle from G1 to S phase, by inhibiting the action of cyclin D3 on cdk4. Ras oncogene, in cooperation with c-myc gene, prevents the binding of pRb with E2F, which is necessary for preventing progression cell cycle, resulting in progression of cell cycle from G1 to S phase. Nm23 gene inhibits the action of cyclin B and arrests the cell in G2 phase. Further studies will not only be helpful in understanding the genetic pathogenesis and prognosis of pituitary tumors, but also in developing a novel treatment for patients with pituitary adenomas.

Apoptosis in Nontumorous and Neoplastic Human Pituitaries: Expression of the Bcl-2 Family of Proteins

Analyses of apoptosis and of the apoptosis regulatory proteins Bcl-2, Bax, Bcl-X, and Bad were done in 95 nontumorous and neoplastic pituitary tissues by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL), immunohistochemistry, and Western blotting. The apoptotic index was relatively low in all groups but was at least fourfold higher in pituitary carcinomas compared with any other groups. Pituitaries from pregnant and postpartum women had a fivefold higher apoptotic index compared with matched controls from nonpregnant females. Preoperative treatment of adenomas with octreotide or dopamine agonists did not change the apoptotic index significantly. The lowest levels of Bcl-2, Bax, and Bcl-X expression were in pituitary carcinomas as detected by immunostaining. An immortalized human pituitary adenoma cell line, HP75, developed in our laboratory using a replication-defective recombinant human adenovirus with an early large T-antigen, had a much higher level of apoptosis than nontumorous and neoplastic pituitaries. Treatment with transforming growth factor (TGF)-beta1 and protein kinase C (PKC) inhibitors increased apoptosis in this cell line. Analysis of the Bcl-2 family of proteins after treatment with TGF-beta1 and PKC inhibitors showed a 20% to 30% decrease in Bcl-X in the treated groups compared with controls. These results, which represent the first study of apoptosis in pituitaries from pregnant and postpartum cases and in pituitary carcinomas, indicate that 1) the apoptotic rate is low in nontumorous and neoplastic pituitary tissues but is relatively higher in pituitary carcinomas, 2) there are alterations in the expression of the Bcl-2 family of proteins in pituitary neoplasms with a decrease in Bcl-2 expression in pituitary carcinomas that may contribute to pituitary tumor pathogenesis and/or proliferation, and 3) cultured pituitary tumor cells respond to TGF-beta1 and PKC inhibitors by undergoing apoptotic cell death.

Pituitary Tumor Pathogenesis

Pituitary Tumor Pathogenesis

Loss of heterozygosity at 11q13: analysis of pituitary tumors, lung carcinoids, lipomas, and other uncommon tumors in subjects with familial multiple endocrine neoplasia type 1.

Loss of heterozygosity (LOH) for polymorphic markers flanking the multiple endocrine neoplasia type 1 (MEN-1) gene in parathyroid and pancreatic islet tumors from subjects with familial MEN-1 (FMEN-1) has been well documented and has led to the hypothesis that the MEN-1 gene functions as a tumor suppressor. To assess the role of the MEN-1 gene in the pathogenesis of tumors less commonly associated with MEN-1, we employed a large number of highly informative polymorphic markers closely linked to the MEN-1 gene to study a series of 13 such tumors from subjects with FMEN-1 for LOH at 11q13. We were able to identify LOH for 1 or more 11q13 markers in 2 of 3 pituitary tumors, 3 lung carcinoids, and 1 of 2 lipomas. In every case studied, the allele lost represented the normal allele inherited from the unaffected parent. No LOH was detected in 3 skin angiofibromas, an esophageal leiomyoma, or a renal angiomyolipoma despite the presence of at least 2 informative markers for each tumor. Our results suggest that, like that for parathyroid and pancreatic islet tumors, the pathogenesis of pituitary tumors, lung carcinoids, and lipomas occurring in subjects with FMEN-1 probably involves loss of the normal tumor suppressor function of the MEN-1 gene. Our inability to detect 11q13 LOH in skin angiofibromas, leiomyoma, and angiomyolipoma from subjects with FMEN-1 is consistent with the possibility that these neoplasms arose independently by a mechanism unrelated to the MEN-1 gene, but a role for the MEN-1 gene in the pathogenesis of these tumors cannot be definitively excluded until the gene itself is identified and evaluated for small intragenic deletions or point mutations in such tumors.

Tumour suppressor genes in the pathogenesis of human pituitary tumours.

Abnormal cell proliferation is controlled by opposing actions of oncogene products (stimulatory) and tumour suppressor gene (TSG) products (inhibitory). The former are dominantly acting, i.e. only one copy needed for tumorigenesis, whilst for TSG both copies of the gene must be inactivated so these are recessive at a cellular level. For anterior pituitary tumours only one oncogene (Gsp) has been identified in a variable proportion (4-40%) of a single tumour subtype (somatotrophinomas). Contrariwise, allelic deletion studies, using a PCR-based microsatellite polymorphism analysis of DNA extracted from archival specimens, have shown significant loss of heterozygosity in 20-40% of all tumour subtypes at the locus of the putative MEN-1 gene (chr. 11q13); the retinoblastoma gene (chr. 13q 12-14), and 10q26. Moreover, these DNA microdeletions were concentrated in radiologically invasive tumours compared to noninvasive tumours (modified Hardy gdes 3 and 4 vs. 1 + 2). In addition, 50% of Cushing's adenomas showed presence of p53 immunopositivity, though no point mutations in exons 4-9 were found, by SSCP analysis, to account for this. These studies show that analysis of TSGs in pituitary adenomas may provide clues to their pathogenesis, and more importantly relate to clinical behaviour of the tumour, and hence aid decisions regarding management.

Expression of bcl-2 oncoprotein in pituitary tumours: comparison with c-myc.

Whereas the control of hormone secretion from pituitary adenomas has been studied in considerable detail, the molecular events underlying the development of these tumours are still poorly understood. Abnormalities of some oncogenes and tumour suppressor genes have been previously reported to occur at very low frequencies. The aim of the present study was to assess the possible expression of the bcl-2 oncoprotein and to compare it with that of c-myc in pituitary adenomas. Monoclonal antibodies were used, along with microwave antigen retrieval and the avidin-biotin immunohistochemical method, to investigate expression of the oncoproteins bcl-2 and c-myc in 30 primary pituitary tumours from five broad diagnostic groups and in five normal pituitaries. Bcl-2 and c-myc immunoreactivities were detected in nine (30%) and eight (27%) tumour samples, respectively. Of the nine bcl-2 and eight c-myc positive tumours, seven were positive for both oncoproteins and included one of the four corticotrophinomas studied, four of seven prolactinomas, one of two somatotrophinomas, and one of four oncocytomas. All 13 null cell adenomas studied were negative for both bcl-2 and c-myc immunoreactivities. These results indicate that the bcl-2 and c-myc oncoproteins are expressed abnormally in over one quarter of pituitary tumours. Most these tumours co-expressed both oncoproteins. The genetic complementation of simultaneously deregulated bcl-2 and c-myc is implicated, through the regulation of apoptosis, in the pathogenesis of pituitary tumours.

G s protein mutations and the pathogenesis and function of pituitary tumors

Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) production and somatotroph proliferation by binding to a seven transmembrane-domain receptor, linked to G s. G s stimulates production of cyclic adenosine 3′–5′-monophosphate (cAMP) and hence activation of protein kinase A (PKA). A subgroup of pituitary somatotroph adenomas has been demonstrated, which has constitutive activation of G s, with reduced in vitro responsiveness to agents that stimulate G s. Subsequently, somatotroph adenomas have been identified, which have activating mutations of G s ( gsp). However, there are no clear clinical or biochemical phenotypic characteristics that enable gsp-positive and gsp-negative tumors to be differentiated from one another. Gsp mutations occur in 35% to 40% of somatotroph adenomas in caucasians, but have a much lower reported prevalence of 4% to 9% in the Japanese population. G-protein mutations also occur in clinically nonfunctioning pituitary tumors and, rarely, in corticotroph adenomas. There is little direct evidence at present to suggest that the gsp mutation has a primary oncogenic role in the pathogenesis and function of pituitary tumors. Further functional studies are needed. The gsp mutation is probably one of several oncogenic mutations required for pituitary tumor development.

Molecular pathogenesis of pituitary tumours

Human pituitary tumours account for 10% of intracranial neoplasms. These tumours are usually sporadic and benign; malignant change and metastasis are extremely rare events. Autosomal dominant inheritance of MEN 1 accounts for a minority of pituitary tumours. Pituitary tumours have been found to be monoclonal in several studies. This would suggest that an intrinsic genetic pituitary defect is pivotal in the pathogenesis of these tumours. However, this concept does not exclude a role for the hypothalamus in the genesis of pituitary tumours; the trophic function of several hypothalamic peptides could promote initiation of the genetic event or facilitate a sequence of events leading to clonal expansion of the transformed cell. There has been modest progress made in the elucidation of the intrinsic genetic pituitary cell abnormalities that underlie pituitary tumorigenesis. A mutant alpha subunit of the Gs gene, designated gsp, which results in constitutive activation of adenylyl cylcase has been described in a subset of GH cell adenomas. Loss of genetic material on chromosome 11q13, the locus of the MEN 1 gene, is found in under 20% of pituitary adenomas, suggesting that inactivation of a tumour suppressor gene at this locus may be significant in the tumorigenic process. H-ras point mutations have been described in distant metastatic pituitary tumour secondaries. The genetic abnormalities described occur in only a small subset of pituitary tumours, indicating that the more significant tumour promoting genes are still to be discovered.

Pathogenesis of pituitary tumours

Pathogenesis of pituitary tumours

Human pituitary adenomas express endogenous inhibin subunit and follistatin messenger ribonucleic acids.

Specific factors involved in the pathogenesis of tumors that stimulate clonal human pituitary adenoma cell proliferation remain unknown. An important question regarding the pathogenesis of human pituitary tumors is whether they synthesize autocrine regulatory factors that regulate both hormone biosynthesis and neoplastic growth. Activin and inhibin are both comprised of inhibin subunits and have diverse regulatory roles as growth and differentiation factors in normal and neoplastic tissue. Activin stimulates FSH beta messenger ribonucleic acid (mRNA) biosynthesis and FSH secretion, and these effects are down-regulated in normal gonadotrophs by the endogenous glycoprotein follistatin. In addition to its effects on gonadotrophs, activin modulates hormone secretion by somatotroph and corticotroph cell lines. It is not known whether human neoplastic pituitary tissue synthesizes inhibin subunits or follistatin or whether their expression is cell type specific. We investigated whether alpha-, beta A-, and beta B-inhibin subunit and follistatin mRNAs could be detected in 27 human pituitary adenomas [clinically nonfunctioning (n = 11), somatotroph (n = 5), corticotroph (n = 5), and lactotroph (n = 6)] using reverse transcriptase-polymerase chain reaction techniques. Twenty-six of the tumors contained mRNAs encoding one or more inhibin subunits. beta B-Inhibin mRNA was the most prevalent (81% of tumors), followed by beta A-inhibin (59% of tumors) and alpha-inhibin (52% of tumors). Endogenous alpha-, beta A-, and beta B-inhibin subunit mRNA synthesis was also examined in normal human pituitary and testicular complementary DNA libraries, and all subunit mRNAs were detected. In contrast to the widespread expression of inhibin subunits in pituitary tumors, follistatin mRNA was detected in a subset of nonfunctioning tumors (54%) as well as in control normal human pituitary and testicular complementary DNA libraries. Tumor-specific follistatin biosynthesis was not observed in other pituitary tumor subtypes. These data are the first to demonstrate that 1) endogenous inhibin subunits are synthesized in human pituitary adenomas of all known secretory phenotypes as well as normal pituitary tissue; and 2) follistatin gene expression in pituitary adenomas is specific to clinically nonfunctioning or gonadotropin subunit-producing tumors. The characterization of inhibin subunit and follistatin biosynthesis by human pituitary tumors will be important in investigating their potential roles in regulating both tumor phenotype and cell proliferation.

C-myc, c-fos, and c-myb gene expression in human pituitary adenomas.

The possible roles of certain oncogenes in the development of pituitary tumors has not been investigated. We have examined the expression of c-myc, c-fos, and c-myb in a number of human pituitary tumors by ribonuclease protection assays, as these oncogenes have been implicated to have roles in the pathogenesis of other human tumors (12, 13, 15, 16). In several tumors examined (9 of 30) c-myc was expressed at levels 4-9 times greater than the level detected in normal postmortem pituitary. Although a larger percentage of negative immunohistochemical-staining tumors overexpressed c-myc, c-myc over-expression was not limited to this group of tumors. c-Fos was overexpressed in 1 of 30 tumors examined at a level 5.8-fold higher than that detected in normal postmortem pituitary. This tumor stained positive for ACTH by immunohistochemistry and was considered highly aggressive, demonstrating invasion beyond the sella turcica; however, when other ACTH-staining and invasive pituitary tumors were examined, no abnormality in the expression of c-fos was detected. In 30 tumors, c-myb was expressed at approximately the same level as that detected in normal postmortem pituitary. We conclude that c-myc is overexpressed in a subgroup of pituitary tumors and that this overexpression occurs broadly among the different groups of immunohistochemical-staining tumors. c-Fos overexpression appears to be much less common in pituitary tumors and does not necessarily correlate with the ability of the tumor to become invasive. c-Myb does not appear to have a role in the pathogenesis of pituitary tumors.

Ras mutations in human prolactinomas and pituitary carcinomas.

Pituitary adenomas have been shown to be clonal in origin, indicating that one or more somatic mutations underlie tumor pathogenesis. Mutated oncogenic forms of ras protein have been identified in a number of human neoplasms, including thyroid adenomas and carcinomas. However, the potential role of activated ras in the development of specific human pituitary tumor phenotypes has not been determined. Although ras mutations were not found in glycoprotein hormone-secreting or somatotroph adenomas, we recently identified a mutation in the H-ras gene (Gly-Val) at codon 12 in a highly invasive prolactinoma. These data raise the possibility that ras mutations might play a role in the pathogenesis of PRL-secreting pituitary tumors and/or may be a marker for tumor invasiveness and malignant transformation. Therefore, we investigated 78 pituitary tumors (59 prolactinomas, 13 invasive prolactinomas, and 6 pituitary carcinomas) for activating point mutation in the three ras genes using oligonucleotide-specific hybridization. In contrast to the relatively high frequency of ras mutations in many different tumor types, no ras mutations were identified in either prolactinomas or pituitary carcinomas. Our data indicate that ras mutations are rare in prolactinomas and pituitary carcinomas.

The retinoblastoma gene in human pituitary tumors.

Functional inactivation of the retinoblastoma (RB) tumor suppressor gene is important in the pathogenesis of many human tumors. Recently, the frequent occurrence of pituitary tumors was reported in mice genetically engineered to have one defective RB allele, a genetic background analogous to that of patients with familial retinoblastoma. The molecular pathogenesis of human pituitary tumors is largely unknown, and the potential role of RB gene inactivation in these neoplasms has not been examined. Consequently, we studied 20 human pituitary tumors (12 clinically nonfunctioning tumors, 4 somatotroph adenomas, 2 prolactinomas, and 2 corticotroph adenomas) for tumor-specific allelic loss of the RB gene using a highly informative polymorphic locus within the gene. Control leukocyte DNA samples from 18 of these 20 patients were heterozygous at this locus, permitting genetic evaluation of their paired tumor specimens. In contrast to the pituitary tumors in the mouse model, none of these 18 human tumors exhibited RB allelic loss. These findings indicate that RB gene inactivation probably does not play an important role in the pathogenesis of common types of human pituitary tumors.

Towards the pathogenesis of human pituitary tumours

Towards the pathogenesis of human pituitary tumours

Further Evidence for a Somatic Mutation Theory in the Pathogenesis of Human Pituitary Tumors

Further Evidence for a Somatic Mutation Theory in the Pathogenesis of Human Pituitary Tumors

Immunocytochemical studies on the pituitary gland and spontaneous pituitary tumors of sprague-dawley rats

The review of our studies indicates a predictive value of the pituitary gland and spontaneous pituitary tumors of Sprague-Dawley rats for detecting and evaluating the effects and interactions of estrogens and dopamine agonists on the pathogenesis, functional morphology and therapy of human pituitary tumors, such as prolactinomas, gonadotroph adenomas and null cell adenomas. The functional classification of spontaneous pituitary tumors in old female Sprague-Dawley rats reveals a diversity of hormone content and morphologic appearance. They seem to be useful models of the human disease.

Pathogenesis of Pituitary Tumors

Evidence for and against the hypothesis that GH-, PRL-, and ACTH-secreting tumors arise as the result of hypothalamic dysregulation has been presented. For each of these types of tumor it appears that similar proportions--perhaps 80 to 90 per cent arise de novo within the pituitary. Although it is quite possible, it is not yet proven that the remaining 10 to 20 per cent of cases arise as a result of underlying hypothalamic dysregulation. The number of cases of TSH- and gonadotropin-producing tumors is too small to allow this type of analysis, but there is no completing reason to suspect that they differ in etiology from these other tumor types. The subsets of gonadotropin- and TSH-secreting tumors that arise as a result of primary target organ failure are discussed in "Thyrotropin-secreting Pituitary Tumors" and "Gonadotroph Cell Pituitary Tumors," respectively.