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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1675-1681
Copyright © 1997 by The Endocrine Society

Special Articles

Pituitary Tumor Pathogenesis1

Ilan Shimon and Shlomo Melmed

Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute-University of California School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, B-131, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu


   Introduction
Top
 Introduction
Hypothalamic Influences vs....
 Activating Genetic Mutations
 Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
 Growth Factors
 Note Added in Proof
 References
 
Pituitary tumors are mostly benign monoclonal adenomas arising from adenohypophyseal cells in the anterior pituitary. These tumors usually autonomously express and secrete pituitary hormones, leading to endocrinological syndromes, such as hyperprolactinemia (most common), acromegaly, Cushing’s disease, and, rarely, hyperthyroidism. Alternatively, they may be functionally silent and initially diagnosed as an expanding sellar mass resulting in hypopituitarism, usually with central hypogonadism, visual field defects, or headaches. Although our understanding of subcellular mechanisms for the pathogenesis and progression of these common tumors is incomplete, during recent years important new information on the role of intrinsic pituitary genetic alterations, disordered transcription factors and growth factors, and signaling proteins involved in pituitary tumorigenesis has been reported in both sporadic and hereditary adenomas (Table 1Go).


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  		Table 1. Genetic alterations in pituitary tumors

 

   Hypothalamic Influences vs. Intrinsic Pituitary Defect
Top
 Introduction
 Hypothalamic Influences vs....
Activating Genetic Mutations
 Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
 Growth Factors
 Note Added in Proof
 References
 
As normal pituitary function is under tight hypothalamic control mediated by the effects of releasing and inhibiting hormones, it has been suggested that hypothalamic hormones may be involved in pituitary tumorigenesis. GHRH, for example, induces somatotroph cell proliferation (1), and ectopic GHRH-secreting tumors (bronchial carcinoids, small cell lung carcinomas, and pancreatic islet cell tumors) and eutopic hypothalamic GHRH-producing tumors (hamartomas and gangliocytomas) result in somatotroph stimulation, hyperplasia, and consequent GH hypersecretion, but rarely in true somatotroph adenoma formation (2). Thus, the majority of these patients do not develop pituitary adenomas. In addition, patients with Cushing’s syndrome caused by ectopic CRH oversecretion from an intrasellar gangliocytoma (3) or prostate carcinoma (4) did not develop corticotroph adenoma despite the presence of corticotroph hyperplasia. Moreover, histological studies of pituitary adenomas clearly reveal distinct tumor borders that are not surrounded by hyperplastic pituitary tissue (5). Furthermore, hormonal secretion from the adenomatous cells is usually independent of physiological hypothalamic control, and surgical resection of small, well defined tumors usually results in definitive short term anatomical and functional cure of pituitary adenomas. The occurrence of mixed plurihormonal tumors originating from primitive pluripotent progenitor cells further supports a de novo pituitary origin for these tumors. Thus, these persistent latter observations strongly suggest that pituitary tumors are derived from an intrinsic pituitary cell defect leading to monoclonal expansion of a single transformed cell, rather than from excessive polyclonal proliferation due to generalized hypothalamic overstimulation. However, hypothalamic hormones and other local growth factors may have an important role in promoting the growth of already transformed pituitary cell clones and the expansion of small adenomas into large or invasive tumors.

The clonal origin of pituitary adenomas was determined by X-chromosomal inactivation analysis in female patients heterozygous for variant alleles of the X-linked genes hypoxanthine phosphoribosyltransferase and phosphoglycerate kinase. Using restriction fragment length polymorphisms and differential methylation patterns in these genes and other polymorphic locations that are dependent on whether the gene is active or inactive (6), monoclonality was confirmed in nonfunctioning pituitary tumors (7, 8) as well as in GH-, PRL- (8), and ACTH-secreting adenomas (8, 9, 10, 11). Thus, all cells in each tumor contained the same inactivated X-chromosome allele. In contrast, normal pituitary (8) and corticotroph hyperplastic tissue (10) were, not unexpectedly, found to be polyclonal, as these tissues contained an equal number of cells containing either the paternal or maternal activated allele. These data strongly indicate that both secreting and nonsecreting pituitary adenomas result from clonal expansion of a single mutated pituitary cell. However, tumor shrinkage after administration of dopamine agonists to prolactinomas (12) or of somatostatin analogs to GH cell adenomas (13) and, conversely, the rapid tumor enlargement of ACTH-secreting adenomas after bilateral adrenalectomy (14) are clinical demonstrations of the importance of hypothalamic and peripheral hormones in controlling subsequent pituitary tumor progression.


   Activating Genetic Mutations
Top
 Introduction
 Hypothalamic Influences vs....
 Activating Genetic Mutations
Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
 Growth Factors
 Note Added in Proof
 References
 
Oncogenes are mutated proteins leading to inappropriate or constitutive signaling of downstream effectors without regulated upstream signals. Gain of function mutations are dominant, and thus, heterozygous germ-line or localized somatic mutations will usually be phenotypically expressed in tumors.

gsp oncogene and cAMP

The G proteins, involved in transmembrane signal transduction, are a group of GTP-binding proteins coupled to a superfamily of polypeptide receptors with seven membrane-spanning domains (15). The G proteins are heterotrimers composed of three distinct subunits: {alpha}, ß, and {gamma}. The {alpha}-subunit (Gs{alpha}) binds guanine nucleotides with high affinity and differs from one G protein to another.

Up to 40% of screened human GH-secreting adenomas harbor somatic heterozygous missense activating point mutations of the Gs{alpha} gene in positions 201 in exon 8 (arginine replaced by cysteine or histidine) or 227 in exon 9 (glutamine replaced by arginine or leucine) (16, 17, 18, 19). Surprisingly, gsp mutations are rare (5%) in GH-secreting adenomas encountered in Japan (20). These tumors contain constitutively active Gs{alpha} protein, persistently active adenylyl cyclase, and high intracellular cAMP levels (21). Both residues 201 and 227 are critically important in GTP binding and hydrolysis, and their alterations inhibit intrinsic GTPase activity of Gs{alpha} protein, thus constitutively activating the protein and converting it into an oncogene (gsp). As cAMP normally mediates GHRH signaling, the mutated somatotroph G protein activation bypasses the requirement for GHRH ligand-mediated receptor activation, and persistent high cAMP activates protein kinase A, leading to phosphorylation of the cAMP response element-binding protein (CREB), which results in constitutive GH hypersecretion and enhanced somatotroph proliferation. Compared with nonmutant tumors, the gsp-expressing adenomas are smaller, have increased intratumoral cAMP, do not respond briskly to GHRH, are frequently responsive to TRH administration, and are extremely sensitive to the inhibitory effect of somatostatin (22, 23, 24). However, no difference was found in age, sex, duration of the disease, or cure rate between patients with and without the mutation. Morphologically, tumors expressing the gsp oncogene are usually densely granulated adenomas (25), which are believed to be slowly growing GH cell adenomas.

Interestingly, similar, early occurring, postzygotic dominant somatic mutations in codon 201 of the Gs{alpha} were identified in several hyperplastic endocrine tissues derived from patients with McCune-Albright’s syndrome, including pituitary hyperplasia and GH-secreting adenomas (26, 27, 28).

The gsp-activating mutations are rarely detected in nonfunctioning adenomas (<10%) and are absent in prolactinomas (29, 30) and TSH-secreting pituitary tumors (31). Recently, gsp mutations have been identified in 6% of ACTH-secreting adenomas (32). Thus, these mutations are relatively specific to GH cell pituitary tumorigenesis. In addition to mutations in the stimulatory G proteins (gsp), mutations in the {alpha}-subunit of the inhibitory GTP-binding protein gene (gip2), at codon 205 of the Gi2{alpha} protein, replacing glutamine with arginine, were reported in several nonfunctioning adenomas (30). Interestingly, these mutations result in adenylyl cyclase inhibition and cAMP suppression, in contrast to the gsp mutation effects.

The direct mechanism by which cAMP stimulates somatotroph proliferation and GH secretion is unknown, but the phosphorylated cAMP-regulated factor CREB may be involved in mediating the transcriptional effects of cAMP. Transgenic mice overexpressing a phosphorylation-deficient and transcriptionally inactive mutant of CREB in the anterior pituitary exhibit dwarfism and somatotroph hypoplasia (33). In a series of 15 human GH-secreting adenomas studied recently, all tumors contained elevated levels of Ser133-phosphorylated, and hence activated, CREB, compared with low levels of phospho-CREB in nonfunctioning pituitary adenomas (34). Interestingly, CREB phosphorylation was elevated not only in the four pituitary tumors that contained the mutant gsp oncogene, but also in other GH cell tumors expressing wild-type Gs{alpha} protein at high levels (34). Thus, Gs{alpha} overexpression in some human GH-producing adenomas may promote CREB phosphorylation.

ras oncogenes

Three homologous ras protooncogenes, H-ras, K-ras, and N-ras, encode 21-kDa monomeric proteins (p21) that possess GTPase activity and are structurally related to G proteins (35). Missense mutations at codons 12, 13, and 61, which convert ras protooncogenes into active oncogenes, are commonly identified in a variety of different human cancers (36) and benign and malignant endocrine tumors (37).

Four studies (19, 38, 39, 40) examining more than 200 secreting and nonsecreting pituitary tumors identified only one H-ras gene mutation in an aggressive prolactinoma (38). H-ras mutations were, however, identified in metastatic pituitary carcinomas in three of five patients studied, but not in the respective primary pituitary tumors or in six other invasive adenomas (41). Thus, ras oncogene point mutation and activation are uncommon events in pituitary tumor initiation, but may be important in aggressive tumors and in the very rare pituitary metastasis formation and growth.


   Tumor Suppressor Genes
Top
 Introduction
 Hypothalamic Influences vs....
 Activating Genetic Mutations
 Tumor Suppressor Genes
Releasing and Inhibiting Hormone...
 Growth Factors
 Note Added in Proof
 References
 
In contrast to the dominant protooncogenes, which induce cancer when converted to active oncogenes and which are usually associated with a point mutation, tumor suppressor genes that normally suppress cell proliferation when present as two normal alleles initiate tumor cell growth after both recessive alleles are lost or altered. According to Knudson’s two-hit theory, neoplasia may be generated by two consecutive genetic changes, where the first hit is a dominantly inherited germ-line mutation or a somatic mutation of one allele in the involved tissue, and the second hit is usually a somatic deletion of the second allele of the tumor suppressor gene with its flanking sequences, resulting in a loss of tumor heterozygosity (LOH) that renders the cell hemizygous for the original allelic mutation. This second event, revealed by a comparison of leukocyte and tumor alleles, inactivates the remaining normal suppressor gene allele and leads to unrestrained growth of clonal cancer cell populations.

p53

The p53 suppressor gene is the most common gene mutated or deleted in human neoplasia; it is associated with 50% of cancer types. However, p53 mutations were not detected in exons 5–8 (where these mutations usually occur) (42) in nonsecreting and secreting pituitary adenomas (39, 43) or in pituitary carcinomas and their respective metastases (41). Thus, p53 probably has little or no role in pituitary tumorigenesis.

Multiple endocrine neoplasia type 1 (MEN-1) gene

MEN-1 is an autosomal dominant hereditary syndrome characterized by the combined occurrence of hyperfunction or tumor formation of the parathyroids, anterior pituitary, pancreatic islets, and, rarely, carcinoid, thyroid, and adrenocortical tumors. The MEN-1 gene has not yet been characterized, but was mapped to chromosome 11q13 (44, 45). LOH involving the 11q13 region has been shown in the majority of parathyroid tumors removed from MEN-1 patients (46, 47, 48), in 29% of sporadic parathyroid lesions (48), in pancreatic islet tumors associated with MEN-1 syndrome (44, 49), and in 78% of sporadically occurring carcinoid tumors (50). These observations indicate that inactivation of a tumor suppressor gene in the 11q13 region is pathogenetically involved in the development of both hereditary and sporadic MEN-1-associated tumors.

Allelic deletions of chromosome 11q markers were studied in both MEN-1-associated and sporadic pituitary adenomas. Allelic loss involving 11q13 was demonstrated in a prolactinoma (51) and a somatotropinoma (52) obtained from patients with MEN-1 syndrome. Several studies investigated the association of putative MEN-1 chromosomal locus deletion with sporadic pituitary adenomas. Bale et al. (49) and Eubanks et al. (53) failed to demonstrate LOH of chromosome 11 regions in 8 sporadic adenomas. Bystrom et al. (48) studied 26 sporadic nonsecreting and secreting adenomas of all types and observed loss of 11q alleles in only 2 prolactinomas. Herman et al. (39) detected LOH of 11q13 and 11p loci in 1 of 7 sporadic PRL-secreting adenomas, and Thakker et al. (52) revealed allelic loss involving the 11q13 region in 4 of 12 non-MEN-1 GH cell adenomas. Boggild et al. (19) studied 88 sporadic pituitary tumors and identified chromosome 11q13 marker deletions in 20% of nonfunctioning adenomas, 28% of ACTH-secreting tumors, 16% of somatotropinomas, and 12% of prolactinomas. Thus, recessive genetic events in a tumor suppressor gene located on chromosome 11q13 are associated with pituitary tumorigenesis in MEN-1 pituitary adenomas and in 10–15% of all sporadic adenomas. However, this suppressor gene and related oncogenic alterations associated with pituitary transformation have not yet been characterized.

Retinoblastoma gene

The retinoblastoma (Rb) gene product regulates the cell cycle and has an important role in controlling cell differentiation and survival. Inactivation of both Rb alleles on chromosome 13q14 by somatic mutations leads to disappearance of the protein and to sporadic retinoblastomas (54, 55). Breast cancer (56) and nonendocrine carcinomas are associated with LOH on chromosome 13q.

Heterozygous dysruptions of the Rb gene in mice result in an approximately 100% incidence of POMC-expressing pituitary tumors (57, 58). These tumors are adenocarcinomas and originate from the pituitary intermediate lobe. In human benign pituitary adenomas, however, no Rb gene deletions or mutations were detected by several groups (59, 60, 61, 62, 63). Pei et al. (63) demonstrated LOH in proximity to the Rb locus on chromosome 13q in 13 malignant or highly invasive pituitary tumors and their respective metastases. The Rb protein, however, was identified by immunohistochemistry in all aggressive tumors with chromosome 13 allelic loss (63), suggesting that another suppressor gene located on chromosome 13q adjacent to the Rb locus, and not the Rb gene itself, may be involved in the development of invasive pituitary adenomas and carcinomas.

nm23

Another tumor suppressor gene that may be associated with pituitary tumorigenesis is the purine-binding factor gene, nm23. In highly metastatic cancer, including breast, hepatic, and colorectal carcinomas, nm23 expression is reduced (64). Recently, nm23 ribonucleic acid (RNA) expression was studied in 22 pituitary tumors, and H2 isoform expression and H2 protein immunoreactivity were significantly reduced in invasive adenomas and correlated inversely with cavernous sinus invasion (65). However, these invasive tumors did not express structural nm23 gene alterations.

Cyclin-dependent kinase (CDK) inhibitors

CDK complexes play a central role in controlling cell cycle progression. Rb phosphorylation by CDK4 to its inactive form neutralizes its ability to regulate the cell cycle (66). p16, the specific inhibitor of CDK4, is inactivated in several human cancer cell lines and was found to be low or undetectable in pituitary tumors (67). However, no p16 mutations or gene loss was detected in these adenomas.

p27 is another inhibitor of the kinase activity of the cyclin-CDK complexes and suppresses cell cycle progression. Targeted disruption of the p27 coding sequence in transgenic mice resulted in larger knockout mice with normal serum levels of GH or insulin-like growth factor I (IGF-I). These mice had multiorgan hyperplasia, pituitary intermediate lobe hyperplasia and benign intermediate lobe pituitary tumors, retinal dysplasia, and female sterility (68, 69, 70). Interestingly, gene deletions of both Rb (57, 58) and p27 genes uniquely induce pituitary pars intermedia neoplastic growth, suggesting interaction of p27 and Rb proteins in the same regulatory pathway controlling pituitary cell proliferation and differentiation.


   Releasing and Inhibiting Hormone Receptors
Top
 Introduction
 Hypothalamic Influences vs....
 Activating Genetic Mutations
 Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
Growth Factors
 Note Added in Proof
 References
 
GH secretion by pituitary somatotrophs is normally regulated by the stimulatory effect of hypothalamic GHRH and the inhibitory effect of somatostatin and IGF-I (71). The GHRH receptor is also involved in somatotroph cell proliferation and differentiation (72). However, no mutations were found in the GHRH receptor in human GH-secreting adenomas (73). Interestingly, some GH cell adenomas expressed an alternatively spliced truncated GHRH receptor (73), whose pathophysiological significance is unknown. Similarly, 19 somatotropinomas screened for IGF-I receptor ß-subunit exhibited intact regions of the receptor critical for signal transduction (74). Functional pituitary tumors express heterogeneous somatostatin receptor subtypes (75, 76). The hormonal responses to somatostatin analogs appear to be determined by selective somatostatin receptor subtype signaling in secreting tumors (77). TRH binds to its specific G protein-coupled receptor to normally stimulate TSH and PRL secretion from pituitary thyrotrophs and lactotrophs. In addition, patients with acromegaly or nonfunctioning adenomas may respond to TRH administration by brisk GH and glycoprotein subunit secretion, respectively. Recently, the coding region of the TRH receptor was found to be unaltered in PRL-, GH-, and TSH-secreting and nonfunctioning pituitary adenomas (31, 78). In addition, no dopamine type 2 receptor gene mutations were detected in prolactinomas or TSH-secreting and nonfunctioning adenomas studied recently (79). Therefore, based on mutational analyses of several cell surface receptors for hypothalamic releasing and inhibitory factors, there are no current data to support their role in pituitary tumor pathogenesis.


   Growth Factors
Top
 Introduction
 Hypothalamic Influences vs....
 Activating Genetic Mutations
 Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
 Growth Factors
Note Added in Proof
 References
 
Fibroblast growth factor (FGF)

The FGF family comprises at least nine structurally related proteins (80). Two FGF family prototypes (basic FGF, 146 amino acids), FGF-1 (acidic FGF, 140 amino acids) and FGF-2 (basic FGF) lack the characteristic signal peptide sequence of secreted proteins (81). FGF-4, a 206-amino acid protein, is encoded by the heparin-binding secretory transforming gene (hst) and contains the signal sequence for secretion. FGF-2 and FGF-4 both have potent angiogenic activity, which may increase the vascularity of and blood supply to the tissues expressing them.

FGF-2

FGF-2 is abundantly found in normal pituitary tissue (82, 83), where it is predominantly expressed within folliculostellate cells. This growth factor stimulates PRL secretion from both normal (84) and adenomatous pituitary cells (85). Human pituitary adenomas express FGF-2 (86, 87). However, FGF-2 is not mitogenic for pituitary cells in vivo (84, 85), and transgenic mice overexpressing FGF-2 in the pituitary do not develop pituitary adenomas (88).

Recent observations have identified increased pituitary FGF-2 secretion in MEN-1 patients. Circulating FGF-2 is detectable in 40% of patients with this syndrome and in most MEN-1 patients with untreated pituitary adenomas (89, 90). Interestingly, surgical or medical treatment of tumors resulted in lowering of circulating FGF-2 immunoreactivity, as measured by RIA (90), thus suggesting that the pituitary is the source of plasma FGF-2. Moreover, several MEN-1 patients with PRL cell pituitary adenomas developed FGF-2-like autoantibodies (91). Thus, although the MEN-1 syndrome is associated with loss of a putative tumor suppressor gene on chromosome 11q13, FGF-2 may have a role in promoting pituitary tumorigenesis in MEN-1 patients, but the exact interaction between the suppressor gene and the local growth factor is as yet unknown.

FGF-4 (hst)

hst expression is restricted to embryonic tissues, whereas adult tissues do not normally express the protein. However, several human malignant tumors express hst (92). Interestingly, hst has been located on chromosome 11q13 (93), in relative proximity to several other known oncogenes, including the putative MEN-1 suppressor gene locus.

The hst oncogene and the protein it encodes, FGF-4, enhance PRL gene transcription and secretion in rat pituitary cells (94), and hst transfection of rat pituitary cells is associated with in vivo aggressiveness and invasiveness of tumor cells after sc injection (94). In addition, transforming sequences of the hst gene were identified in messenger RNA derived from several human prolactinomas (95). Immunostaining for FGF-4 detected the protein product of hst in about a third of prolactinomas studied, compared with only 5% in other pituitary adenomas, both secreting (GH and ACTH) and nonsecreting (Shimon, I., Hinton D. R., Weiss, M. H., Melmed, S., unpublished data), and no immunoreactivity was present in normal pituitary tissue. Tumor proliferation activity correlated with prolactinoma hst/FGF-4 expression. However, the mechanism by which the hst protooncogene is activated and converted to a transforming gene is as yet unknown, as hst gene rearrangements were not detected in prolactinomas (39). All of these observations indicate that hst/FGF-4 may have an important role in the pathogenesis of PRL-secreting adenomas, as either a tumor initiator or a promotor for both lactotroph proliferation and hormone secretion.

Transforming growth factor-{alpha} (TGF{alpha})

TGF{alpha} is a 50-amino acid mitogenic peptide expressed in normal tissues and in several malignant tumors (96), and exerts its biological effects through the epidermal growth factor receptor.

TGF{alpha} was purified from the conditioned medium of bovine anterior pituitary cultures (97, 98), and immunohistochemical studies have localized it to PRL-secreting cells (99), where the epidermal growth factor receptor has also been detected (100). Normal human pituitary tissue and secreting and nonsecreting adenomas variably express the growth factor (101, 102). A lactotroph-targeted TGF{alpha} overexpressing transgenic mouse demonstrated lactotroph hyperplasia and developed PRL cell adenomas (103). Thus, TGF{alpha} may play a critical role in prolactinoma pathogenesis.

Pituitary tumor-transforming gene (PTTG)

Recently, a powerful transforming gene, PTTG, that encodes a novel protein of 199 amino acids was isolated from rat GH-secreting pituitary tumors by differential RNA display (104). PTTG, which is not expressed in normal pituitary tissue, exerts striking transforming effects both in vitro and in vivo. As functional human adenomas also appear to express PTTG, this observation implies the presence of a specific transforming gene in human adenomas.

Summary

It is clear that multiple molecular events may occur to initiate pituitary adenoma pathogenesis (Fig. 1Go). These include early chromosomal mutations and possibly expression of pituitary-specific protooncogenes. Subsequent permissive factors allowing clonal expansion of the transformed pituitary cell include hypothalamic hormone receptor signals, paracrine growth factor signals, and disordered cell cycle regulation. This cascade of events results in unrestrained hormone transcription and secretion, and cell proliferation, which are hallmarks of the pituitary adenoma. Nevertheless, only monoclonality and gsp mutations have reproducibly been shown to be operative in sporadic human pituitary adenomas. Thus, despite comprehensive recent information on the multiple subcellular events associated with the formation and growth of pituitary tumors, the fundamental intrinsic defect leading to adenoma formation remains elusive.



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  		Figure 1. Multistep mechanisms of pituitary tumorigenesis.

 

   Note Added in Proof
Top
 Introduction
 Hypothalamic Influences vs....
 Activating Genetic Mutations
 Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
 Growth Factors
 Note Added in Proof
References
 
The gene for MEN-I has now been identified on chromosome 11q13 (Chandrasekharappa S, et al. Science 1977; 276:404–407.)


   Footnotes
 
1 This work was supported by NIH Grants DK-42792 and DK-50238, and the Doris Factor Molecular Endocrinology Laboratory. Back

Received December 16, 1996.

Revised February 13, 1997.

Accepted February 25, 1997.


   References
Top
 Introduction
 Hypothalamic Influences vs....
 Activating Genetic Mutations
 Tumor Suppressor Genes
 Releasing and Inhibiting Hormone...
 Growth Factors
 Note Added in Proof
 References
 

  1. Billestrup N, Swanson LW, Vale W. 1986 Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro. Proc Natl Acad Sci USA. 83:6854–6857.[Abstract/Free Full Text]
  2. Sano T, Asa SL, Kovacs K. 1988 Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev. 9:357–373.[Abstract]
  3. Asa SL, Kovacs K, Tindall GT, Barrow DL, Horvath E, Vecsei P. 1984 Cushing’s disease associated with an intrasellar gangliocytoma producing corticotropin-releasing factor. Ann Intern Med. 101:789–793.
  4. Carey RM, Varma SK, Drake Jr CR, et al. 1984 Ectopic secretion of corticotropin-releasing factor as a cause of Cushing’s syndrome. N Engl J Med. 311:13–20.[Abstract]
  5. Molitch M. 1987 Pathogenesis of pituitary tumors. Endocrinol Metab Clin. 16:503–527.
  6. Vogelstein B, Fearon ER, Hamilton SR, et al. 1987 Clonal analysis using recombinant DNA probes for the x-chromosome. Cancer Res. 47:4806–4813.[Abstract/Free Full Text]
  7. Alexander JM, Biller BMK, Bikkal H, Zervas NT, Arnold A, Klibanski A. 1990 Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest. 86:336–340.
  8. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. 1990 Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. 71:1427–1433.[Abstract]
  9. Schulte HM, Oldfield EH, Allolio B, Katz DA, Berkman RA, Ali IU. 1991 Clonal composition of pituitary adenomas in patients with Cushing’s disease: determination by X-chromosome inactivation analysis. J Clin Endocrinol Metab. 73:1302–1308.[Abstract]
  10. Biller BMK, Alexander JM, Zervas NT, Hedley-Whyte ET, Arnold A, Klibanski A. 1992 Clonal origins of adrenocorticotrpin-secreting pituitary tissue in Cushing’s disease. J Clin Endocrinol Metab. 75:1303–1309.[Abstract]
  11. Gicquel C, Le Bouc Y, Luton J-P, Girard F, Bertagna X. 1992 Monoclonality of corticotroph macroadenomas in Cushing’s disease. J Clin Endocrinol Metab. 75:472–475.[Abstract]
  12. Molitch ME. 1995 Prolactinoma. In: Melmed S, ed. The pituitary. Cambridge: Blackwell; 443–477.
  13. Ezzat S, Snyder PJ, Young WF, et al. 1992 Octreotide treatment of acromegaly: a randomized, multicenter study. Ann Intern Med. 117:711–718.
  14. Nelson DH, Meakin JW, Thorn GW. 1960 ACTH-producing pituitary tumors following adrenalectomy for Cushing’s syndrome. Ann Intern Med. 52:560–569.
  15. Strader CD, Ming Fong T, Tota MR, Underwood D. 1994 Structure and function of G protein-coupled receptors. Annu Rev Biochem. 63:101–132.[CrossRef][Medline]
  16. Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. 1989 GTPase inhibiting mutations activate the {alpha} chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 340:692–696.[CrossRef][Medline]
  17. Clementi E, Malgaretti N, Meldolesi J, Taramelli R. 1990 A new constitutively activating mutation of the Gs protein {alpha} subunit-gsp oncogene is found in human pituitary tumours. Oncogene. 5:1059–1061.[Medline]
  18. Lyons J, Landis CA, Harsh G, et al. 1990 Two G protein oncogenes in human endocrine tumors. Science. 249:655–659.[Abstract/Free Full Text]
  19. Boggild MD, Jenkinson S, Pistorello M, et al. 1994 Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab. 78:387–392.[Abstract]
  20. Hosoi E, Yokogoshi Y, Hosoi E, et al. 1993 Analysis of the Gs {alpha} in growth hormone-secreting pituitary adenomas by the polymerase chain reaction-direct sequencing method using paraffin-embedded tissues. Acta Endocrinol (Copenh). 129:301–306.[Medline]
  21. Vallar L, Spada A, Giannattasio G. 1987 Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature. 330:566–568.[CrossRef][Medline]
  22. Landis CA, Harsh G, Lyons J, Davis RL, McCormick F, Bourne HR. 1990 Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein. J Clin Endocrinol Metab. 71:1416–1420.[Abstract]
  23. Spada A, Arosio M, Bochicchio D, et al. 1990 Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab. 71:1421–1426.[Abstract]
  24. Spada A, Vallar L, Faglia G. 1992 G protein oncogenes in pituitary tumors. Trends Endocrinol Metab. 3:355–360.[Medline]
  25. Spada A, Vallar L, Faglia G. 1994 Cellular alterations in pituitary tumors. Eur J Endocrinol. 130:43–52.[Abstract]
  26. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. 1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 325:1688–1695.[Abstract]
  27. Schwindinger WF, Francomano CA, Levine MA. 1992 Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G-protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA. 89:5152–5156.[Abstract/Free Full Text]
  28. Dotsch J, Kiess W, Hanze J, et al. 1996 Gs{alpha} mutation at codon 201 in pituitary adenoma causing gigantism in a 6-year-old boy with McCune-Albright syndrome. J Clin Endocrinol Metab. 81:3839–3842.[Free Full Text]
  29. Tordjman K, Stern N, Ouaknine G, et al. 1993 Activating mutations of the Gs {alpha}-gene in nonfunctioning pituitary tumors. J Clin Endocrinol Metab. 77:765–769.[Abstract]
  30. Williamson EA, Daniels M, Foster S, Kelly WF, Kendall-Taylor P, Harris PE. 1994 Gs{alpha} and Gi2{alpha} mutations in clinically non-functioning pituitary tumours. Clin Endocrinol (Oxf). 41:815–820.[Medline]
  31. Dong Q, Brucker-Davis F, Weintraub BD, et al. 1996 Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the G{alpha}q, G{alpha}11, G{alpha}s, or thyrotropin-releasing hormone receptor genes. J Clin Endocrinol Metab. 81:1134–1140.[Abstract]
  32. Williamson EA, Ince PG, Harrison D, Kendall-Taylor P, Harris PE. 1995 G-Protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas. Eur J Clin Invest. 25:128–131.[Medline]
  33. Struthers RS, Vale WW, Arias C, Sawchenko PE, Montminy MR. 1991 Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant. Nature. 350:622–624.[CrossRef][Medline]
  34. Bertherat J, Chanson P, Montminy M. 1995 The cyclic adenosine 3',5'-monophosphate-responsive factor CREB is constitutively activated in human somatotroph adenomas. Mol Endocrinol. 9:777–783.[Abstract]
  35. Lochrie MA, Hurley JB, Simon MI. 1985 Sequence of the alpha subunit of photoreceptor G protein: homologies between transducin, ras, and elongation factors. Science. 228:96–99.[Abstract/Free Full Text]
  36. Bos JL. 1989 ras oncogenes in human cancer: a review. Cancer Res. 49:4682–4689.[Abstract/Free Full Text]
  37. Namba H, Rubin SA, Fagin JA. 1990 Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 4:1474–1479.[Abstract]
  38. Karga HJ, Alexander JM, Hedley-Whyte ET, Klibansky A, Jameson JL. 1992 ras mutations in human pituitary tumors. J Clin Endocrinol Metab. 74:914–919.[Abstract]
  39. Herman V, Drazin NZ, Gonsky R, Melmed S. 1993 Molecular screening of pituitary adenomas for gene mutations and rearrangements. J Clin Endocrinol Metab. 77:50–55.[Abstract]
  40. Cai WY, Alexander JM, Hedley-Whyte ET, et al. 1994 ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab. 78:89–93.[Abstract]
  41. Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D. 1994 H-ras mutations in human pituitary carcinoma metastasis. J Clin Endocrinol Metab. 78:842–846.[Abstract]
  42. Hollstein M, Sidransky D, Vogelstein B, Harris CC. 1991 p53 mutations in human cancers. Science. 253:49–53.[Abstract/Free Full Text]
  43. Levy A, Hall L, Yeudall WA, Lightman SL. 1994 p53 gene mutations in pituitary adenomas: rare events. Clin Endocrinol (Oxf). 41:809–814.[Medline]
  44. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M. 1988 Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 322:85–87.
  45. Fujimori M, Wells SA, Nakamura Y. 1992 Fine mapping of the gene responsible for multiple endocrine neoplasia type 1 (MEN1). Am J Hum Genet. 55:399–403.
  46. Friedman E, Sakaguchi K, Bale AE, et al. 1989 Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med. 321:213–218.[Abstract]
  47. Thakker RV, Bouloux P, Wooding C, et al. 1989 Association of parathyroid tumors in multiple endocrine neoplasia 1 with loss of alleles on chromosome 11. N Engl J Med. 321:218–224.[Abstract]
  48. Bystrom C, Larrson C, Blomberg C, et al. 1990 Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Proc Natl Acad Sci USA. 87:1968–1972.[Abstract/Free Full Text]
  49. Bale AE, Norton JA, Wong EL, et al. 1991 Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. Cancer Res. 51:1154–1157.[Abstract/Free Full Text]
  50. Jakobovitz O, Nass D, DeMarco L, et al. 1996 Carcinoid tumors frequently display genetic abnormalities involving chromosome 11. J Clin Endocrinol Metab. 81:3164–3167.[Abstract]
  51. Beckers A, Abs R, Reyniers E, et al. 1994 Variable regions of chromosome 11 loss in different pathological tissues of a patient with the multiple endocrine neoplasia type 1 syndrome. J Clin Endocrinol Metab. 79:1498–1502.[Abstract]
  52. Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN. 1993 Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest. 91:2815–2821.
  53. Eubanks PJ, Sawicki MP, Samara GJ, et al. 1994 Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation. Am J Surg. 167:180–185.[CrossRef][Medline]
  54. Knudson AGJ. 1971 Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 68:820–823.[Abstract/Free Full Text]
  55. Friend SH, Bernards R, Rogelj S, et al. 1986 A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 323:643–646.[CrossRef][Medline]
  56. Lee EY-HP, To H, Shew JY, Brookstein R, Scully P, Lee WH. 1988 Inactivation of the retinoblastoma susceptibility gene in human breast carcinoma. Science. 241:218–221.[Abstract/Free Full Text]
  57. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. 1992 Effects of an RB mutation in the mouse. Nature. 359:295–300.[CrossRef][Medline]
  58. Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY. 1994 Heterozygous Rb-1 delta/+ mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene. 9:1021–1027.[Medline]
  59. Cryns VL, Alexander JM, Klibanski A, Arnold A. 1993 The retinoblastoma gene in human pituitary tumors. J Clin Endocrinol Metab. 77:644–646.[Abstract]
  60. Zhu J, Leon SP, Beggs AH, Busque L, Gilliliard DG, Black PM. 1994 Human pituitary adenomas show no loss of heterozygosity at the retinoblastoma gene locus. J Clin Endocrinol Metab. 78:922–927.[Abstract]
  61. Woloschak M, Roberts JL, Post KD. 1994 Loss of heterozygosity at the retinoblastoma locus in human pituitary tumors. Cancer. 74:693–696.[CrossRef][Medline]
  62. Woloschak M, Yu A, Xiao J, Post KD. 1996 Abundance and state of phosphorylation of the Rb gene product in human pituitary tumors. Int J Cancer. 67:16–19.[CrossRef][Medline]
  63. Pei L, Melmed S, Scheithauer B, Kovacs K, Benedict WF, Prager D. 1995 Frequent loss of heterozygosity at the retinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors: evidence for a chromosome 13 tumor suppressor gene other than RB. Cancer Res. 55:1613–1616.[Abstract/Free Full Text]
  64. Bevilaqua G, Sobel ME, Liotta LA, Steeg PS. 1989 Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymphnode involvement and other histopathological indicators of high metastatic potential. Cancer Res. 49:5185–5190.[Abstract/Free Full Text]
  65. Takino H, Herman V, Weiss M, Melmed S. 1995 Purine-binding factor (nm23) gene expression in pituitary tumors: marker of adenoma invasiveness. J Clin Endocrinol Metab. 80:1733–1738.[Abstract/Free Full Text]
  66. Weinberg RA. 1995 The retinoblastoma protein and cell cycle control. Cell. 81:323–330.[CrossRef][Medline]
  67. Woloschak M, Yu A, Xiao J, Post KD. 1996 Frequent loss of the p16ink4a in human pituitary tumors. Cancer Res. 56:2493–2496.[Abstract/Free Full Text]
  68. Nakayama K, Ishida N, Shirane M, et al. 1996 Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 85:707–720.[CrossRef][Medline]
  69. Kiyokawa H, Kineman RD, Manova-Todorova KO, et al. 1996 Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1. Cell. 85:721–732.[CrossRef][Medline]
  70. Fero ML, Rivkin M, Tasch M, et al. 1996 A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice. Cell. 85:733–744.[CrossRef][Medline]
  71. Herman-Bonert VS, Prager D, Melmed S. 1995 Growth hormone. In: Melmed S, ed. The pituitary. Cambridge: Blackwell; 98–135.
  72. Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG. 1993 Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature. 364:208–213.[CrossRef][Medline]
  73. Hashimoto K, Koga M, Motomura T, et al. 1995 Identification of alternatively spliced messenger ribonucleic acid encoding truncated growth hormone-releasing hormone receptor in human pituitary adenomas. J Clin Endocrinol Metab. 80:2933–2939.[Abstract/Free Full Text]
  74. Greenman Y, Prager D, Melmed S. 1995 The IGF-I receptor sub-membrane domain is intact in GH-secreting pituitary tumours. Clin Endocrinol (Oxf). 42:169–172.[Medline]
  75. Greenman Y, Melmed S. 1994 Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab. 78:398–403.[Abstract]
  76. Greenman Y, Melmed S. 1994 Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab. 79:724–729.[Abstract]
  77. Shimon I, Taylor JE, Dong J, et al. 1997 Somatostatin receptor subtype specificity in human fetal pituitary cultures: differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone and prolactin regulation. J Clin Invest. 99:789–798.[Medline]
  78. Faccenda E, Melmed S, Bevan JS, Eidne KA. 1996 Structure of the thyrotrophin-releasing hormone receptor in human pituitary adenomas. Clin Endocrinol (Oxf). 44:341–347.[CrossRef][Medline]
  79. Friedman E, Adams EF, Hoog A, et al. 1994 Normal structural dopamine type 2 receptor gene in prolactin-secreting and other pituitary tumors. J Clin Endocrinol Metab. 78:568–574.[Abstract]
  80. Mason IJ. 1994 The ins and outs of fibroblast growth factors. Cell. 78:547–552.[CrossRef][Medline]
  81. Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G. 1987 Structural characterization and biological functions of fibroblast growth dactor. Endocr Rev. 8:95–114.[Medline]
  82. Gospodarowicz D, Neufeld G, Schweigerer L. 1986 Fibroblast growth factor. Mol Cell Endocrinol. 46:187–204.[CrossRef][Medline]
  83. Bohlen P, Baird A, Esch F, Ling N, Gospodarowicz D. 1984 Isolation and partial molecular characterization of pituitary fibroblast growth factor. Proc Natl Acad Sci USA. 81:5364–5368.[Abstract/Free Full Text]
  84. Baird A, Mormede P, Ying SY, et al. 1985 A nonmitogenic pituitary function of fibroblast growth factor: regulation of thyrotropin and prolactin secretion. Proc Natl Acad Sci USA. 82:5545–5549.[Abstract/Free Full Text]
  85. Atkin SL, Landolt AM, Jeffreys RV, Diver M, Radcliffe J, White MC. 1993 Basic fibroblast growth factor stimulates prolactin secretion from human anterior pituitary adenomas without affecting adenoma cell proliferation. J Clin Endocrinol Metab. 77:831–837.[Abstract]
  86. Li Y, Koga M, Kasayama S, et al. 1992 Identification and characterization of high molecular weight forms of basic fibroblast growth factor in human pituitary adenomas. J Clin Endocrinol Metab. 75:1436–1441.[Abstract]
  87. Ezzat S, Smyth HS, Ramyar L, Asa SL. 1995 Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab. 80:878–884.[Abstract]
  88. Weiner RI, Windle J, Mellon P, Schechter J. 1991 Role of FGF in tumorigenesis of the anterior pituitary [Abstract]. J Endocrinol Invest. 14(Suppl 1):10.
  89. Zimering MB, Brandi ML, deGrange DA, et al. 1990 Circulating fibroblast growth factor-like substance in familial multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 70:149–154.[Abstract]
  90. Zimering MB, Katsumata N, Sato Y, et al. 1993 Increased basic fibroblast growth factor in plasma from multiple endocrine neoplasia type 1: relation to pituitary tumor. J Clin Endocrinol Metab. 76:1182–1187.[Abstract]
  91. Zimering MB, Riley DJ, Thakker-Varia S, et al. 1994 Circulating fibroblast growth factor-like autoantibodies in two patients with multiple endocrine neoplasia type 1 and prolactinoma. J Clin Endocrinol Metab. 79:1546–1552.[Abstract]
  92. Sakamoto H, Mori M, Taira M, et al. 1986 Transforming gene from human stomach cancers and a noncancerous portion of stomach mucosa. Proc Natl Acad Sci USA. 83:3997–4001.[Abstract/Free Full Text]
  93. Yoshida MC, Wada M, Satoh H, et al. 1988 Human HST1 (HSTF1) gene maps to chromosome band 11q13 and coamplifies with the INT2 gene in human cancer. Proc Natl Acad Sci USA. 85:4861–4864.[Abstract/Free Full Text]
  94. Shimon I, Huttner A, Said J, Spirina O, Melmed S. 1996 Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription. J Clin Invest. 97:187–195.[Medline]
  95. Gonsky R, Herman V, Melmed S, Fagin J. 1991 Transforming DNA sequences present in human prolactin secreting pituitary tumors. Mol Endocrinol. 5:1687–1695.[Abstract]
  96. Derynck R, Goeddel DV, Ullrich A, et al. 1987 Synthesis of messenger RNAs for transforming growth factors {alpha} and ß and the epidermal growth factor receptor by human tumors. Cancer Res. 47:707–712.[Abstract/Free Full Text]
  97. Samsoondar J, Korbin MS, Kudlow JE. 1986 {alpha}-Transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture. I. Purification from conditioned media. J Biol Chem. 261:14408–14413.[Abstract/Free Full Text]
  98. Korbin MS, Samsoondar J, Kudlow JE. 1986 {alpha}-Transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture. II. Identification using a sequence-specific monoclonal antibody. J Biol Chem. 261:14414–14419.[Abstract/Free Full Text]
  99. Korbin MS, Asa SL, Samsoondar J, Kudlow JE. 1987 {alpha}-Transforming growth factor in the bovine anterior pituitary gland: secretion by dispersed cells and immunohistochemical localization. Endocrinology. 121:1412–1416.[Abstract]
  100. Mueller SG, Korbin MS, Paterson AJ, Kudlow JE. 1989 Transforming growth factor-{alpha} expression in the anterior pituitary gland: regulation by epidermal growth factor and phorbol ester in dispersed cells. Mol Endocrinol. 3:976–983.[Abstract]
  101. Driman DK, Korbin MS, Kudlow JE, Asa SL. 1992 Transforming growth factor-{alpha} in normal and neoplastic human endocrine tissues. Hum Pathol. 23:1360–1365.[CrossRef][Medline]
  102. Ezzat S, Walpola IA, Ramyar L, Smyth HS, Asa SL. 1995 Membrane-anchored expression of transforming growth factor-{alpha} in human pituitary adenoma cells. J Clin Endocrinol Metab. 80:534–539.[Abstract]
  103. McAndrew J, Paterson AJ, Asa SL, McCarthy KJ, Kudlow JE. 1995 Targeting of transforming growth factor-{alpha} expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas. Endocrinology. 136:4479–4488.[Abstract]
  104. Pei L, Melmed S. Isolation and characterization of a pituitary tumor-specific transforming gene. Mol Endocrinol. 11:433–441.



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