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
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Introduction
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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, Cushings 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 1
).
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Hypothalamic Influences vs. Intrinsic Pituitary Defect
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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 Cushings 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.
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Activating Genetic Mutations
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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:
, ß, and
.
The
-subunit (Gs
) 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
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
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
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
were
identified in several hyperplastic endocrine tissues derived from
patients with McCune-Albrights 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
-subunit of the inhibitory
GTP-binding protein gene (gip2), at codon 205 of the
Gi2
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
protein at high
levels (34). Thus, Gs
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.
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Tumor Suppressor Genes
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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 Knudsons 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 58 (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 1015% 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.
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Releasing and Inhibiting Hormone Receptors
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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.
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Growth Factors
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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-
(TGF
)
TGF
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
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
overexpressing
transgenic mouse demonstrated lactotroph hyperplasia and developed PRL
cell adenomas (103). Thus, TGF
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. 1
). 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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Note Added in Proof
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The gene for MEN-I has now been identified on chromosome 11q13
(Chandrasekharappa S, et al. Science 1977; 276:404407.)
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Footnotes
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1 This work was supported by NIH Grants DK-42792 and DK-50238, and the
Doris Factor Molecular Endocrinology Laboratory. 
Received December 16, 1996.
Revised February 13, 1997.
Accepted February 25, 1997.
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