Topic of the month.... Pathogenesis of pituitary adenomas http://yassermetwally.com http://yassermetwally.net

1. INDEX www.yassermetwally.com
INTRODUCTION

INTRODUCTION
Pituitary tumors exhibit a spectrum of biology, with variable growth and hormonal behaviors. They therefore provide an
opportunity to examine pathogenetic mechanisms that underlie the neoplastic process. These include alterations in hormone
regulation, growth-factor stimulation, cell-cycle control and cell-stromal interactions that result from genetic mutations or
epigenetic disruption of gene expression. Mouse models have validated the roles of these alterations, which can be targets for the
development of therapies that can manage these lesions. These therapies are increasingly recognized as critical for quality of life.
The pituitary, a small bean-shaped gland at the base of the brain, maintains multiple homeostatic functions including metabolism,
growth and reproduction. Most pituitary tumors are adenomas that develop in the adenohypophysis (the anterior lobe of the
pituitary gland), which is composed of six epithelial cell types that secrete peptide hormones.
Pituitary adenomas exhibit a wide range of hormonal and proliferative behaviors.[1] They may be small, slowly growing and
hormonally in active, and might only be detected as radiographic quot;incidentalomasquot; or at postmortem examination. If, however,
they produce hormones in excess, they can cause mood disorders, sexual dysfunction, infertility, obesity and disfigurement,
hypertension, diabetes mellitus and accelerated heart disease. If untreated, hormone-excess syndromes can be lethal.
Some pituitary adenomas grow rapidly, producing symptoms of an intracranial mass, loss of normal anterior pituitary hormone
production, and visual-field disturbances due to stretching of the overlying optic chiasm. They can invade downward into
paranasal sinuses, laterally into the cavernous sinuses (thereby disrupting coordinated eye movement) and upwards into the
brain. They can cause death by invasion of the brain.
Studies using X-chromosome inactivation proved that pituitary adenomas are monoclonal neoplasms.[2] Results that suggest

2. polyclonality are attributed to contamination by normal tissue; the small adenomas associated with Cushing's syndrome are
particularly subject to this phenomenon.
In contrast to their high frequency of local invasion, only rarely do pituitary tumors metastasize to distant locations in the central
nervous system, lymph nodes and liver. This pattern of spread is the criterion of malignancy, allowing a diagnosis of pituitary
carcinoma. Many tumors classified as benign are nevertheless associated with significant morbidity and mortality.
In this review we will focus on our understanding of the pathogenetic mechanisms underlying the biologic and morphologic
features of human pituitary tumors. These include alterations in hormonal regulation and hormone receptors, dysregulated
growth factors and alterations in their receptors, abnormalities in signaling proteins that transduce the signals of these stimuli,
and changes in cell-cycle regulators (Figure 1). In addition, the neoplastic process is associated with altered cell-stromal
interactions that have a role in the morphogenesis of pituitary tumors (Figure 2). These changes are summarized below.
Figure 1. Maintaining the delicate balance in
pituitary endocrine cell survival. The
contribution from some of the characterized
factors in anterior pituitary cell growth is
shown. Many hormones bind G-protein-
coupled receptors, which wind back and forth
through the cell membrane seven times and
can exert either stimulatory or inhibitory
effects. Growth-factor receptors can similarly
be stimulatory or inhibitory, and expression
levels of, or mutations in, either the receptors
or their ligands can affect signaling. The
relative contributions of cell-cycle control
proteins involved in pituitary cells are
becoming better defined. Estradiol,
endogenous T3 and glucocorticoids act
through dedicated nuclear steroid hormone
receptors to mediate negative feedback on
respective pituitary stimulatory signals.
CRH, corticotropin-releasing hormone; D2R, dopamine receptor 2; E2, estradiol; EGF, epidermal growth factor; FGFs,
fibroblast growth factors; GC, glucocortiocoids; GH, growth hormone; GHRH, GH-releasing hormone; Gi, inhibitory G protein;
GnRH, gonadotropin-releasing hormone; Gs, stimulatory G protein; PRL, prolactin; ptd-FGFR-4, pituitary-tumor-derived
fibroblast growth factor receptor 4; PTTG, pituitary tumor-transforming gene; Ras, intracellular GTP-binding protein that is
implicated in cell-signaling pathways; Rb1, retinoblastoma 1; SST, somatostatin; TGF, transforming growth factor; TRH, TSH-
releasing hormone.
Epidemiology and Classification of Pituitary Adenomas

There are limited data on the prevalence of pituitary tumors. Although classically considered to be rare, systematic assessments
from autopsy and radiologic studies have shown a prevalence of 17% of the population.[3] The sex incidence is equal. These
tumors are rare in childhood and the incidence increases with age.[1]
Prolactin-producing adenomas are the most common type.[1] One-third are unassociated with hypersecretory syndromes; the
majority of these produce but do not secrete the gonadotropins follicle-stimulating hormone and/or luteinizing hormone. Growth-
hormone (GH)-producing or adrenocorticotropic hormone (ACTH)-producing adenomas each account for 10-15% of pituitary
adenomas. Adenomas producing thyrotropin (TSH) are rare.
Hormonal activity classifies pituitary adenomas: ACTH-producing adenomas are associated with Cushing's or Nelson's
syndromes; GH-producing adenomas are associated with acromegaly and/or gigantism; prolactin-producing adenomas cause
hyperprolactinemia; TSH-producing tumors are associated with thyroid dysfunction; there are rare, clinically detectable,
gonadotroph adenomas; and there are quot;endocrinologically inactivequot; adenomas. Anatomic and/or radiographic classification is
based on tumor size and degree of invasion, information that is critical for patient management and, when surgery is indicated,
guides the surgical approach. Immunohistochemistry allows identification of hormone content that usually correlates with the
clinical presentation ( Table 1 ). Ultrastructural classification by electron microscopy allows identification of sub cellular variants

3. that now can be characterized using immunohistochemical markers, such as keratins;[1] these variants respond to therapy
differently, with variable prognosis and should, therefore, be considered in patient management. Transcription factors that
regulate hormone expression are used to classify cytogenesis even in hormone-negative adenomas;[1] tumors derived from
different cell lines behave differently, making tumor cytogenesis important for clinical care. It remains to be established whether
other characteristics, such as proliferation markers, growth factors and/or their receptors, or oncogene products, will prove to be
more reliable predictors of invasive growth, recurrence, or metastasis.
Table 1. Pituitary Cells, Hormones, Tumors and Hormone-excess Syndromes
Alterations in Hormone Regulation

The development of the adenohypophysis is dependent on hormones for expansion of differentiated cell populations.
Adenohypophysiotropic hormones that are produced by the hypothalamus and target organs are involved in complex regulatory
feedback mechanisms, which are tightly controlled to maintain homeostasis.[4] Pathology external to the pituitary itself Results in
hyperplasia or atrophy of the relevant adenohypophysial cell population.[1,2,4] For this reason, hormonal stimulation or impaired
feedback inhibition has been thought to underlie the pathogenesis of pituitary tumors.
The data suggest, however, that although hormones may promote cell proliferation, hormonal stimulation is not implicated in the
neoplastic transformation that underlies the development of human pituitary tumors.
GH-releasing hormone (GHRH) stimulates somatotroph proliferation and causes somatotroph hyperplasia in mice ( Table 2 );[2]
in patients with endocrine carcinomas that secrete GHRH ectopically, there is somatotroph hyperplasia but tumors do not
develop in this situation.[2] During pregnancy, estrogen causes lactotroph hyperplasia; conversely, antiestrogen activity induces
lactotroph apoptosis and also suppresses tumor formation.[5] Some lactotroph adenomas grow during gestation;[6] however,
although estrogen was implicated in the pathogenesis of a lactotroph adenoma in male-to-female transsexuals,[7] the clinical use
of estrogen in contraceptive agents or in postmenopausal hormone replacement has not been associated with an increased risk of
pituitary tumor development.[8] TSH-releasing hormone (TRH) stimulates thyrotrophs and lactotrophs, and patients with
primary hypothyroidism develop pituitary thyrotroph and lactotroph hyperplasia.[1] Excess of corticotropin-releasing hormone
causes pituitary corticotroph hyperplasia and Cushing's syndrome in humans with ectopic hormone production by tumors, but
tumor development has not been reported in this setting.[9]

4. Table 2. Summary of Known Genetic Alterations in
Pituitary Tumors
Loss of hormonal inhibition might also be involved in hormonal dysregulation. Dopamine maintains tonic inhibition of
lactotrophs. In prolactinomas, neovascularization that bypassed the hypothalamus was observed, which implicated the presence
of diminished hypo thalamic inhibition, and allowed the tumor cells to escape local inhibition by dopamine.[10] Although
dopamine-receptor-deficient mice develop massive lactotroph hyperplasia,[11] no mutations in the DRD2 gene have been
identified in human pituitary adenomas and most lactotroph tumors respond to dopamine agonists.
Hypothalamic somatostatin inhibits GH secretion, and somatostatin receptors are expressed on somatotroph adenomas.[12,13] A
rare, germline, inactivating mutation in somatostatin receptor 5 was reported in a patient with acromegaly,[14] and expression of
somatostatin is reported to be lower in invasive, GH-secreting tumors than in normal pituitary tissue;[15-18] however, there is no
evidence that loss of somatostatin inhibition is etiologically important in somatotroph adenoma development. GH secretion is also
inhibited by insulin-like growth factor 1 (IGF1). Patients with GH-producing adenomas have elevated levels of circulating IGF1
that would be expected to suppress adenoma cells, but no alterations in IGF1 response have been identified that explain
tumorigenesis.
Patients with long-standing primary hypogonadism develop pituitary gonadotroph adenomas.[1] Similarly, those with primary
hypothyroidism develop thyrotroph hyperplasia that can progress to adenoma if untreated.[1] Primary adrenal failure, in the
setting of prolonged glucocorticoid deficiency, leads to corticotroph hyperplasia and adenoma,[1] suggesting that loss of
glucocorticoid feedback might cause Cushing's disease. A novel germ-line mutation was implicated as the cause of pituitary
Cushing's disease in a small number of patients.[19] Similarly, rare glucocorticoid-receptor mutations that diminished
glucocorticoid inhibition were found in corticotroph tumors.[20,21] The majority of tumors, however, do not exhibit alterations
that would explain dysregulated hormonal inhibition.
Old transgenic mice that overexpress GHRH develop pituitary adenomas, and dopamine-receptor-deficient mice ultimately
develop invasive lactotroph adenomas,[2] but the delayed neoplasia observed in both settings, as in humans with primary failure
of the thyroid, adrenals or gonads, implicates additional genetic events in neoplastic transformation. Indeed, it is distinctly
unusual to find hyperplasia underlying the vast majority of sporadic human pituitary adenomas, suggesting that hormonal
stimulation is not a primary etiologic mechanism. Sustained exposure to hormonal stimulation does not, moreover, always lead to
adenoma formation in humans.[22] Although they might promote proliferation of transformed pituitary cells, it seems that
hormones do not cause pituitary tumors. The role of promotion of established tumors by hormones is supported by the finding of
exaggerated intrapituitary GHRH expression in aggressive somatotroph adenomas.[23]

5. Alterations of Hormone Receptors

Activating mutations of the GHRH receptor might explain transformation of somatotrophs, but this possibility has been excluded.
[24] Instead, a truncated, alternatively spliced form of the receptor with limited signaling properties was identified in GH-
producing pituitary adenomas.[25] There are no reports of activating mutations of the corticotropin-releasing hormone receptor
in corticotroph adenomas.
Recently, the concept of GH and prolactin autoregulation in the pituitary was proven. Prolactin regulates its own secretion at
both hypothalamic and pituitary levels.[26] Prolactin-receptor (PRLR)-deficient mice develop earlier lactotroph hyperplasia, and
adenomas that are larger and more invasive, than the hyperplasia seen in dopamine D2 receptor-deficient mice,[27] proving the
importance of this short autoregulatory loop. Prolactin-producing adenomas have higher levels of PRLR messenger RNA
(mRNA) than other types of adenomas. Dopamine-agonist therapy decreases the levels of PRLR mRNA in human prolactin
adenomas.[28] There is no evidence, however, of disrupted pro lactin autoregulation in lactotroph adenomas. In contrast to the
situation with prolactin, where mouse models indicate autoregulation but there is no human pathology implicating this process,
GH has a more subtle autoregulatory role in mice and a pathogenetic significance in humans. Disruption of GH autoregulation in
mice Results in subtle somatotroph enlargement and hyperplasia.[29] GH-receptor antagonism in human somatotrophs leads to
formation of fibrous bodies–abnormal aggregates of keratin filaments characteristic of a subset of human somatotroph adenomas,
the quot;sparsely granulatedquot; variant.[1] Consistent with this finding, somatic mutations of the GH-receptor were found in these
tumors (Asa SL et al., unpublished data), implicating disruption of GH autoregulation in the development of this subtype of
tumor.
The TRH receptor is expressed in thyrotroph adenomas.[30] In some adenomas, the TRH receptor mRNA is alternatively spliced;
deletion of exon 3 Results in a truncated product that does not bind its ligand efficiently. Elevated levels of similar truncated
products in lactotroph adenomas[31] might explain paradoxical in vivo responses to TRH administration.
Thyroid-hormone receptors (TRs) that bind DNA regulatory elements mediate thyroid hormone regulation. TRa mRNA mis-
sense mutations, and an alternatively spliced TRß2 variant with a 135-base-pair deletion in the ligand-binding domain have been
described in TSH-producing tumors.[32]
These data indicate that abnormal hormone receptor signaling can contribute to dysfunctional responses to feedback inhibition;
however, apart from one subtype of GH-secreting adenomas, hormone receptor alterations do not seem to be common events that
could be implicated in the etiology and pathogenesis of the majority of pituitary adenomas.
Dysregulated Growth Factors and Their Receptors

The pituitary is the target for and site of synthesis of several growth factors that modulate hormone production and regulate
pituitary cell growth.[2] Some growth factors are critical for normal pituitary development. Alterations in their expression or
action might have important roles in the growth of tumors.
The epidermal growth factor (EGF) family and its receptors have been implicated in tumorigenesis in a number of neoplasms.
The pituitary gland expresses the ligands transforming growth factor (TGF)-a and EGF, which alter pituitary hormone secretion
and induce cell proliferation.[2] In fact, TGF-a has been implicated as the mediator of estrogen-induced lactotroph proliferation,
since TGF-a antisense expression specifically inhibits this response.[33] Overexpression of TGF-a, under the control of the
prolactin promoter, Results in lactotroph adenomas in transgenic mice,[34] indicating a role for this growth factor in pituitary
tumorigenesis. The common receptor of EGF and TGF-a, EGFR, is one of a family of four highly homologous receptors
possessing tyrosine kinase activity, along with ErbB2/HER2/neu/p185, ErbB3/HER3, and ErbB4/HER4. EGFR expression
correlates with pituitary tumor aggressiveness–especially among GH-producing tumors.[35] In contrast to other human
neoplasms, however, ERBB2 is not mutated or amplified in human pituitary tumors.[2]
The TGF-ß family is represented in the pituitary by inhibin A (a-ßA heterodimers), inhibin B (a-ßB), activin (ßA-ßB), activin A
(ßA-ßA) and activin B (ßB-ßB). Inhibin subunits are expressed by pituitary gonadotroph adenomas and activin stimulates
hormone secretion by these tumors.[2] The effects of activin are modulated by follistatin and activin receptors. Follistatin binds
activins and downregulates their activity. Activin receptors are expressed in gonadotroph adenomas and follistatin expression is
reduced or diminished,[36] implicating enhanced activin signaling as a pathogenetic mechanism. Additionally, a truncated activin
receptor type-IB isoform that fails to transduce activin-induced growth-arrest signaling was described exclusively in tumors, but
not normal human pituitary cells,[37] underscoring the importance of the activin/follistatin balance in modulating pituitary cell
growth.
The fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate development, growth, and angiogenesis. There are
currently 23 known FGF ligands. Basic (b)FGF was originally described in the bovine pituitary folliculostellate cell, and regulates
pituitary hormones; bFGF is expressed by human pituitary adenomas and elevated circulating FGF is found in patients with
pituitary adenomas.[2] FGF-4 sequences are present in transforming DNA from human pro lactin-secreting tumors,[38] and

6. FGF-4 facilitates lactotroph proliferation.[39] FGF-8 is necessary for pituitary development,[40] and expression of a soluble
dominant-negative FGFR Results in pituitary dysgenesis.[41] The product of the endogenous FGF antisense gene (NUDT6)
inhibits pituitary cell proliferation.[42] A truncated kinase-containing variant of FGFR-4 with an alternative initiation site[43,44]
was isolated from human pituitary tumors.[45] This pituitary-tumor-derived (ptd)-FGFR-4 isoform (ptd-FGFR-4) causes
transformation in vitro and in vivo and, when expressed in transgenic mice, recapitulates invasive pituitary adenoma formation.
[46]
These studies provide convincing evidence for the important role of growth factors, and in particular, the FGF system, in
pituitary development and tumor formation.
Abnormal Signaling Proteins

Altered signaling by proteins involved in signal transduction of hormones and growth factors might be implicated in pituitary
tumorigenesis.
G-proteins transduce signals from cell-surface ligand-receptor complexes to downstream effectors. The family of stimulatory G
proteins (Gs) transduces GHRH signals. Point mutations in Gsa codon 201 (Arg201Cys) and codon 227 (Gln227Arg) activate
adenylyl cyclase by interfering with GTP hydrolysis, Gsa in a constitutively active state.[45] These G-protein oncogenes (GSPs)
were first described in a subset of pituitary somatotroph adenomas and hormone-secreting tumors of other endocrine glands.
[45,47] GSP mutations are more frequently detected in the maternal allele, which is consistent with monoallelic imprinting of this
gene. There is no correlation between GSP mutations and patient age, sex, tumor size, or circulating GH levels;[48] however, this
mutation correlates with the densely granulated phenotype of somatotroph tumors,[49] elevated levels of phosphorylated cyclic
AMP (cAMP) response element binding protein,[50] and higher circulating levels of free glycoprotein-subunit.[51] These features
might be predictive of GH responsiveness to somatostatin-analog therapy.[52] Inactivating mutations in the a-subunit of GIP2, a
protein coupled to the inhibitory G-protein Gi2a, have been identified.[53] No mutations have been identified in the stimulatory
Gaq or the highly similar Ga11.[54]
Ras proteins are also involved in transducing signals from ligand–receptor complexes at the membrane to downstream effectors.
Ras mutations are common in nonendocrine malignancies, most frequently involving the GTP-binding domain (codons 12/13) or
the GTPase domain (codon 61).[55] Mutation in HRas causing a Gly12Val substitution is distinctly uncommon in pituitary
tumors.[56] Initially described in a highly aggressive prolactinoma, Ras mutations are largely restricted to the rare pituitary
carcinomas.[57]
Protein kinase A is a tetrameric holoenzyme involved in cAMP binding. Adequate levels of the cAMP-dependent protein kinase
type 1 regulatory subunit (the product of PRKAR1A) are critical for intracellular protection against unrestrained catalytic
activity. Consistent with this model, germline mutations in PRKAR1A are associated with Carney's complex,[58] an autosomal-
dominant disorder characterized by development of pituitary and other endocrine tumors.
Deregulated Cell Cycle Control Elements

The autosomal-dominant syndrome, multiple endocrine neoplasia type I (MEN1), to which pituitary tumors are integral, is caused
by germline mutations of the MEN1 tumor-suppressor gene on chromosome 11q13, with loss of heterozygosity (LOH) inactivating
the normal allele in tumors. LOH at this region, observed in 10–30% of sporadic endocrine tumors, suggested that MEN1 could
be implicated in sporadic pituitary adenomas. MEN1 is not, however, responsible for sporadic pituitary adenomas, nor is it
altered in patients with inherited pituitary tumors that are not associated with the MEN1 syndrome. Reduced expression of menin
in sporadic adenomas would indicate that menin functions as a tumor suppressor, but MEN1 mRNA expression is not
downregulated in sporadic pituitary tumors.[2]
Retinoblastoma 1 (Rb1), a tumor-suppressor gene on chromosome 13q, is associated with pituitary intermediate-lobe tumors in
Rb1-deficient mice.[59] Mutations of Rb1 have not been identified in human pituitary adenomas, but the Rb1 promoter is
methylated, resulting in gene silencing.[2] There is LOH at13q in tumors with unmethylated Rb1, suggesting an independent
tumor-suppressor gene at that locus.[2]
Cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) regulate cell-cycle progression. CDK activity is
modulated by the CDKIs p27kip1, p57kip2, p16ink4A, p15ink4B, p18ink4C, and p19ink4D. Although CDKN2A (which encodes
p16ink4A) is not mutated in pituitary adenomas, it is frequently silenced by promoter methylation.[60] The CDKI p27kip1 is
important in the pathogenesis and prognosis of several human malignancies. Mice that are Cdkn1b-null do not express p27kip1,
and develop multiorgan neoplasia, including pituitary tumors.[61] Although the CDKN1B gene is not mutated in human pituitary
tumors, expression of its product p27kip1 is reduced in corticotroph adenomas and recurrent human pituitary adenomas.[2]
Protein stability is critical in maintaining p27 protein expression, suggesting epigenetic mechanisms of p27 alteration that can be
targeted for therapy.[62] Mice lacking both p18ink4C and p27kip1 succumb to rapidly lethal pituitary adenomas;[61] however,
there are no reports of p18 alterations in human pituitary tumors.

7. The growth ? arrest and DNA-damage-inducible gene GADD45G negatively regulates cell growth. Expression of GADD45G
mRNA is significantly diminished in clinically nonfunctioning and hormonally active GH-secreting or prolactin-secreting
pituitary tumors,[63] because of gene silencing through CpG island promoter methylation.[64]
Maternally expressed gene 3 (MEG3) is a human homolog of the mouse MATERNALLY IMPRINTED Gtl2 gene. The MEG3a
isoform, containing an extended exon 5 sequence, inhibits cell growth in vitro. As with GADD45?, MEG3a expression is
diminished in human pituitary tumors associated with 5' promoter hypermethylation.[65]
A number of other cell-cycle regulators have received attention as candidate causes of pituitary tumors. Pituitary tumor
transforming gene 1 (PTTG1) is a member of the securin family that is involved in sister chromatid separation. As expected of a
gene with this function it is upregulated in proliferating cells.[2] Pituitary tumor apoptosis gene (PTAG; this name has not yet
been approved) is a novel antiapoptotic gene on chromosome 22 identified in pituitary tumors but with no known significance.[66]
The tumor suppressor p53, which is mutated or lost in many other forms of cancer, is expressed in pituitary tumors; however,
there is no evidence of TP53 gene mutation or LOH in pituitary tumors.[2] Upregulated expression of this gene probably
represents a compensatory mechanism, so that there might be some prognostic value of p53 staining;[67] however, this is
controversial as there is no consistent correlation between p53 immunoreactivity and tumor invasion or recurrence.[68]
Dysadhesion and Abnormal Stromal Interactions

Progression to neoplasia involves changes in cell-cell and cell-matrix adhesion. Indeed, loss of the reticulin network is the
morphological hallmark of the transition from hyperplasia to adenoma that is commonly used as a diagnostic feature in the
pituitary.[1]
Changes in cell adhesion have been correlated with the abnormal expression of ptd-FGFR-4 in cell lines, transgenic mice and
human pituitary adenomas that result in loss of affinity for extracellular matrix.[69] This loss is due to disruption of a
multiprotein complex involving FGFR-4, N-cadherin (a cell adhesion molecule) and neural cell adhesion molecule 1 (NCAM-1).
Expression of ptd-FGFR-4 Results in diminished and ectopic cytoplasmic expression of N-cadherin, associated with invasive
growth.[69] Uncoupling of N-cadherin from the cytoskeleton destabilizes ß-catenin,[69] and reduced ß-catenin expression in
human pituitary adenomas correlates with tumor invasiveness.[70] Similarly, expression of the polysialated form of NCAM-1
correlates with tumor growth and invasiveness;[71] polysialation Results in steric inhibition of membrane-membrane apposition
and cell adhesiveness and, therefore, probably disrupts the multiprotein complex as does ptd-FGFR-4 (Figure 2). Estrogen, a
known stimulus of pituitary cell proliferation, reduces membranous N-cadherin protein expression to barely detectable levels,
whereas antiestrogen treatment reverses this effect.[72]
Figure 2. The balance between adhesive and dysadhesive forces in pituitary cells. In this model, the membrane location of neural
cell adhesion molecule 1, fibroblast growth factor receptor 4 and N-cadherin is critical for the formation of a proadhesive
multiprotein complex. As shown on the right, wild-type fibroblast growth factor receptor 4 resides predominantly in the cell
membrane and interacts heavily with neural cell adhesion molecule 1 to support stability of N-cadherin and ß-catenin and

8. maintain actin cytoskeletal structure. By contrast, as shown on the left, receptor isoforms such as pituitary-tumorderived
fibroblast growth factor receptor 4 are located in the cytoplasm, and can displace fibroblast growth factor receptor 4 from neural
cell adhesion molecule 1, thereby disrupting cell-cell and cell-matrix adhesion, which are mediated by N-cadherin and ß-catenin.
A similar form of steric hindrance with this multiprotein proadhesive complex can be achieved by polysialated neural cell
adhesion molecule 1.
FGFR-4, fibroblast growth factor receptor 4; NCAM-1; neural cell adhesion molecule 1; PSA, polysialated; ptd-FGFR-4,
pituitary-tumor-derived fibroblast growth factor receptor 4.
Implications For Therapy

The treatment of pituitary tumors involves medical, surgical, and radiotherapeutic approaches. Pharmacotherapy represents the
cornerstone for treatment of several hormonally active adenomas. Prolactin-secreting tumors are generally treated with
dopamine agonists. Somatostatin analogs are widely adopted to restrain hormone secretion by GH-producing pituitary tumors;
the varying response to somatostatin analogs is now understood to be reflective of the differing pathogenetic mechanisms
underlying the various morphologic tumor types that cause acromegaly. Some of the currently available agents suppress hormone
excess, some result in reduction of tumor size, but they do not achieve a tumoricidal effect. Comparison of somatostatin-sensitive
and somatostatin-resistant tumors, by use of genomic and proteomic approaches, will undoubtedly pave the way for the
development of effective tumoricidal drug treatments; moreover, dopamine and somatostatin analogs are not effective in the
treatment of tumors arising from gonadotrophs or corticotrophs, creating a need for more-effective agents.
Since Rb1 inactivation underlies corticotroph tumor development in mice, this provides a model for the evaluation of gene
therapy approaches in the management of pituitary tumors. Spontaneous pituitary tumors in immunocompetent Rb1-deficient
mice were treated with a recombinant adenovirus carrying Rb1-complementary DNA. Intratumoral Rb1 gene transfer decreased
tumor cell proliferation, re-established innervation by growth-regulatory dopaminergic neurons, and resulted in inhibition of
tumor growth and enhanced animal survival,[73] providing proof of principle.
Deficient or defective delivery of dopamine has been implicated in lactotroph adenomas. This system has been investigated by
transfection of human lactotroph adenomas in vitro with an adenoviral vector that expresses tyrosine hydroxylase. Introduction
of this rate-limiting enzyme in dopamine biosynthesis enhanced dopamine synthesis and diminished prolactin secretion.[74]
Similarly, the pro-opiomelanocortin promoter has also been used to allow selective expression of the toxic herpes simplex virus
thymidine kinase, in mouse pituitary corticotroph cell lines. Infection in vitro or injection in vivo results in selective gene
expression and cytotoxicity.[5] This hormone promoter might, therefore, be used in selective targeting of gene therapy vectors to
tumors associated with excessive ACTH production and Cushing's disease. These studies provide evidence for the feasibility of
gene therapy and the use of pituitary-specific promoters to confer selectivity in treating pituitary tumors.
Corticotroph adenomas are characterized by loss of the tumor suppressor p27, as a result of protein degradation.[62] The actions
of vitamin D3 in restoring p27 protein levels[62] could have therapeutic significance for these tumors, which as yet have no other
targeted medical therapies.
Also close to the clinical horizon is the application of selective tyrosine kinase inhibitors. These agents should be tested in
therapeutic trials in defined patient populations–especially those in whom surgical or medical therapies have failed. Selective
inhibitors of the FGFR and EGFR pathways might be used to treat pituitary tumors effectively. Tumor-associated EGFR and
FGFR could, moreover, be targeted, by delivering toxins or antiproliferative monoclonal antibodies to tumor cells.
Conclusions

The individual contributions of the components involved in the complex cascade of events leading to human neoplasia are finally
unraveling. The delicate balance maintained by the dominant factors in the pituitary is summarized in Figures 1 and 2. It is
important to emphasize that it is becoming increasingly evident, in many systems, that no single factor can effectively explain the
many facets of the tumorigenic process. It is nevertheless anticipated that specific interruption of several signaling cascades will
afford new approaches to the therapeutic armamentarium, permitting more-effective strategies in the management of pituitary
tumors.
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Addendum
A new version of topic of the month publication is uploaded in my web site every month (it remains for a month and is changed

with the monthly update of the neurology bulletin at:.http://neurology.yassermetwally.com)
To download the current version of topic of the month publication follow the link quot;http://neurology.yassermetwally.com/topic.zipquot;

You can also download the current version of topic of the month publication from within the publication or go to my web site at:

quot;http://yassermetwally.comquot; to download it.
At the end of each year, all the publications are compiled on a single CD-ROM, please author to know more details.

Screen resolution is better set at 1024*768 pixel screen area for optimum display

For an archive of the previously published topics in downloadable PDF format go to http://yassermetwally.net, then under pages in

the right panel, scroll down and click on the text entry quot;topic of the monthquot;
In order to view a list of the previously published topics in downloadable PDF format, follow the link:

http://wordpress.com/tag/neurological-topic-of-the-month/
The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt
www.yassermetwally.com