Expression of pituitary developmental signalling molecules and TFs
Pituitary adenomas (PA) are frequent and typically benign endocrine neoplasia, which clinical prevalence is estimated around 1/1000 inhabitants . The vast majority are sporadic. PA are endowed with significant clinical morbidity related to hormonal hypersecretion, neurological symptoms due to intracranial mass effects or invasion of the surrounding structures and/or secondary hypopituitarism. Their evolution is quite variable, ranging from indolent tumours with an extremely slow growing potential, to recurrent, aggressive, and exceptionally malignant tumours. Their current clinical management is based on pharmacological treatment, mainly dopamine-agonists (DA) and somatostatin analogues (SSA), surgery and radiotherapy . Despite considerable progress in the management of PA, a significant subset of patients are not satisfactorily controlled. Long-term uncontrolled pituitary hormone hypersecretion, leading to potential severe systemic diseases, and tumour recurrence or aggressiveness still represent a difficult clinical challenge. Understanding the mechanisms involved in the pathogenesis of PA is essential for the development of new therapeutic strategies. In this chapter, we will summarize current concepts in pituitary tumorigenesis and focus our attention on the most recent insights and new perspectives in this field.
2. Pituitary tumours
Primary pituitary tumours in human are mainly represented by PA arising from endocrine cells in the anterior lobe and craniopharyngiomas. These latter are divided into adamantinomatous, which derive from the Rathke’s pouch, and papillary craniopharyngiomas. Additional tumour types deriving from non-endocrine cells of the anterior pituitary and the neurophypohysis can be found , which pathogenesis is poorly known and will not be considered in this review.
PA may be classified according to their macroscopic characteristics into micro- (< 1 cm) or macro-adenomas (≥ 1 cm), and enclosed or invasive adenomas. Invasion of the surrounding structures (cavernous sinuses, bone, sphenoidal sinus) is generally defined according to neuroradiological imaging – especially magnetic resonance imaging -, although intra-operative findings may introduce some correction to the pre-operative radiological classification or reveal macroscopic dural invasion. Of note, microscopic evidence of dural invasion is rarely present on surgical samples. The functional classification of PA is based on their hormone-secreting potential, which may be associated with bio-clinical evidence of hormone hypersecretion or recognized by immunohistochemistry (IHC) for pituitary hormones and/or by specific ultrastructural features. From an epidemiological point of view, prolactinomas are by far the most frequent (50-60%), followed by clinically non-functioning PA (NFPA) (20-30%), somatotrophinomas (10-15%), corticotrophinomas (5-10%) and thyreotrophinomas (1-2%) [1,2,4]. Recruitment bias are frequently encountered in pathological series, since most prolactinomas are treated by DA only. Clinico-pathological correlations in PA have been recently reviewed . In the large majority of PA associated with bio-clinical evidence of hormone secretion, except functional hyperprolactinemia, pathological examination will confirm the diagnosis of PRL, GH, ACTH or TSH-secreting tumours and potentially identify bi- or multi-hormonal secretion. This is especially true for GH-secreting PA, which may also secrete PRL, less frequently glycoprotein hormones, or both (multihormonal). TSH-secreting adenomas are rare and frequently multihormonal. Ultrastructural studies of secreting PA may disclose a “densely granulated” (DG) or “sparsely granulated” (SG) pattern, which may reflect significant differences in hormone secretion and tumour behaviour. This has been well studied in somatotrophinomas, where IHC for cytokeratin can be used to disclose the typical “dot-like” staining pattern of SG adenomas. Although a continuum exists between the SG and DG types, pure SG are typically more aggressive than DG somatotrophinomas . Pathological examination of NFPA may show negative immunostaining for all pituitary hormones (the “null cell” or endocrine inactive histotype), positive immunostaining for FSH and/or LH (gonadotrophinomas) or reveal silent secretion of other pituitary hormones, in particular ACTH and GH (“silent” secreting PA). Cell lineage may also be identified by the expression of specific transcription factors (see “pituitary ontogenesis”) . It is generally accepted that most NFPA derive from the gonadotroph lineage, since data obtained from primary cultures or molecular analysis of these tumours frequently reveal a silent expression of gonadotropins or their subunits, including α−subunit only. Also, transgenic mice overexpressing SV40 under the control of the βFSH promoter develop gonadotroph hyperplasia and PA with reduced gonadotropin immunoreactivity and ultrastructural characteristics similar to human null cell PA . Silent corticotroph adenomas are commonly aggressive and different subtypes have been described. Pituitary carcinomas are strictly defined by the presence of extra-pituitary dissemination (see “pituitary carcinomas”). Therefore, no diagnosis of pituitary carcinoma can be made on a surgical pituitary sample. Considerable efforts have been made to recognize the aggressive potential of PA according to pathological criteria. However, mitoses are generally rare and the percentage of cells immunopositive for the Ki67 antigen (which is expressed throughout the cell cycle and detected with the MIB1 monoclonal antibody) is currently considered as the best marker of cell proliferation. A Ki67 index ≥3% is commonly associated with invasiveness , although it can be reduced by pre-operative pharmacological treatment in secreting PA . Immunostaining for p53 is also frequently associated with invasiveness and is typically present in carcinomas . For these reasons, the 2004 WHO conference has proposed to define as “atypical adenomas” a subset of invasive PA characterized by Ki67 labelling ≥ 3% and extensive p53 nuclear staining . However, many criticisms remain and search for reliable markers of aggressiveness or malignancy is going on. Gene expression profiling comparing non-invasive adenomas with their invasive counterpart [9, 10] or with pituitary carcinomas  represents a promising approach.
The pathogenesis of PA is multifactorial. Traditionally, two theories have been proposed: the primary pituitary origin, and the hypothalamic origin of PA or, more generally speaking, the concept that PA may derive from abnormal pituitary regulation. Acromegaly or Cushing’s disease resulting from ectopic secretion of GHRH or CRH by neuroendocrine tumours, respectively, or estrogen-induced prolactinomas, represent the main evidence for the second theory. However, the chief lesion in such conditions is hyperplasia, with PA developing in a very minority of cases, whereas hyperplasia is exceptionally observed surrounding the tumoral tissue in human PA. Although hyperplasia may be difficult to identify (reticulin staining is not routinely proposed), there is accumulating evidence supporting the primary pituitary origin of PA. Indeed, PA are essentially monoclonal in origin, and a number of genetic abnormalities have been identified these tumours, which include somatic events and inherited predisposition. The relatively low rate of recurrences following complete surgical removal of enclosed PA, especially microadenomas, also favours a primary pituitary hypothesis. However, polyclonality can also be observed on PA, and different clones may develop in a synchronous or delayed pattern, possibly accounting for tumour progression or regrowth . A unifying view is that pituitary tumorigenesis is a multistep and multifactorial process, which includes early initiating genetic events, growth promotion by extracellular factors (including the extracellular matrix, growth factors, cytokines, neuropeptides and peripheral hormones) and additional genetic events contributing to a further progression of the tumour in terms of invasiveness, recurrences and, exceptionally, metastasis [13,14].
3. Pituitary developmental pathways and their potential alterations in pituitary tumours
Because the expanding knowledge about the molecular mechanisms involved in pituitary ontogenesis is providing new clues in the understanding of pituitary tumorigenesis, relevant findings in this field will be summarized.
3.1. Ontogenesis of the pituitary gland
The anterior pituitary lobe (AP) derives from an invagination of the oral ectoderm forming the Rathke’s pouch (RP), which cells proliferate and subsequently undergo progressive terminal differentiation into the 5 adult pituitary cell types (corticotrophs; somatotrophs, lactotrophs, gonadotrophs and thyreotrophs), whereas the posterior lobe (or neurohypophysis) derives from a specialized region of the neuroectoderm, the infundibulum. The intermediate lobe also arises from the RP and contains melanotrophs in rodents but is virtually absent in humans. The molecular mechanisms of pituitary ontogenesis have been mainly studied in the mouse and, in addition to genetic models which have contributed to elucidate the role of single proteins , analysis of transcriptomes obtained from cDNA libraries in the developing embryo represents a promising tool to identify new genes involved in this process [15,16]. Complex interactions between signalling molecules (in particular opposite signals coming from the diencephalon and the ventral ectoderm) and pituitary transcriptions factors (TFs) are involved and tightly regulated in a spatially and temporally organised manner. Extensive reviews are available on this topic [17,18]. Genetic defects in pituitary TFs are responsible for inherited abnormalities in pituitary development, spanning from syndromic diseases due to defects in early factors (
(BMP 2 and 4)
|VD||BMP4: essential for the invagination of Rathke’s pouch;
|BMP4: overexpressed in prolactinomas, underexpressed in corticotrophinomas|
(FGF 8 and 10)
|VD/RP||FGF10 : essential for cell survival
FGF8: involved in the maintenance of RP cells proliferation opposing gradients with BMP2
|WNT4 and 5A/
|VD/RP||Involved in pituitary development and in the induction of
||Wnt4 : expressed in GH/PRL/TSH-secreting PA|
||VD; oral ectoderm except RP||Involved in early proliferation and cell type determination as well as in the control of adult pituitary cell function and proliferation||Shh: underexpressed in PA, including corticotrophinomas|
|Notch 2 and 3||VD/RP||Required for early lineage commitment and the terminal differentiation of distinct cell lineages||Notch3: overexpressed in NFPA|
|Sox2||VD/RP||Required for pituitary development and the maintenance or proliferation of pituitary progenitor cells||Expressed in adamantinomatous craniopharyngiomas|
|Hesx1||VD/RP||Involved in early pituitary development||Expressed in all PA phenotypes|
|Otx2||RP||Involved in RP development, in particular in the expression of
|Lhx3-4||RP||Required for cell survival and prevention of apoptosis||NA|
|Isl1||RP||Required for the proliferation and differentiation of pituitary progenitors||NA|
|Six 1, 3 and 6||RP||Six1 regulates cell proliferation; Six6 is required for pituitary development and cell proliferation; Six3 interacts with Hesx1||NA|
|Pitx 1 and 2||RP||Pitx1 e Pitx2 activate the early transcription of the
Pitx1 also binds the
|Pitx1: expressed in all PA phenotypes
Pitx2: overexpressed in NFPA
|FOXL2||AP||A transcriptional activator of
||Overexpressed in NFPA|
|NeuroD1||RP||A transcriptional activator of
||Expressed in corticotrophinomas and a subset of NFPA|
|Tpit||POMC precursor||A transcriptional activator of
||Expressed in secreting and silent corticotrophinomas|
|Prop1||RP||A transcriptional activator of
||Expressed in all PA phenotypes|
|Gata2||RP||Interacts and cooperates with
||Expressed essentially in gonadotroph and thyreotroph PA|
|Pit-1||Pit-1 lineages||Essential for the terminal differentiation and expansion of GH/PRL/TSH-secreting cells; an enhancer of
||Expressed in GH/PRL/TSH-secreting PA (including NFPA with silent secretion)|
|CREB||Pit-1 lineages||Required in somatotrophs||Expressed in all somatotrophinomas|
|Gata2||RP/pituitary||A promoter of
|SF1||Gonadotrope||A promoter of
||Expressed in the majority of gonadotroph/NFPA, not in GH/PRL-secreting PA|
3.2. Developmental pathways in pituitary adenomas
Three master developmental pathways – Wnt, Hedgehog and Notch – have been involved in several human diseases, in particular in cancer. We will attempt to summarize current knowledge about their role in pituitary development and tumorigenesis, which is likely to expand significantly in the next years.
3.2.1. The Wnt/beta-catenin pathway
The canonical Wnt/β-catenin signalling pathway plays a role in the specification of pituitary progenitor/stem cells and β-catenin modulates the transcriptional activity of several pituitary TFs, in particular Pitx2, PROP-1 (thereby promoting the activation of
3.2.2. Sonic hedgehog
Sonic hedgehog (Shh) is involved in pituitary ontogenesis and regulates pituitary hormone release. Shh signalling is mediated by Patched receptors (Ptc1, Ptc2) and the Gli family of TFs. During ontogenesis, Shh is expressed by the ventral diencephalon and by the oral ectoderm immediately adjacent to RP. There is recent evidence that Shh signalling is of particular importance before the RP detachs from the oral ectoderm, and that Gli2 is responsible for the proliferation of early pituitary progenitors and for the diencephalic induction of FGF8 and BMP4 . This is consistent with reports of human inactivating Gli2 germline mutations associated with severe pituitary developmental defects and different degrees of craniofacial abnormalities . In the adult pituitary Shh/Ptc2/Gli1 signalling is active in corticotrophs and stimulates POMC transcription and ACTH release; Gli1 is necessary for CRF signalling . Contrasting with the corticotroph specificity of Shh, Ptc receptors are also expressed in other pituitary secreting cells, although in a phenotype-specific manner . Shh immunostaining was found low or absent in a large series of PA, including corticotrophinomas, whereas the expression of Ptch receptors was retained . Shh was also found to stimulate ACTH, GH and PRL secretion by normal and tumorous pituitary cells
Notch signalling regulates progenitor cell differentiation during embryogenesis. Notch is a cell-to-cell signalling network composed by transmembrane ligands (in mammals Delta-like 1,3,4 and Jagged 1,2), the transmembrane Notch receptors (Notch 1-4), and a transcription factor (in mammals RBPJ), which is activated by the intracellular fragment of Notch after ligand-induced Notch cleavage has occurred. Notch target genes encode beta-helix loop-helix (bHLH) TFs, in particular the
3.3. Pituitary stem cells
The pituitary gland is characterized by a high degree of plasticity, which is involved in pituitary function changes through life and adaptation to physiological and pathological variations in peripheral hormone feed-back. Several conditions require a re-organization of pituitary cell composition, with an expansion of a specific cell pool (
4. Genetics of pituitary tumours
PA are triggered by a variety of genetic abnormalities [13,14,47]. The vast majority occur at a somatic level, but inherited predisposition is being increasingly recognized.
4.1. Inherited predisposition to pituitary tumours
Although inherited predisposition to PAs is often recognized in a familial setting, a sporadic presentation may occur. In addition to their implications for familial screening, genes involved in hereditary tumours may provide important clues in the comprehension of the molecular basis of tumorigenesis. We have recently reviewed this topic and proposed an algorithm for genetic screening in patients with PA .
4.1.1. Multiple Endocrine Neoplasia type 1 (MEN1)
MEN1 is an autosomal dominant condition defined by the presence, in a single subject or within a single family, of two or more hyperplastic and/or adenomatous lesions of the parathyroid glands (~90%), the gastro-entero-pancreatic (GEP) tract (30-80%) and/or the anterior pituitary (~40%). The clinical characteristics of MEN1-related PA have been recently reviewed elsewhere [48,49]. Briefly, their phenotypic distribution is unremarkable when compared to sporadic PA, with a predominance of prolactinomas (~60%), but they are more frequently invasive and resistant to pharmacological treatment. Pediatric onset is not uncommon, especially for PRL- and ACTH-secreting PA, and carcinomas have been reported. Peri-tumoral hyperplasia is rare, but multiple and plurihormonal adenomas are more frequent than in sporadic PA . Since the identification of the
4.1.2. Carney Complex (CNC)
The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity” is a rare and heterogeneous condition, characterized by the association of endocrine overactivity and tumors - Primary Pigmented Nodular Adrenocortical Disease (PPNAD), acromegaly, thyroid and gonadal tumors – with cardiac myxomas, schwannomas and skin pigmented lesions . Primary pituitary presentation is rare and pituitary abnormalities are mainly represented by an hyperplasia of GH/PRL-secreting cells, which frequently translates into mild hyperprolactinemia and/or subclinical alterations of GH/IGF1 secretion. Early onset GH/IGF1 hypersecretion may induce gigantism, but acromegaly and somatotrophinomas develop in a minority of patients (15%). Up to 70% of CNC patients present in a familial setting, with an autosomal dominant transmission. Germline heterozygote mutations in the
4.1.3. McCune Albright Syndrome (MAS)
MAS is a rare sporadic disease due to post-zygotic activating mutations in the α
4.1.4. MEN-4 and other CDKI-related disorders
Inactivating mutations in the
4.1.5. The pituitary adenoma-paraganglioma/pheochromocytoma association: A new syndrome?
Succinate dehydrogenase (SDH) is a mitochondrial enzyme composed of four functionally different subunits A,B,C,D. Mutations in genes encoding the SDH B,C and D subunits predispose to pheochromocytomas/ paragangliomas and additional tumours, including thyroid cancer. Recently, a germline mutation in the
4.1.6. Familial Isolated Pituitary Adenomas (FIPA) and the Aryl hydrocarbon receptor Interacting Protein (AIP) gene
Familial Isolated Pituitary Adenomas (FIPA) are defined by the familial presentation of PA in the absence of syndromic features. In 2006, 64 European FIPA kindreds were reported, including patients affected by prolactinomas (55%), somatotrophinomas (~30%), non-secreting PA (~15%) and corticotrophinomas (<5%) . The prevalence of FIPA among PA was estimated about 2-3% and kindreds were almost equally divided into homogeneous and heterogeneous, as defined by the familial association of PA with a single or multiple phenotypes, respectively. Familial homogeneous somatotrophinomas, previously reported as “Isolated Familial Somatotrophinomas”, accounted for ~20% of the whole series. In the same year, the
4.2. Somatic events in pituitary tumours
Somatic events in pituitary tumours include genetic and epigenetic changes. Intragenic mutations are less frequently encountered than in other solid tumours. Indeed, oncogene activation is mainly triggered by the overexpression of genes involved in extracellular signalling and cell cycle progression, with a few gain-of-function mutations and occasional rearrangements being reported. Inactivation of tumour suppressor genes is very common and occurs through epigenetic changes more frequently than through loss-of-function mutations and/or allelic deletions. MicroRNAs (miRs) have also recently emerged as important regulators of gene/protein expression in pituitary tumours.
4.2.1. Chromosome and DNA alterations in PA
Several chromosome abnormalities have been reported in PA, although on limited series of tumours, and include aneuploidy and evidence for intrachromosomal gain or loss of DNA. For example, trisomies involving chromosomes 5, 8 and 12 appear to be very frequent in prolactinomas , whereas trisomies involving chromosomes 7, 9 and 20 were reported in NFPA . Conversely, monosomy of chromosome 11 was observed in an aggressive MEN1-related prolactinoma  and LOH with single or multiple allelic deletions at different loci have been reported, which also appear to be more frequent in invasive PA. For instance, the frequency of LOH in 11q13, 13q12-14 and/or 10q26 was found to increase from <10% in low grade to nearly 75% in high grade PA, according to a modified Hardy’s classification . As compared to other solid tumours, classical somatic oncogenic mutations are relatively rare in PA [reviewed in 13,47]. The most frequent oncogenic mutation is represented by activating missense mutations in the
4.2.2. Epigenetics in PA
Epigenetic changes are mainly characterized by DNA methylation and histone modifications, leading to chromatin remodelling and regulation of gene expression through a modulation of DNA accessibility to TFs. Epigenetic changes may coexist with genetic events (
4.2.3. The emerging role of microRNAs and other non-coding RNAs
MicroRNAs (miRs) are small non-coding RNA molecules (18-25 nucleotides) involved in the post-transcriptional regulation of mRNAs stability. More than 600 miRs have been reported in the human genome and up to 30% of genes are believed to be regulated by miRs. Briefly, miRs derive from the intracellular processing of precursors called pri- and pre-miRNAs, and mature miRs bind to the 3’ untranslated sequence of mRNA target molecules, leading to the formation of miRs duplexes. MiRs duplexes are incorporated into protein containing RNA-induced silencing complexes (RISC) and, according to their degree of complementarity with miRs, target mRNAs can be cleaved (perfect complementarity) or undergo partial degradation and translational inhibition (imperfect complementarity, which is the most common figure). MiRs have been involved in the control of pituitary development  and function . Alterations in miRs expression profile, including loss or gain of expression, have been increasingly involved in pituitary tumorigenesis. Since the first report on miR15a and miR16-1 downregulation in GH- and PRL-secreting macroadenomas , more than 100 dysregulated miRs have been identified in PA, with phenotype-specific expression profiles being reported in GH- and/or PRL-secreting, ACTH-secreting or NFPA [103-112]. Although in most cases their biological significance is not fully understood, several miRs have been involved in the control of pituitary cell cell proliferation, differentiation, apoptosis, cell adhesion and metabolism, and a subset has been linked to a more aggressive behavior or even to malignant transformation [103, 104, 110]. Target mRNAs are also being increasingly recognized. For instance,
|Potential target genes:
Target gene (miR26b):
|miR-191||3p21||Overexpression||All PA||Cell proliferation||103|
|miR-24-1||9q22.1||Down-regulation||All PA||Predicted target genes:
|Let7-a||9q22.32||Down-regulation||All PA||Target genes:
Potential target genes:
|103, 104, 112|
|miR-126||9q34.3||Down-regulation||GH||Amplification of PI3K signalling;
|miR-107||10q23||Overexpression||GH/ NFPA||Target gene:
|miR-326||11q13.4||Down-regulation||GH, some PRL
|miR-141||12p13||Down-regulation||ACTH||Tumor growth and tumor local invasion||103|
|miR-16-1||13q14||Down-regulation||All PA||Target genes:
|miR-15a||13q14||Down-regulation||All PA, in particular GH/PRL||Target genes:
|miR-493||14q32.2||Overexpression||ACTH (carcinoma)||Target genes:
|miR-140||16q22.1||Overexpression||NFPA (macroadenomas)||Tumor growth||103|
|miR-212||17p13.3||Overexpression||All PA||Target gene:
|miR-152||17q21||Overexpression||All PA||Cell proliferation||103|
|Down-regulation||ACTH/ NFPA||See miR-24-1||103|
||Xp11.2||Down-regulation||All PA||Predicted target genes involved in cell progression, cytoskeleton and vesicle organization||103|
5. Alterations in neuropeptide signalling in pituitary tumours
Hypothalamic peptides play an essential role in normal pituitary cells and their biological effects are mediated by G-protein coupled receptors (GPCRs) . In addition to their dynamic control on pituitary hormone secretion and release, they may exert trophic effects on target cells - such as GHRH and CRH on somatotrophs and corticotrophs, respectively – or limit their proliferation – such as dopamine in lactotrophs. The expression of neuropeptide receptors is generally conserved in pituitary tumours and represents the molecular basis for their pharmacological treatment with DA and SSA . However, abnormal expression of these receptors may be involved in paradoxical responses or in pharmacological resistance. Neuropeptides may also be produced by the pituitary gland or ectopically by neuroendocrine tumours, and their ectopic secretion may lead to pituitary hyperplasia and/or adenoma. Finally, abnormal intracellular signalling may occur in PA, contribute to pituitary tumorigenesis and potentially influence the response to pharmacological treatment. An extensive review of such processes would be beyond the scope of this work, so we will focus on the most relevant and recent findings in this field.
5.1. Abnormalities in the cAMP-PKA pathway
The cAMP/PKA pathway is essential in pituitary cells, especially in somatotrophs and in corticotrophs. Briefly, the α-subunit of the stimulatory G protein (Gsα), encoded by the
5.2. Neuropeptides, neuropeptide receptors and their implications in pituitary tumour pathogenesis and treatment
Abnormal hypothalamic neuropeptide signalling has long been involved in the pathogenesis of PA. GHRH stimulates somatotroph proliferation and causes somatotroph hyperplasia in mice, with PA developing in old transgenic GHRH animals. Hypothalamic acromegaly has been exceptionally reported in patients with gangliocytomas  and ectopic secretion of GHRH by neuroendocrine tumours has been well characterized. In a retrospective analysis of 21 patients with ectopic acromegaly , most patients showed radiological evidence of pituitary enlargement, but 5 had normal pituitary imaging and 6 had suspected PA, respectively. Out of the four cases who underwent pituitary surgery, all had somatotroph hyperplasia and 2 had concomitant GH/PRL-secreting PA. Noteworthy, a MEN1 context was identified in 8/11 cases. Ectopic secretion of CRH by neuroendocrine tumours may cause ACTH-dependent hypercortisolism, but this is an exceptional condition and ectopic secretion of ACTH and other POMC-derived peptides is by far most frequent. TRH stimulates thyrotrophs and lactotrophs, mainly through the IP3/calcium pathway, and patients with long-standing, severe, primary hypothyroidism may develop pituitary thyrotroph and lactotroph hyperplasia due to an altered feedback on TRH/TSH secretion. Similar mechanisms are involved in gonadotroph hyperplasia secondary to long-standing hypogonadism (of note, pituitary hyperplasia is not a feature of menopause). However, true “feed-back” PA are rare and are likely to require additional somatic events. Abnormal/ectopic, expression of neuropeptide receptors may also occur in PA and account for some “paradoxical” responses observed
6. Dysregulated cell growth and survival in pituitary tumours
Alterations in cell cycle control and imbalance between cell proliferation and apoptosis are general mechanisms in tumours. Such alterations may be driven by abnormal extracellular signalling and/or abnormal intracellular responses to extracellular signals, including constitutive activation of proliferative pathways and/or escape to normal regulatory signals.
6.1. Extracellular signalling in PA
In addition to neuropeptides, pituitary cells depend on extracellular signalling from the extracellular matrix, a variety of growth factors (GFs) and peripheral hormones secreted by target glands. Extracellular signalling molecules are involved in a complex network of paracrine and autocrine pathways, which are tightly regulated in the developing and adult pituitary . Cell-to-cell signalling regulates pituitary hormone secretion, cell differentiation, growth, survival and plasticity, as well as angiogenesis. Abnormal signalling may therefore participate in pituitary tumorigenesis.
6.1.1. Growth factors and cytokines
The pituitary gland is an abundant source of GFs, in particular the FGF, EGF and VEGF families, and cytokines (the TGFβ family, interleukins and chemokines) [19,125]. Due to the abundant literature in this field, we will present an overview of the best studied GFs and related pathways in PA. FGFs play an important role in pituitary development. FGFs include >20 members and FGF signalling is mediated by 4 FGF receptors (FGFR1-4), with different isoforms (cell-bound, secreted, truncated) generated by alternative splicing. FGFs and FGFRs are involved in proliferative and anti-proliferative signals. The
6.1.2. Steroid hormones
Steroid hormones may play an important role in pituitary tumorigenesis. The best characterized model is represented by estrogen-induced lactotroph hyperplasia and prolactinomas. Estrogen-induced lactotroph hyperplasia occurs physiologically during pregnancy, but sustained estrogen exposure may lead to prolactinomas in some strains of rats. Although evidence for estrogen-induced prolactinomas in humans is very poor, prolactinoma growth and/or intra-tumoral hemorrhage may occur during pregnancy, especially in macroprolactinomas . Among PA, prolactinomas express the higher concentration of ER  and estrogens can increase PA cell proliferation in primary culture . Importantly, ERα and ERβ play distinct roles and an imbalance between these two isoforms has been reported in PA. Indeed, nuclear overexpression of ERα has been linked to tumour aggressiveness in prolactinomas and NFPA, whereas invasive NFPA were found to express lower ERβ . Ablation of ERβ in mice was also associated with the development of invasive gonadotrophinomas in females . Estrogens exert multiple effects on pituitary cells, especially on lactotrophs. They enhance the transcription of the
6.1.3. Adhesion molecules
Adhesion molecules are important to maintain cell-to-cell contact and a normal cell morphology and tissue architecture. Similarly to other epithelial tumours, PA may develop some degree of epithelial-to-mesenchymal transition, which is associated with loss of cell adherence and tumour aggressiveness. The N- and C-cadherins are involved in pituitary development and in the organization of the adult pituitary into a functional network involving FCS cells . E-cadherin has been largely recognized as a TSG in the pituitary. Reduced E-cadherin expression was first associated with an aggressive behavior in prolactinomas . Subsequently, downregulation of the E-cadherin gene (
6.2. Abnormalities in cell cycle control
The main positive regulators of the cell cycle are the cyclin dependent kinases (CDKs), which are activated by specific associations with cyclins (A, B, D, E). The progression through the different phases of the cell cycle, in particular the G1/S and G2/M transitions, are stimulated by cyclin/CDK complexes and suppressed by their inhibitors, CKIs. The latter are divided into the INK4 family (p16Ink4a, p15Ink4b, p18Ink4c), which negatively regulates the G1/S transition through a direct interaction with the CDK4/6 containing complexes, and the so-called “universal” Cip/Kip family (p21Cip1, p27Kip1, p57Kip2), which is involved at various phases of the cell cycle by interacting with different cyclin/CDK complexes. Down-regulation of cell cycle inhibitors (
6.2.1. Abnormalities in cell cycle progression
Increased expression of D-type cyclins is a key event in the exit from the quiescent G0 state under mitogenic stimulation by GFs. They activate CDK4 and CDK6, which phosphorylate pRB and therefore indirectly induce the transcription of S-phase genes by releasing TFs of the E2F family from their interaction with pRB. Transition from late G1 to the S phase is also driven by Cyclin E/ CDK2 complexes. Overexpression of cyclins D1 and D3 has been reported in PA of different histotypes . In particular, Cyclin D1 is overexpressed in ~70% of NFPA and 40% of somatotrophinomas, especially in invasive PA, with allelic imbalance suggesting gene amplification in 25% of the cases . Increased GFs and Wnt/β-catenin signalling is also likely to contribute to
6.2.2. The universal Cip/kip CDKI family
Both p27Kip1 and p21Cip1/Waf1 have been involved in pituitary tumorigenesis. The p27Kip1 protein is normally localized in the nucleus of quiescent cells and undergoes rapid degradation upon mitogenic stimulation. Phosphorylation of p27Kip1 is involved in its degradation through the ubiquitin/proteasome pathway. Loss of nuclear p27 Kip1 due to a reduced expression or an abnormal cytoplasmic localization has a negative prognostic value in a variety of human neoplasia.
Although PTTG1 – the most abundant and widely studied member of the PTTG family, commonly referred to as PTTG - was first identified in the rat pituitary GH4 cells, it has important oncogenic properties in a number of additional endocrine and non-endocrine neoplasia and cells overexpressing PTTG are tumorigenic
6.2.4. HMGA proteins
The HMGA family of nuclear proteins - HMGA1
6.3. Abnormal proliferative pathways in pituitary tumours
The Raf/MEK/ERK and PI3K/Akt/mTor pathways are typically activated by GFs but crosstalks with neuropeptide/GPCRs signalling pathways are being increasingly recognized . Crosstalks between the Raf/MEK/ERK and PI3K/Akt/mTor pathways result in the modulation of ERK1/2 activity, which is involved in the regulation of cell growth and differentiation, depending on the cellular context, and represents an important proliferative pathway in cancer. Secondary activation of mTOR signalling represents an important link between cell proliferation and metabolism . These pathways are essential in oncology, many drugs have been designed to target their effector molecules at different steps  and similar strategies may be of interest in selected PA [189,190].
6.3.1. The Ras/Raf/MEK/ERK pathway
The Ras/Raf/MEK/ERK pathway originates at the cell membrane with receptors for GFs or cytokines, which activate the GTPAse Ras protein family through the coupling complex Shc/Grb2/SOS. The active, GTP bound, form of Ras recruits Raf proteins, which in turn activate a cascade of phosphorylations on cytoplasmic MAP kinases (MEKs and ERKs). A large number of cytoplasmic and nuclear proteins have been recognized as ERK1/2 targets, including the ribosomal S6 kinase (which in turns phosphorylates CREB), TFs (
6.3.2. The PI3K/Akt/mTOR pathway
The PI3K/AKT/mTOR pathway also initiates at the cell membrane in response to a variety of GFs and hormones, including insulin. PI3K phosphorylates phosphoinositides, resulting in the production of phosphoinositide 3-phosphate which in turn regulates the activity and intracellular localization of a number of target proteins, among which the best characterized is Akt (also known as Protein Kinase B/PKB). PI3K is negatively regulated by the tumour suppressor PTEN. The activation of Akt/PKB results in a cascade of phosphorylations, including mTOR, GSK3β, crosstalks with the Raf/MEK/ERK pathway at different levels, and has been involved in cell proliferation and motility in a number of cancers. Moreover, repression of the tumour suppressor Zac1 and activation of β-catenin through GSK3β are indirect effects of PI3K/Akt activation. The mTOR pathway is also activated by nutrients, cellular energy levels (ATP, O2) and stress conditions; it is a major regulator of ribosomal biogenesis and protein synthesis, in particular through the activation of the ribosomal S6 kinase p70S6K and 4EBP1, which enhances the translation of
6.4. Angiogenesis and hypoxia-pathways
Although angiogenesis is involved in the progression of many solid tumours, its pathogenetic role in PA is still not well defined. The normal pituitary gland is already highly vascularised and different studies on microvessel density (MVD) in PA have provided evidence for a reduced vascularity as compared to the normal tissue. On the other hand, increased vascularity can occur, as reported in estrogen-induced prolactinoma models and in some human pituitary tumours . Despite conflicting results about potential factors associated with an increased vascularity (
6.5. Apoptosis in pituitary tumours
As in other tissues, apoptosis is a physiological event during pituitary ontogenesis . It is also believed to contribute to pituitary plasticity and may occur in PA, either spontaneously or in response to pharmacological treatment. Apoptosis is generally low in normal pituitaries and in PA, but is increased in pituitary carcinomas . Apoptotic cells in PA can be detected on routine examination on the basis of their morphological changes, though they can be missed even by experienced pathologists, so that specific assays are more suitable for the definition of apoptotic indexes . The ISEL and TUNEL assays, which are based on the visualization of DNA breaks, can be used on paraffin-embedded sections, but should be combined with morphological criteria to minimize artefacts . Immunohistochemical detection of proteins involved in the apoptotic process such as activated caspase 3, cleaved cytokeratins or annexin-5 are also useful. As a general rule, apoptosis can be triggered by extra-cellular signalling by Fas ligand (FasL) or TNF interacting with “death receptors” or by endogenous signalling following mitochondrial or DNA damage, which is able to induce apoptosis in a p53-dependent manner. No significant relationship between p53 expression and apoptosis have been reported in PA, with the exception of nuclear p53 in corticotrophinomas . An important determinant of apoptosis is the cellular expression of the Bcl2 family of proteins, which contains pro-apoptotic (
Senescence is an alternative tumour-suppressive cell faith to apoptosis in benign neoplasia. It is characterised by an irreversible arrest in cell proliferation and accompanied by an increase in cell cycle inhibitors such as p53, p19ARF, p21Cip1 and p16Ink4a. Because PA remain typically benign, even in the presence of invasive features, it has been proposed that a senescence buffer in PA cells exerts a protective effect against malignancy. This could in particular explain the very low prevalence of GH-secreting carcinomas and NFPA. Indeed, beta-galactosidase, a marker of senescence, was recently found overexpressed in somatotrophinomas and NFPA . Interestingly, this could be explained by different molecular mechanisms. Somatotrophinomas show intranuclear p21 accumulation (possibly induced by aneuploidy and/or p53), which is able to restrain cell proliferation [176,231]. In gonadotroph PA, which express low nuclear p21Cip1, high levels of clusterin have been proposed to restrain cell proliferation by triggering the CKIs p15Ink4b/p16Ink4a/p27Kip1 . However, in both cases overexpression of PTTG and DNA damage are present [231,232]. Because senescence may also be activated by oncogenes, as originally described for Ras, this may apply to PTTG in pituitary tumours. Oncogene-induced senescence (OIS) is a protective mechanism against cancer which may also involve cytokines. Due to its role in pituitary development and its frequent expression in PA, IL6 is an attractive candidate for OIS in PA .
7. Pituitary carcinomas
Pituitary carcinomas represent about 0.2% of symptomatic primary pituitary tumours and are defined exclusively by the presence of metastases. Their prevalence may be somewhat underestimated, since metastases can be discovered post-mortem and the number of reported cases has been significantly increasing during the last 15 years [233-235]. The current interest in pituitary carcinomas certainly reflects the recent improvements in their diagnosis and therapeutic management. Their clinical characteristics have been reviewed in details elsewhere [233-236]. Briefly, most pituitary carcinomas are secreting (>80%), with malignant prolactinomas and corticotrophinomas being the most frequently encountered. They usually present as recurrent invasive macroadenomas, with an increasing degree of pharmacological resistance. Noteworthy, silent ACTH-secreting PA may become functional as malignant transformation occurs. Metastases may develop in the central nervous system (with intracranial and/or spinal localizations) or present as systemic secondary tumours, in particular in the bones, lungs or liver. Therefore, malignant transformation is a late event, which typically complicates the evolution of an aggressive PA, although exceptions have been reported. Yet, there is no specific biological marker of pituitary carcinoma and no reliable prognostic marker of potential malignant transformation in PA. The primary pituitary tumour often displays a high mitotic index and extensive p53 immunostaining, the apoptotic index is typically higher than in PA, but none of these features is invariably present and no threshold value of Ki67 or p53 immunopositivity can be defined. Several molecular abnormalities are encountered more frequently in pituitary carcinomas, such as chromosome gains,
Pituitary tumours are very heterogeneous and their pathogenesis is multifactorial. During the last two decades, increasing knowledge about factors involved in pituitary ontogenesis, physiology and genetics have provided significant new information concerning dysregulated pathways in pituitary tumorigenesis. The rapid development of new methodological approaches allowing to explore hundreds of genes and proteins simultaneously (genomics/epigenomics/proteomics) has become an essential tool to unravel new players in pituitary tumourigenesis, although data obtained with such screening methods need to be validated on large series of pituitary tumours and integrated with functional studies. Molecular signatures of functional PA phenotypes are emerging and may provide significant information in terms of pathogenesis, prognosis and treatment. The identification of reliable markers of aggressiveness remains a priority for a better understanding and management of secreting PA resistant to conventional pharmacological treatment, NFPA and pituitary carcinomas.
|αGSU= α-glycoprotein subunit
ACP: adamantinomatous craniopharyngioma
ACTH: adrenocoticotropic hormone
AHR: aryl hydrocarbon receptor
AIP: aryl hydrocarbon receptor interacting protein
AP: anterior pituitary
BAG1: Bcl2-associated athanogene 1
Bcl2: B-cell lymphoma 2
BMP: bone morphogenetic protein
CDK: cyclin dependent kinase
CKI: cyclin dependent kinase inhibitor
CNC: Carney complex
CREB: cAMP response element-binding protein
CRH: corticotrophin-releasing hormone
CTNNB1: cadherin-associated protein β1 (β-catenin)
D2R: D2 dopamine receptor
DA: dopamine agonist
DAPK1: death-associated protein kinase 1
EGF: epidermal growth factor
ER: estrogen receptor
Erk: extracellular-signal-regulated kinase
FasL: Fas ligand
FCS: folliculostellate cells
FGF: fibroblast growth factor
FIPA: familial isolated pituitary adenomas
FISH: Fluorescence in situ hybridization
FSH: follicle-stimulating hormone
GADD45: growth arrest and DNA damage gene
|GF: growth factor
GH: growth hormone
GHRH: growth-hormone-releasing hormone
GNAS1: α-subunit of the stimulatory G protein
GnRH: gonadotropin-releasing hormone
GPCR: G-protein coupled receptor
GSK-3β: glycogen synthase kinase 3β
HDAC: hystone deacetylase
HIFα: hypoxia-inducible factor α
HMGA: high mobility group AT-hook protein
IGF1: insulin-like growth factor 1
IP3: inositol triphosphate
ISEL: immunogold electron microscopy in situ end-labeling
LOH: loss of heterozigosity
MAGE-A3: melanoma-associated antigen 3
MAPK: mitogen-activated protein kinase
MAS: McCune Albright syndrome
MEG3: maternally expressed gene 3
MEN1: multiple endocrine neoplasia type 1
MEN4: multiple endocrine neoplasia type 4
MGMT: methylguanine methyltransferase
MMP: matrix metalloproteinase
mTor: mammalian target of rapamycin
MVD: microvessel density
NFPA: non-functioning pituitary adenoma
PA: pituitary adenoma
|PAP: pituitary adenoma predisposition
PI3K: phosphatidylinositide 3-kinases
PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α
PKA: protein kinase A
PKC: protein kinase C
PKRAR1A: regulatory subunit type 1A of cAMP-dependent protein kinase
PPAR: peroxisome proliferator-activated receptor
PROP-1: Prophet of Pit1
PTAG: pituitary tumor derived apoptosis gene
PTTG: pituitary tumour trasforming gene
RIα: regulatory subunit type 1A
RP : Rathke’s pouch
Shh: Sonic Hedgehog
SSA: somatostatin analogues
SSTR: somatostatin receptor
TGF: trasforming growth factor
TF: transcriptions factor
TNF: tumor necrosis factor
TPR: tetratricopeptide repeats
TRH: TSH-releasing hormone
TSG: tumor suppressor gene
TSH: thyroid-stimulating hormone
TUNEL: terminal deoxynucleotidyl transferase
VEGF: vascular endothelial growth factor
WHO: world health organization
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