New Pituitary Oncogenes

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Endocrine-Related Cancer (2000) 7 3–15

New pituitary oncogenes

A P Heaney and S Melmed

Department of Medicine, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA (Requests for offprints should be addressed to S Melmed, Academic Affairs, Room 2015, Cedars-Sinai Research Institute, 8700 Beverly Boulevard, Los Angeles, California 90048, USA; Email: [email protected])

Abstract Pituitary tumors are common monoclonal neoplasms which cause considerable morbidity and mortal- ity. Several molecular events underlying pituitary tumorigenesis have been elucidated in recent years, but no tumor marker has clearly emerged which assists clinical and therapeutic decisions. Activating mutations and loss of inactivating mutations, together with hypothalamic hormones, circulating hor- mones, growth factors and cytokines cooperatively ensure the inexorable expansion of the initial mutated pituitary cell clone. This review describes new developments in our understanding of the molecular mechanisms involved in the pathogenesis of pituitary tumors. The availability of molecular probes will allow the early prediction of tumor behavior, identify targets for designing subcellular pituitary tumor therapy and provide novel approaches to pituitary tumor management. Endocrine-Related Cancer (2000) 7 3–15

Introduction headache secondary to an expanding sellar mass (Mukai et al. 1986). Pituitary tumors rarely metastasize outside the Detailed histological studies in unselected autopsies have pituitary bed but large invasive tumors are commonly en- identified pituitary tumors in up to 27% of pituitary tissues countered, and microscopic dural invasion occurs frequently. (Costello 1936, Burrow et al. 1981), and high resolution Therefore despite their ‘benign’ categorization, these tumors computed tomography and magnetic resonance imaging per- cause considerable post-operative patient morbidity and ulti- formed on a general population show incidental clinically mately mortality, and often present diagnostic and manage- silent pituitary tumors measuring 3 mm or more in diameter ment challenges. in approximately 20% of apparently ‘normal’ pituitary glands Our understanding of many of the molecular events (Kovacs & Horvath 1986). Pituitary tumors account for 10– involved in pituitary tumor pathogenesis has increased con- 15% of all intracranial neoplasms (Terada et al. 1995), are siderably, but current tumor markers cannot accurately infrequent in childhood (Mukai et al. 1986, Kane et al. 1994) identify those patients who require intensive initial therapy and are more common in females (Kane et al. 1994). Women for their pituitary tumor and close follow-up. This review usually present at a younger age, most commonly with pro- describes several new developments in our understanding of lactin (PRL)- and adrenocorticotropin (ACTH)-secreting the molecular mechanisms involved in the pathogenesis of tumors. The most common presentation is with menstrual or pituitary tumors. fertility dysregularity secondary to hyperprolactinemia. ACTH excess causing Cushing’s or Nelson’s syndromes or growth hormone (GH) hypersecretion leading to acromegaly Intrinsic pituitary lesion or hypothalamic are other syndromes which may present to the physician. origin Thyrotropin (TSH)-secreting hormone-producing tumors, and gonadotroph (follicle stimulating-hormone (FSH) and/or Highly differentiated mature cell types populate the anterior luteinizing hormone (LH) secreting) adenomas are compara- pituitary and each of these may give rise to unique tumor tively rare and the remaining endocrinologically silent types. Commitment of pituitary cell function is governed by tumors grow insidiously for many years. Men tend to present a variety of cell-specific transcriptional factors which deter- in middle age with clinically non-functioning tumors which mine the final pituitary phenotype. Expression of these cell- lead to compressive hypopituitarism, visual deficit, or specific pituitary genes is closely regulated by hypothalamic

Endocrine-Related Cancer (2000) 7 3–15 Online version via http://www.endocrinology.org 1351-0088/00/007–003  2000 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 01:08:06PM via free access

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Heaney and Melmed: New pituitary oncogenes

and peripheral hormones as well as paracrine growth factors. independent cellular events such as generalized hyperplasia Virtually all functional and non-functional pituitary tumors do not necessarily precede adenoma formation. are monoclonal in origin, indicating that an intrinsic defect in a single pituitary cell is the primary event in pituitary tumor Candidate genes in human pituitary pathogenesis (Alexander et al. 1990, Herman et al. 1990, tumors Melmed 1999) (Fig. 1). However, it is likely that hypo- thalamic hormones, local growth factors and circulating sex During pituitary cellular transformation, a spectrum of suc- steroid hormones are also implicated in pituitary tumor cessive genetic alterations are observed, which include pathogenesis by creating a permissive environment which dysregulation of cell proliferation, differentiation, and spe- potentiates cell mutation and subsequent clonal expansion of cific hormone production. This multistep transformation the initial mutated cell. In some surgical series, detection of process encompasses seemingly different molecular events more than one tumor has been reported, and in random leading to similar tumor phenotypes and it is the accumula- autopsies 0.9% of pituitary adenomas were of multiple origin tion of alterational events rather than the temporal order in (Kontogeorgos et al. 1991). However, adenohypophyseal which they occur which appears to be important (Fearon & tissue surrounding pituitary tumors is normal (Molitch Vogelstein 1990). Furthermore, the transformation process & Russell 1990), supporting the notion that multiple quickly gains momentum as each new ‘hit’ renders the

Figure 1 Model of pituitary tumorigenesis. Cells responding to endocrine or paracrine stimuli may expand in a polyclonal manner. This ‘non-committed’ cell may return to a normal pituicyte, undergo apoptosis, or acquire activating mutations or loss of inactivating mutations, prompting the emergence of a monoclonal cell population (light shaded arrow). Alternatively, a normal cell may acquire sufficient activating mutations or loss of inactivating events to prompt a rapidly expanding mononclonal cell population from the onset (lower sequence). Following additional genetic events, this monoclonal expansion may evolve into an invasive pituitary tumor, with further events promoting the progression to metastatic pituitary carcinoma. The progress of both these pathways will be driven by a variety of hormonal stimuli, growth and angiogenic factors, and altered receptor expression (dark shading). ER = estrogen receptor.

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Endocrine-Related Cancer (2000) 7 3–15

cell susceptible to subsequent mutational events. Numerous (Simpson et al. 1999), suggesting that an alternate tumor sup- extrinsic factors and intrinsic pituitary defects may cause pressor gene in this region may be involved in controlling irreversible pituitary cell DNA mutations (Table 1) leading the propensity for tumor invasion. to a broad spectrum of molecular abnormalities. Two categories of genes promote the outgrowth and Multiple endocrine neoplasia type 1 (MEN-1) evolution of a neoplastic clone. Oncogenes bear a ‘gain-of- gene function’ mutation in their regulatory or coding regions, lead- ing to either the formation of an abnormal protein product or MEN is an autosomal dominant disorder, features of which dysregulation of their normal product. The proto-oncogene, include pituitary and parathyroid adenomas, and/or tumors of which is the normal non-mutated endogenous version of an the endocrine pancreas. The MENIN tumor suppressor gene oncogene, can be activated by chromosomal translocations maps to chromosome 11q13 (Larsson et al. 1998, Qian et al. or inversions, point mutations or fusion of key components 1998), and encodes a 610 amino acid protein nuclear product of its coding region with another gene. (Chandrasekharappak et al. 1997, Guru et al. 1998). How- Tumor suppressor genes normally act to restrain cell ever, despite LOH in the 11q13 region, MENIN RNA and proliferation, by regulating the cell cycle or by maintaining menin protein product are appropriately expressed in spor- genomic stability, thus preventing other malignant cell mani- adic pituitary adenomas (Prezant et al. 1998, Tanaka et al. festations. Gene deletions or point mutations lead to ‘loss of 1998) and, similar to 13q LOH, another candidate gene in function’ of both alleles of a tumor suppressor gene. The this region is now being sought. ensuing inactivation or elimination of the functional protein product leads to tumor formation. Cyclin-dependent kinase (CDKI)inhibitors

Tumor suppressor genes In mammalian cells, CDK4 and CDK6 enzymes in combina- tion with three D-type cyclins (D1, D2 and D3), and CDK2 Loss of heterozygosity (LOH) involving chromosomes in association with cyclin E, play distinct roles in regulating 11q13, 13 and 9 occurs in up to 20% of sporadic pituitary G1 progression. CDK4/6–cyclin D couple extracellular tumors (Herman et al. 1993, Boggild et al. 1994, Farrell et growth signals to cell cycle substrates, such as the Rb pro- al. 1997), mainly in macroadenomas or invasive tumors. tein, while CDK2–cyclin E controls initiation of DNA Although allelic loss of a retinoblastoma RB1 intragenic replication (Sherr & Roberts 1995). The activity of these marker on chromosome 13q has been described in aggressive cyclin–CDK complexes is regulated by the INK4 (p16, p18, and metastatic pituitary tumors (Woloschak et al. 1992, Pei p15, p19) and Kip/Cip (p21, p27, p57) families of CDKI et al. 1995, Simpson et al. 1999), only a single study has proteins (Weinberg 1995). Frequent LOH of 9p21, the locus observed associated loss of Rb protein in these tumors of the CDKN2A gene, has been reported in pituitary ade- nomas and low expression of its protein product, p16, has been described in pituitary tumor tissue extracts. Interest- Table 1 Predisposing factors involved in pituitary tumor ingly, mice lacking p16, while developing spontaneous pathogenesis tumors at multiple sites and at an early age, do not display a ¼ Inherited traits (e.g. MEN-1) pituitary abnormality (Serrano et al. 1996). Another member ¼ Environmentasl factors (e.g. irradiation, environmental of the INK4 family, p18 protein, functions similarly to p16, estrogens) inactivating CDK and hence inhibiting Rb phosphorylation. ¼ Alterations in transcription factors or cytokines (e.g. Pit-1, Targeted disruption of either p18INK4 or p27kip1 in LIF) ¼ Mutations in pituitary signal transducing units (e.g. gsp, transgenic mice produced animals with increased body size, CREB, ras) multiorgan hyperplasia, female sterility and pituitary tumors ¼ Hypothalamic factor excess (e.g. GHRH, CRH) (Franklin et al. 1999). Mice lacking both p18 and p27 died ¼ Hormonal imbalance (e.g. ovarian, thyroid or adrenal from pituitary adenomas at 3 months, suggesting that p18 failure) and p27 mediate two separate pathways which synergistically ¼ Disrupted paracrine growth factor control of local suppress pituitary tumorigenesis (Franklin et al. 1999). angiogenesis (e.g. FGF, hst) ¼ Loss of tumor suppressor gene function (e.g. Although p27 mRNA levels are normal in human pituitary chromosomes 11 and 13) tumors, a recent study has demonstrated low p27 protein ¼ Intrapituitary paracrine hypothalamic hormone action (e.g. expression in pituitary tumors in comparison with normal tumoral SRIF, GHRH, TRH) pituitary tissue (Lidhar et al. 1999). hst, heparin binding secreted transforming gene; SRIF, Tumor suppressor gene abnormalities have been somatostatin releasing inhibitory factor. observed mostly in large invasive pituitary tumors, appear to be relatively late events and as yet, no clear-cut loss of tumor

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Heaney and Melmed: New pituitary oncogenes

suppressor activity which results in increased pituitary prolif- late sequela, unlike other human tumors, such as colorectal erative activity has emerged. Therefore, the specificity of or thyroid cancer, where ras activation is considered an these LOH patterns is unclear and they imply that earlier early event. genetic abnormalities predispose cells to the LOH patterns, which accelerate subsequent cell growth. Pituitary tumor transforming gene (PTTG) Recently we isolated a novel pituitary tumor transforming Oncogenes gene (PTTG) by differential display PCR using mRNA derived from rat pituitary tumor cells (GH4) and normal Stimulatory guanine nucleotide-binding pituitary tissue (Pei & Melmed 1997). Subsequently we protein (G-protein) α-subunit gene (gsp) cloned the human homologue of this transforming gene from a fetal liver cDNA library. The nucleotide sequence The stimulatory G (Gs) protein activates adenyl cyclase and of human PTTG (hPTTG) cDNA is 85% identical to rat somatotroph cAMP accumulation. Point mutations of residue PTTG cDNA and the encoded proteins are 89% similar Ǟ Ǟ 201 (Arg Cys or His) or 227 (Gln Arg or Leu) result in (Zhang et al. 1999a). The 609 bp open reading frame of ligand-independent constitutive activation of cAMP and GH hPTTG encodes a unique protein which may be the index hypersecretion. The missense mutations (Gsp) have been member of a novel family of human securin-like proteins. ȁ demonstrated in 40% of GH-secreting pituitary tumors in PTTG associates with another nuclear separin protein, Caucasians and a lower incidence reported in Japanese sub- Esp1p, to inhibit chromatid separation during mitosis (Zou jects (Yoshimoto et al. 1993) with acromegaly, possibly et al. 1999). Increased expression of PTTG/securin would reflecting a geographical or ethnic influence. Although the result in disrupted chromatid separation, resulting in chro- presence of Gsp mutations in GH-secreting pituitary tumors mosomal gain or loss. The subsequent chromosomal aneu- is readily apparent, their clinical significance is not apparent ploidy and genetic instability may lead to activation of and Gsp mutations do not provide a unifying mechanism of proto-oncogenes or LOH of tumor suppressors. The human oncogenesis in pituitary tumors as these mutations are infre- PTTG family consists of at least three homologous genes, quently observed in other pituitary tumor subtypes (Spada et of which PTTG1 is located on chromosome 5q33 (Prezant al. 1990). et al. 1999). Weak PTTG expression is observed in most normal adult tissues including colon, small intestine, brain Activated cAMP-response element binding and pancreas with stronger PTTG expression found in proteins (CREB) thymus, and abundant expression in testis. In contrast, abundant PTTG expression is observed in all cancer cell cAMP may stimulate somatotroph GH transcription directly lines tested. PTTG overexpression has also been reported mediated by the cAMP-responsive nuclear transcription in several solid human tumors including pituitary, ovary, factor (CREB). Transgenic mice overexpressing a phos- endometrium, liver, adrenal and kidney and also in a vari- phorylation-deficient and transcriptionally inactive mutant ety of hemopoietic neoplasms (Dominguez et al. 1999, of CREBin the anterior pituitary exhibit dwarfism and Zhang et al. 1999b). somatotroph hypoplasia (Struthers et al. 1991), indicating Transfectants overexpressing PTTG cDNA were tested that phosphorylated CREBplays a role as a biochemical for transformation as assayed by anchorage-independent intermediate in the somatotroph proliferative response. Sig- growth in soft agar. NIH3T3 fibroblasts overexpressing nificantly higher amounts of Ser133-phosphorylated, and PTTG formed large colonies on soft agar in comparison hence activated, CREBwere detected in a series of GH- with minimal colony formation with mock-transfected con- secreting pituitary tumors compared with a group of non- trol cells, and when PTTG-transfected cells were injected functioning tumors. Therefore, constitutively activated into athymic nude mice, large tumors formed within 2 CREB, possibly promoted by Gs-α overexpression, may weeks in all animals (Pei & Melmed 1997, Zhang et al. facilitate somatotroph transformation (Berthrat et al. 1995). 1999a). The PTTG protein contains a proline-rich (P-X-X-P) potential SH-3 docking motif, suggesting that it Ras may be involved in intracellular signaling. In addition to its role in cellular transformation, conditioned medium from This family of three related ras proto-oncogenes (H-ras, wild-type PTTG-transfected cells contained higher levels of K-ras and N-ras), encode 21 kDa proteins which are struc- basic fibroblast growth factor (bFGF) and these cells turally similar to the membrane anchored G-proteins. H-ras expressed higher bFGF mRNA levels that control- mutations have been identified in metastases from pituitary transfected cells. Thus, it appears that PTTG stimulates carcinomas (Cai et al. 1994, Pei et al. 1994) and in a bFGF expression and secretion (Zhang et al. 1999a). Muta- single aggressive PRL-secreting pituitary adenoma (Karga tions of the proline-rich region of the PTTG protein pre- et al. 1992). ras activation in pituitary tumors is thus a vents the ability of PTTG to cause in vitro transformation,

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Endocrine-Related Cancer (2000) 7 3–15

in vivo tumorigenesis and bFGF induction, indicating the estrogen treatment, at which time groups of PRL- importance of this SH3-binding motif. bFGF is a potent immunopositive cells close to newly formed blood vessels angiogenic factor which is expressed in both normal pituit- were observed. Displacement of the reticulin fibers around ary tissue and pituitary tumors and also stimulates PRL the lactotroph cells, a feature typical of lactotroph hyperpla- secretion in vitro (Larson et al. 1990). Patients with sia, was apparent 1 week after commencement of the MEN-1 harboring pituitary adenomas had elevated serum estrogen infusion. Complete disruption of reticulin fibers, in immunoreactive bFGF levels and these were lowered signi- association with vacuolation and nuclear pleomorphism her- ficantly following medical or surgical treatment (Zimmering alded the appearance of true adenoma formation and was et al. 1993). apparent 4 weeks after commencement of estrogen. These results indicate that estrogen-induced pttg expression is coin- cident with early pituitary lactotroph transformation (normal PTTG in pituitary tumors cell Ǟ hypertropic/hyperplastic cell), and the appearance of In the normal human pituitary, even using sensitive newly formed pituitary arterial networks. methods such as RT-PCR, PTTG expression is low. In In view of our previous findings that pttg regulated bFGF contrast, more than 50% increases in PTTG expression secretion and the close correlation of PTTG and bFGF were observed in 23 out of 30 non-functioning pituitary expression in human pituitary tumors, we also examined tumors, all 13 GH-secreting tumors, 9 out of 10 prolactin- bFGF expression in experimental rat lactotroph tumors. omas and the single ACTH-secreting tumor examined, with Western blot and immunocytochemical analysis showed that more than 10-fold increases in PTTG expression evident increased pttg and bFGF expression throughout the pituitary in some tumors (Zhang et al. 1999b). Furthermore, highest occurred 24 h after commencement of estrogen infusion and PTTG expression was observed in hormone-secreting pituit- was most prominent 48 h after estrogen commencement. We ary tumors which had invaded the sphenoid bone (Stages also examined immunoreactivity to vascular endothelial III and IV; 95% confidence interval (CI), 3.1- to 9.7-fold growth factor (VEGF) in the experimental rat tumors. PTTG increase) compared with tumors confined to the Increased VEGF immunoreactivity was seen 24 h after pituitary fossa (Stage I and II; 95% CI, 1.7- to 3.0-fold estrogen administration, and was visible throughout the PTTG increase), and concordant bFGF and PTTG mRNA pituitary. Immunoreactivity to both bFGF and VEGF immu- expression was observed in all pituitary tumors (Fig. 2) noreactivity were particularly prominent at the edges of PRL- (Heaney et al. 1999). Preliminary in situ hybridization secreting tumors which invaded the pituitary capsule studies demonstrate that PTTG expression is localized in (Heaney et al. 1999). Our findings that PTTG, bFGF and pituitary adenoma cell cytoplasm in contrast to the normal VEGF expression occur early (24 h) and co-incidentally in pituitary in which no PTTG expression was observed. estrogen-induced pituitary lactotroph transformation, and that PTTG is therefore the first human transforming gene found higher bFGF expression is seen at invasive tumor margins to be overexpressed in the majority of pituitary tumors provide strong evidence in favor of a novel growth factor- tested and may therefore be a novel marker of invasiveness mediated mechanism for pituitary cell transformation and in secreting pituitary tumors. pituitary tumor progression and invasion. In addition to increased expression in human pituitary tumors, we also examined the pattern of PTTG expression Estrogen and bFGF regulate pttg in vitro during early experimental pituitary cell transformation. High- est PTTG expression was observed in prolactinomas, and we In view of our observations in experimental rat lactotroph therefore chose to generate lactotroph pituitary tumors by tumors, and in order to further study the regulation of pituit- administration of estrogen to F344 rats. Following estrogen ary pttg by estrogen, we then examined effects of estrogen administration for 4 weeks, rats developed large pituitary administration on the regulation of rat pttg and the relation- tumors (300% increase in size) along with an expected ship between bFGF and pttg in vitro. Rat pituitary GH/PRL- increase in pituitary PRL mRNA expression and serum PRL secreting cells (GH3) were incubated in medium containing level. In addition, examination of pituitary tissue extracts serum which had been pretreated with activated charcoal from these animals revealed a ȁ6-fold induction of pituitary (CSS) to reduce steroid concentrations. Treatment of the ster- pttg mRNA, and estrogen-induced pituitary pttg in vivo was oid-depleted GH3 cells with diethystilbestrol (10−8–10−10 M), observed to increase in a time- and dose-dependent manner produced a ȁ6-fold increase in pttg mRNA expression (Fig. 3) (Heaney et al. 1999). (P < 0.01) and this increase was first observed 12 h after the As well as increased expression of pituitary pttg,we addition of diethylstilbestrol and was maximal at 24 h observed pituitary histological changes. Twenty-four hours (P < 0.05). Highest pttg expression was observed in GH3 cells after commencement of estrogen, when pituitary pttg was which had been incubated in whole serum (WS)-supplemented first induced, hypertrophy of PRL-secreting cells was visible. medium. This estrogen- or WS-mediated pttg induction was Maximal induction of pituitary pttg was seen after 48 h markedly inhibited by co-incubation of GH3 cells in

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Heaney and Melmed: New pituitary oncogenes

Figure 2 (Upper panel) Representative RT-PCR analysis of PTTG1 and bFGF expression. Left margin, molecular size; right margin, positions of RT-PCR products. NP = normal pituitary. (Lower panel) Graphic representation (Pearson correlation) of PTTG1 and bFGF mRNA densitometry values. Forty-one secretory and non-secretory human pituitary tumors and two normal human pituitary tissues were analyzed. NF = non-functioning (n = 15); GH = GH-secreting (n = 8); PRL = PRL-secreting (n = 7); ACTH = ACTH-secreting (n = 1); TSH = TSH-secreting (n = 1); mixed, plurihormonal immunoreactivity (n = 8). (From Heaney et al. 1999, with permission).

CSS-treated medium containing diethylstilbestrol or WS murine pttg promoter contains several putative estrogen and 1000- (diethylstilbestrol, P < 0.01; WS, P < 0.05) or 100- response elements, which provide a potential mechanism for fold (diethylstilbestrol/WS, P < 0.05) excess of the anti- our observed estrogen-induction of pttg. We had previously estrogen, ICI-182780 (Heaney et al. 1999). Treatment of observed that overexpression of PTTG in 3T3 fibroblasts led GH3 cells with tri-iodothyronine (5 nM) led to increased to increased bFGF expression and secretion. We sought to expression of PRL mRNA but did not significantly alter pttg further elucidate a paracrine mechanism for pituitary PTTG induction. To examine the mechanism of the estrogen- regulation, and as NIH3T3 cells, unlike the GH3 cells, mediated pttg mRNA induction in more detail, we then trans- constitutively exhibit low PTTG expression, we treated fected the full-length mouse pttg promoter-luciferase reporter these cells with bFGF (1 ng/ml). After 24 h of bFGF construct (Wang & Melmed 2000) (4.2 kb) into the GH3 treatment, a ȁ240% induction of pttg mRNA was cells. A ȁ220% increase (P = 0.02) in pttg-luciferase activity observed, which was blocked by co-incubation with a neut- was seen in the pttg-transfected GH3 cells following treat- ralizing bFGF antibody. Administration of bFGF for inter- ment with diethylstilbestrol (10−10 M) and this estrogen- vals less than 24 h did not induce pttg. As pttg stimulates induced pttg-promoter activity was partially inhibited by bFGF secretion and bFGF also induces pttg, these studies co-incubation of the transfected GH3 cells with estrogen suggest the existence of an autocrine/paracrine regulatory and anti-estrogen (ICI-182780, 10−7 M) (P = 0.02). The loop in pituitary pttg regulation.

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a monoclonal cell population, by increasing the odds of mitosis-related cellular DNA damage. Several polypeptide growth factor families may promote pituitary tumorigenesis: some oncogene products share homology with growth factors or their receptors; autocrine or paracrine-growth factor recep- tor interactions regulate cell growth and gene expression; and growth factors modulate hormone production. The majority of the growth factors identified in the pituitary play a role in supporting development and expansion of an established monoclonal growth, but few have been convincingly shown to cause initial cellular transformation. For example, targeted overexpression of bFGF in transgenic mice leads to lacto- troph hyperplasia, but does not progress to true adenoma formation. In contrast, transgenic mice overexpressing trans- forming growth factor (TGF)-α under the control of the PRL promoter in mice, develop lactotroph adenomas (McAndrew et al. 1995).

FGF-4 FGF-4, the protein product of the heparin-binding secretory transforming gene (hst) gene (Sakamoto et al. 1986), is expressed in PRL-secreting pituitary adenomas and possesses potent angiogenic activity, and experimental overexpression of transfected hst oncogene enhances PRL secretion and is associated with tumor cell aggressiveness (Shimon et al. 1996). FGF-4 immunoreactivity is observed in 33% of PRL- secreting pituitary adenomas as compared with absent immunoreactivity in normal pituitary tissue and other adenoma subtypes (Shimon et al. 1998). However, no hst gene rearrangement has been detected in human prolactin- omas, and the mechanism by which hst/FGF-4 complex initi- ates or promotes lactotroph proliferation and PRL secretion Figure 3 In vivo estrogen induction of PTTG in rat lactotroph tumors. Representative rat pituitary tumor, serum PRL and is unclear. pituitary wet weight (upper panel) and Northern (middle panel) and Western blot (lower panel) of pituitary tissue Other growth factors and cytokines extracts derived from estrogen-treated rats (filled bars), intact male rats (n = 2) and ovariectomized controls (Ovx, n = 2, Interleukin-6 (IL-6), IL-8, IL-11, and leukaemia inhibitory clear bars) during prolonged estrogen treatment. Molecular factor (LIF) overexpression have been demonstrated in pituit- β size standards (M), pttg, -actin (internal control) and bFGF ary adenomas (Auernhammer & Melmed 1999, Renner et al. mRNA (middle panel) and PTTG protein induction (lower panel). (From Heaney et al. 1999, with permission). 1998, Sulliman et al. 1999), but as folliculostellate cells pro- duce IL-6, and most studies have employed RT-PCR of whole pituitary extracts, it is unclear if tumor cells them- Growth factors, cytokines, steroid selves produce and/or are responsive to ILs, thus potentially hormones and their receptors in pituitary affording a role for ILs in pituitary tumor pathogenesis. tumorigenesis: permissive and/or causative roles Estrogen and estrogen receptor A generalized proliferative polyclonal cell expansion may be Estrogen is a powerful stimulator of cellular proliferation in physiological, such as the pituitary lactotroph hyperplasia the pituitary, as evidenced by the diffuse hyperplastic observed during pregnancy. Distinct from true neoplasms proliferation of the PRL-secreting cells which occurs during which are monoclonal growths, a generalized stimulus to pregnancy or lactation (Kovacs & Horvath 1986). At term, polyclonal hyperplasia in the pituitary, perhaps growth immunopositivity to PRL is observed in 60–70% of adenohy- factor- or hormonally mediated can foster the emergence of pophyseal cells, and though these changes mostly revert to

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the prepregnant state, multiparous women demonstrate ciency (Wu et al. 1998) and in Ames dwarf mice (Sornson higher pituitary weight and PRL cell number than nulliparous et al. 1996), RT-PCR analyses have demonstrated Prop-1 women (Asa et al. 1982). Unopposed estrogen administration expression in normal pituitary tissue and all pituitary aden- has been implicated in the pathogenesis of prolactinoma in oma subtypes (Nakamura et al. 1999). Therefore, no clear several male–female transsexual individuals (Kovacs et al. role has yet emerged for these transcription factors in pituit- 1994). ary tumor pathogenesis as their ubiquitous pituitary expres- Cellular receptor expression in addition to cellular envir- sion appears independent of hormonal regulation and tumor onmental ligand concentrations combine to determine pituit- phenotype. ary cell responsivity to specific factors, including estrogen. Using a variety of techniques, all pituitary tumor types have Angiogenesis been shown to express estrogen receptors, suggesting a role for estrogen in pituitary tumor growth (Stefeananu et al. Angiogenesis is a discrete component of the tumor pheno- 1994). Highest estrogen receptor expression is observed in type, is a potential rate-limiting step in the developmental prolactinomas, which are the most ‘estrogen-responsive’ pathway of solid tumors (Folkman 1992), and is modulated pituitary tumors (Nakao et al. 1989, Jaffrain-Rea et al. 1996). by a variety of cytokines and growth factors by a paracrine Significant estrogen receptor expression has also been mode of action (Godspodarowicz et al. 1987, Bikfalvi et al. described in mixed somatotroph (GH/PRL) and gonadotroph 1997, Ferrara & Davis-Smyth 1997). The potent angiogenic (FSH and/or LH) pituitary tumors. In contrast, non- factor, bFGF, is localized in the basement membranes and functioning pituitary tumors, which do not exhibit extracellular matrix of pituitary endocrine and folliculostell- gonadotroph immunoreactivity, have lowest estrogen recep- ate cells. In vitro, bFGF regulates rat GH, PRL and TSH tor expression (Jaffrain-Rea et al. 1996). Furthermore, secretion (Baird et al. 1985), and bFGF derived from normal although males have lower circulating estradiol levels, higher pituitary tissue and pituitary tumors stimulates PRL secretion estrogen receptor expression has been described in PRL- (Schechter & Weiner 1991). Furthermore, patients with secreting pituitary tumors derived from males in comparison MEN-1 harboring pituitary adenomas were found to have with PRL-secreting pituitary tumors from females and elevated serum immunoreactive bFGF levels and these fell macro-adenomas (size ͧ1 cm) of all types exhibit higher significantly following medical or surgical treatment estrogen receptor expression than in comparison with mi- (Zimmering et al. 1993). croadenomas (size <1 cm) (Nakao et al. 1989, Stefeananu et In the well-characterized estrogen-induced F344 rat pitu- al. 1994). The higher estrogen receptor expression may partly itary lactotroph tumor model, a striking increase in vascular- explain why macroprolactinomas in males tend to be more ity occurs, in association with increases in the angiogenic invasive. factors, bFGF (Schechter & Weiner 1991) and VEGF (Banerjee et al. 1997). We have demonstrated increased Transcription factors bFGF and VEGF expression early after commencement of estrogen administration and preceding the appearance of The process of adenohypophyseal differentiation is a highly mature vessels in the rat anterior pituitary (Heaney et al. specific and temporally regulated series of events (Barlier et 1999). In the human anterior pituitary, angiogenesis has par- al. 1999). An increasing number of putative transcription ticular significance for PRL cell transformation. In normal regulating factors are key factors for determination of cell circumstances, dopamine released from median eminence specificity in the pituitary and the regulation of hormone nerve terminals tonically inhibits PRL-secreting lactotrophs. gene expression. PTx-1, pituitary homeobox factor, an activ- Destruction of the dopamine-secreting tuberoinfundibular ator of proopiomelanocortin (POMC) gene expression neurons increases serum PRL levels and lactotroph density (Lamonerie et al. 1996) plays a role in brain and facial devel- (Schechter & Weiner 1991), and dopamine D2 receptor- opment and PTx-1 expression has been demonstrated in all deficient mice develop lactotroph adenomas (Asa et al. normal anterior pituitary cell types and the majority of all 1999). In a similar manner, subphysiological pituitary dopa- pituitary adenoma subtypes (Barlier et al. 1999). mine concentrations as a consequence of pituitary–systemic A single study has described absent Ptx-2 expression in anastomoses would allow lactotrophs to escape dopamine corticotroph adenomas, high Ptx-2 expression in gonadotroph inhibition (Weiner et al. 1985). Indeed, PRL-secreting tumors, and although pure lactotroph tumors expressed Ptx-2, adenomas are located in the lateral wings of the pituitary no expression was observed in somatotroph adenomas. This gland, have a close relationship with pituitary capillaries suggests a role for Ptx-2 in the terminal differentiation of the (Kovacs et al. 1978) and well-formed dural-derived arteries somatotroph and lactotroph cell phenotype. Although inactiv- directly enter the anterior pituitary in 80% of human PRL- ating mutations of the prophet of Pit-1 (PROP-1), so-called secreting pituitary tumors (Schechter et al. 1988). Both the as it is necessary for Pit-1 gene expression, have been found VEGF 165 and VEGF 189 protein isoforms of VEGF have in human subjects with combined pituitary hormone defi- been detected in virtually all pituitary tumors examined to

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date (Nishikawa et al. 1998), and pituitary VEGF is posi- roid hormone and is most commonly described in young tively regulated in vitro by pituitary adenylate cyclase- females (Horvath et al. 1999). Although normal pituitary activating peptide and IL-6 (Pagotto et al. 1999). These and some pituitary adenoma cells produce TRH (Le Dafniet

preliminary observations emphasize the complex interac- et al. 1989, 1990), and low β1- and β2-isoform expression tions and paracrine/autocrine ‘cross-talk’ which occurs in has been demonstrated in non-functioning pituitary tumors the pituitary involving hormones, oncogenes, cytokines, in comparison with normal pituitary tissue, TRH signaling growth and angiogenic factors, and contribute to pituitary appears to be intact and no activating mutations have been tumor development and progression. identified in pituitary tumors (Dong et al. 1996)

Hypothalamic factors and their receptors Gonadotropin-releasing hormone (GnRH) A variety of hypothalamic- and pituitary-derived polypep- Gonadotroph adenomas in patients with long-standing tides regulate gene expression and pituitary hormone secre- hypogonadism are well documented (Snyder 1985, Riedl & tion and may promote pituitary tumor development. Frisch 1997), but gonadotroph hyperplasia is rare (Nicolis et al. 1988, Okuda et al. 1989, Horvath et al. 1999) and although pituitary adenomas express both GnRH, GH-releasing hormone (GHRH)and intact GnRH and truncated GnRH receptors (Alexander & somatostatin Klibanski 1994), no activating GnRH receptor mutations GHRH induces somatotroph proliferation and DNA syn- have thus far been described. thesis, targeted overexpression of GHRH in transgenic mice produces mammosomatotroph hyperplasia and mammosomatotroph adenomas (Asa et al. 1990), and extra- Summary and future directions hypothalamic tumors secreting ectopic GHRH induce Our current knowledge of the mechanisms involved in pituit- somatotroph hyperplasia and acromegaly (Melmed 1998, ary tumor pathogenesis show the uniqueness of this tissue Sano 1998). Somatotroph adenoma cells are responsive to which exemplifies the complex interplay between hormones, GHRH in vitro (Adams et al. 1983, Spada et al. 1987) growth factors, oncogenes and tumor suppressor genes. Fur- and, although some pituitary tumors express a truncated ther characterization of the many factors, known and as yet GHRH receptor (Hashimoto et al. 1995), these mutations undiscovered, and the availability of molecular probes will are not associated with constitutive GHRH receptor activa- allow the early prediction of tumor behavior, portend tion. responses to therapeutic interventions, and, in the future, pro- Pituitary adenomas express somatostatin receptor sub- vide screening tests for pituitary tumor prediction. Rational types (Greenman & Melmed 1994a,b) but in contrast to approaches to subcellular therapy for somatotroph adenomas normal pituitary tissue, where both somatostatin precursors are also now feasible experimentally. and somatostatin are expressed, mature somatostatin is not detected in GH-secreting adenomas (Levy et al. 1993). References Corticotropin-releasing hormone (CRH) Adams EF, Winslow CLJ & Mashiter K 1983 Pancreatic growth hormone releasing factor stimulates growth hormone secretion ACTH-secreting pituitary adenomas express both the CRH by pituitary cells. Lancet 1 1100–1101. and the closely related vasopressin V3 receptor, and they Alexander JM & Klibanski A 1994 Gonadotrophin-releasing exhibit POMC mRNA expression following calcium stimu- hormone receptor mRNA expression by human pituitary tumors lation in vitro (Suda et al. 1983). Although Cushing’s in vitro. Journal of Clinical Investigation 93 2332–2339. disease is due to a pituitary microadenoma in 90% of Alexander JM, Biller BMK, Bikkal H, Zervas NT, Arnold A & Klibanski A 1990 Clinically non-functioning pituitary tumors are cases, pituitary corticotroph hyperplasia has been described monoclonal in origin. Journal of Clinical Investigation 86 336– in association with ectopic CRH production (Asa et al. 340. 1984), long-standing Addison’s disease (Scheithauer et al. Asa SL, Penz G, Kovacs K & Ezrin C 1982 Prolactin cells in the 1983), and in animals after continuous CRH infusion human pituitary. Archives of Pathology and Laboratory (Gertz et al. 1987, McNichol et al. 1988). Medicine 106 360–363. Asa SL, Kovacs K, Tindall GT, Barrow DL, Horvath E & Vecsei P 1984 Cushing’ s disease associated with an intrasellar TSH-releasing hormone (TRH) gangliocytoma producing corticotrophin-releasing factor. Annals of Internal Medicine 101 789–793. Thyrotroph hyperplasia in patients with long-standing prim- Asa SL, Kovacs K, Stefaneanu L, Horvath E, Billestrup N, ary hypothyroidism (Scheithauer et al. 1985, Sarlis et al. Gonzalez-Marcelon C & Vale W 1990 Pituitary mammo- 1997) is usually reversible with replacement doses of thy- somatotroph adenomas develop in old mice transgenic for

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