11 -Hydroxysteroid dehydrogenase, expression, corticotroph adenomas 68 70

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1 Subject Index Activin activity decrease, gonadotroph 78 pituitary tumorigenesis, role 99 Adenoma, see also specific cell types angiogenesis, see Angiogenesis clonality, see Clonality, pituitary tumors frequency by type 26, 27 functioning versus nonfunctioning 24, 25 growth factors and cytokines epidermal growth factor fibroblast growth factor 101 gp130 cytokines 102, 103 intrinsic growth factor network leukemia inhibitory factor 103, 104 nerve growth factor 101, 102 overview 96, 97 therapeutic prospects 106 transforming growth factor alpha transforming growth factor beta family hormonal factors, tumorigenesis corticotroph s gonadotroph s hypothalamic versus pituitary site 186, 187 lactotroph tumorigenesis local autocrine and paracrine effects 84, 96, 97 nonfunctioning s somatotroph s thyrotroph tumorigenesis nonfunctioning s, see Nonfunctioning pituitary s null cell s 26, 27 proliferation markers, see specific markers rodent models 29, 30 transcription factor regulation 25, 26 Adrenocorticotropic hormone (ACTH) s, see Corticotroph receptor underexpression, corticotroph s 67 somatostatin, modulation of release 245 Androgen receptor, X-chromosome inactivation analysis 189 Angiogenesis pituitary growth factor regulation hormonal regulation morphologic vascular changes 134 pituitary tumorderived transforming gene regulation 140 therapeutic targeting 141, 142 tumor behavior effects 134, 135 tumor growth, role 133, 134 Annexin-1 expression, corticotroph s 70 Apoptosis assays 121, 122, 221, 222 Bcl-2 regulation 121, 220, 221 Caenorhabditis elegans genes

2 Apoptosis (continued) caspase cascade 218, 219 DNA laddering 222 hormonal regulation 122, 123 mitochondria mediation 221 morphological changes human pituitary studies 224, 225, 227 overview 221, 222 necrosis comparison 218 p27, role 42, 43 p53, role 230 pathway classification 219, 220 pituitary assay studies pituitary cell line experiments 222, 223 Arginine vasopressin (AVP), receptor overactivity, corticotroph s 66 Bax, immunocytochemistry, human pituitary 230 Bcl-2 apoptosis regulation 121, 220, 221 immunocytochemistry, human pituitary 230 Bone morphogenetic proteins (BMPs) BMP-4, role, lactotroph tumorigenesis 82 pituitary development, role 2, 3 pituitary tumorigenesis, role 99 Carney complex (CNC) hormonal derangements 254 pituitary findings hormone staining 255, 256 clonality, pituitary s 188 comparative genomic hybridization findings, pituitary tumors 213, 259 electron microscopy 258, 259 morphology 255 tumor types protein kinase A gene mutations 254, 255, 261 Caspase apoptosis cascade 218, 219 detection, human pituitary 231 Catenin, growth hormone downregulation genetic alterations 130, 131 immunohistochemistry 129, 130 intermediate filament/adhesion molecule abnormalities 129 Cell cycle proliferation markers, see specific markers checkpoints 36, 110 cyclin-dependent kinase regulation 37 39, 110 dysregulation, pituitary tumorigenesis CDK2-p27 pathway CDK4-Rb-INK4 pathway Krüppel-like factor-6 54 p53 53 peroxisome proliferator activated receptor gamma 53, 54 pituitary tumor transforming gene 53 p53, regulation 39, 40 phases 35, 36, 110 pituitary tumor transforming gene overexpression, mitotic disruption 177, 179, 183 separin regulation 39 Clonality, pituitary tumors assays loss of heterozygosity 189, 190, 199 polymerase chain reaction microsatellite analysis 190, 191 primer extension preamplification 190, 191 sampling bias 199 Southern blot 190, 191 X chromosome inactivation analysis 189 Carney complex pituitary s 188 corticotroph s 192, 193 hypothalamic versus pituitary site, tumorigenesis 186, 187 monoclonality, normal tissue 193, 194 morphology independence 201 multiclonal pituitary tumors examples 188, 192, 193 recurrent tumors multiple endocrine neoplasia type 1 pituitary s 188, 200 Comparative genomic hybridization (CGH) Carney complex findings, pituitary tumors 213, 259 Subject Index 294

3 pituitary tumor studies , 206, 207, principles 149, 206 Corticotroph clonality 192, 193 somatostatin modulation, adrenocorticotropic hormone release 245 somatostatin receptor expression 244, 245 DNA microarray analysis, 158 excess adrenocorticotropic hormone secretion, mechanisms, tumorigenesis adrenocorticotropic hormone receptor underexpression 67 annexin-1 expression 70 arginine vasopressin receptor overactivity 66 corticotropin-releasing hormone and receptor overactivity 65, 66 cortisol deficiency 67, 68 glucocorticoid receptor dysregulation hydroxysteroid dehydrogenase expression overview 64 in situ hybridization studies, s 148 lineage development 5, 6 Corticotropin-releasing hormone (CRH), overactivity, corticotroph s 65, 66 Cortisol, deficiency, corticotroph s 67, 68 CUTE, proopiomelanocortin expression, role 6 Cyclic AMP response element binding protein (CREB) activation, somatotroph 74 postdifferentiation pituitary cell proliferation regulation 11 Cyclin cell proliferation analysis, cyclin D 112 types and functions 37 Cyclin-dependent kinase (CDK) activation 37 cell cycle regulation 37 39, 110 dysregulation, pituitary tumorigenesis CDK2-p27 pathway CDK4-Rb-INK4 pathway inhibitors 38, 39, 110, 111 substrates 38 DNA microarray pituitary tumor studies principles specificity, studies 159, 160 DNA topoisomerase II, cell proliferation analysis 117, 118 Dopamine angiogenesis inhibition, s 138 D 2 receptor knockout, prolactinoma development 187 receptor expression, lactotroph tumorigenesis 80 E-cadherin, growth hormone downregulation genetic alterations 130, 131 immunohistochemistry 129, 130 intermediate filament/adhesion molecule abnormalities 129 Epidermal growth factor (EGF), pituitary tumorigenesis, role Estrogen receptor (ER) gonadotroph modulation 10, 11 isoforms gonadotroph 78, 79 lactotroph tumorigenesis 81, 82 pituitary expression, development 7 9 Ets-1, Pit-1 synergism 9 Fibroblast growth factor (FGF) angiogenesis regulation, s, FGF-2 137, 138 intrinsic growth factor network, pituitary 104 pituitary development, role 3 pituitary tumorigenesis, role 101 Subject Index 295

4 Flow cytometry cell cycle analysis 111 ploidy analysis 111 Fluorescence in situ hybridization (FISH) comparison with karyotyping 205, 206 pituitary tumor findings principles 149 sample types 206 techniques utilizing fluorescence in situ hybridization 206, 207 Folliculostellate (FS) cells features 21, 136 growth factor secretion 137 GATA-2 regulation 25, 26 gonadotroph differentiation, role 11 pituitary development, role 9 Ghrelin, dysregulation, somatotroph 75 Glucocorticoid receptor (GR), dysregulation, corticotroph s 68 Gonadotroph somatostatin modulation, gonadotropin release 246 somatostatin receptor expression 245 excess gonadotropin secretion, mechanisms, tumorigenesis activin activity decrease 78 estrogen receptor isoforms 78, 79 gonadotropin isoform alterations 78 gonadotropin-releasing hormone, receptor overactivity 77, 78 leptin/leptin receptor dysregulation 79 overview 77 lineage development 9 11 Growth hormone, see Somatotroph Growth hormone-releasing hormone (GHRH), overactivity, somatotroph 71, 72 Growth hormone secretagogue receptors, overactivity, somatotroph 74, 75 G s, mutations, somatotroph 72, Hydroxysteroid dehydrogenase, expression, corticotroph s Inhibin, pituitary tumorigenesis, role 99 In situ hybridization (ISH), see also Fluorescence in situ hybridization applications 146 pituitary tumor studies polymerase chain reaction combination 149 principles 146, 147 Insulin-like growth factor-i (IGF-I), receptor deficiency, somatotroph 76, 77 Interleukin-6 (IL-6), pituitary tumorigenesis, role 102, 103 Karyotyping comparison with fluorescence in situ hybridization 205, 206 pituitary tumor findings 207 Ki-67, cell proliferation analysis Krüppel-like factor 6 (KLF6), dysregulation, pituitary tumorigenesis 54 Lactotroph DNA microarray analysis 158 prolactin secretion modulation, somatostatin 243, 244 somatostatin analog treatment 244 somatostatin receptor expression 242, 243 estradiol control 105, 106 hormonal derangement, tumorigenesis bone morphogenetic protein-4 82 dopamine receptor expression 80 estrogen receptor isoforms 81, 82 overview 79, 80 pituitary adenylate cyclase activating peptide 82 prolactin feedback 81 prolactin-releasing peptide 81 vasoactive intestinal polypeptide 82 lineage development 6 9 Subject Index 296

5 Lanreotide, see Somatostatin Laser capture microdissection (LCM) disadvantages compared with manual microdissection 154, 155 pituitary tumor studies 155 principles systems 152, 154 technique Leptin, dysregulation, gonadotroph 79 Leukemia inhibitory factor (LIF) angiogenesis regulation, s 138 pituitary tumorigenesis, role 103, 104 Lhx genes, pituitary development, role 4 Loss of heterozygosity (LOH), clonality assay 189, 190, 199 Mammosomatotroph, lineage development 6 9 Matrix metalloproteinase-9 (MMP9), pituitary expression 119 Mib-1, cell proliferation analysis 114, 115 Microarrays, see DNA microarray; Tissue microarray Multiple endocrine neoplasia type 1 (MEN-1) clinical presentation 266, 267 clonality, pituitary s 188, 200 epidemiology 266 familial isolated somatotropinoma 275 fluorescence in situ hybridization findings, pituitary s 210, 211 history of study 266 MEN1 gene detection rate, mutations genotype-phenotype correlation 279, 280 inactivating mutations 270 knockout mouse 281 locus 270 menin product functions, protein interactions mutation distribution, types sporadic pituitary tumor mutations 280 structure tissue distribution, expression 271, 272 pituitary lesion pathology prospects for study 282, 283 variants 275 Nerve growth factor (NGF), pituitary tumorigenesis, role 101, 102 Nonfunctioning pituitary s (NFPAs) DNA microarray analysis 158 excess gonadotropin secretion mechanisms, tumorigenesis activin activity decrease 78 estrogen receptor isoforms 78, 79 gonadotropin isoform alterations 78 gonadotropin-releasing hormone, receptor overactivity 77, 78 leptin/leptin receptor dysregulation 79 overview 77 features 24, 25 growth hormone combination, adrenocorticotropic hormone 27, 29 hormone expression, nonfunctioning s 26, 27 Octreotide, see Somatostatin p16 cell proliferation analysis 115 dysregulation, pituitary tumorigenesis 41 p18 dysregulation, pituitary tumorigenesis 41, 42 knockout mouse 282 p27 cell proliferation analysis 116 apoptosis, role 42, 43 cell adhesion, role 43 cell cycle regulation 42 dysregulation, pituitary tumorigenesis knockout mouse 282 subcellular compartmentalization transcriptional regulation 48, 49 translational regulation 48 ubiquitin-proteasome system, regulation Subject Index 297

6 p53 cell proliferation analysis 117 cell cycle regulation 39, 40 dysregulation, pituitary tumorigenesis 53 immunocytochemistry, human pituitary 230, 231 Pax-6, pituitary development, role 5 Peroxisome proliferator activated receptor gamma (PPAR- ), dysregulation, pituitary tumorigenesis 53, 54 Pit-1 activation, somatotroph 74 regulation 25, 26 hormone expression regulation 7 9 isoforms 6, 7 pituitary development, role 6 Pituitary, see Adenoma; see also specific cell types Pituitary adenylate cyclase activating peptide (PACAP) apoptosis inhibition 122, 123 lactotroph tumorigenesis, role 82 Pituitary gland cell types 1, 2, 20, 21 development adenohypophysial cytodifferentiation 12, 13 adenohypophysis 2, 21, 22 corticotroph lineage 5, 6 early development signaling 2 5 gonadotroph lineage 9 11 immunohistochemistry, functional differentiation 24 intermediate lobe 22 Pit-1, role 6 9 postdifferentiation cell proliferation regulation 11, 12 transcription factors, overview 24, 25 hormones and regulation 1, 2 lobes 21 secretory granules, anterior pituitary 21 vasculature 135, 136 Pituitary tumor transforming gene (PTTG) aneuploidy, role 176 angiogenesis regulation, s 140, 176 apoptosis induction 175 binding factor 177 dysregulation, pituitary tumorigenesis 53 knockout mouse phenotype 180, 181, 183 mitotic disruption 177, 179, 183 overexpression, tumors 176, 177 prospects for study 183 protein-interacting partners 180 regulation of expression 179, 180 P-LIM, pituitary development, role 4 Polymerase chain reaction (PCR) in situ polymerase chain reaction 149 microsatellite analysis, tumor clonality 190, 191 Primer extension preamplification (PEP), clonality assay 190, 191 Prolactin angiogenesis inhibition, s 139 dysregulation, lactotroph tumorigenesis prolactin feedback 81 prolactin-releasing peptide 81 prolactinoma, see Lactotroph regulation of expression, Pit-1 cells 7 9 secretion modulation, somatostatin 243, 244 Proliferating cell nuclear antigen (PCNA), cell proliferation analysis 113 PROP-1 regulation 26 pituitary development, role 5 Protein kinase A (PKA) Carney complex gene mutations 254, 255, 261 regulatory subunit inactivation, somatotroph 73, 74 Protein kinase C (PKC), inhibition and apoptosis induction, cell lines 223 Proteomics pituitary tumor studies 164, 165 principles Ptx1, pituitary development, role 4 Ptx2, pituitary development, role 4 Retinoblastoma protein (Rb) cyclin-dependent kinase substrate 38 dysregulation, pituitary tumorigenesis 41 knockout mouse 281 Subject Index 298

7 RNA interference (RNAi) efficacy/specificity factors 165, 166 mechanisms 165 pituitary studies 167 Rpx/HesX-1, pituitary development, role 4, 5 Separin, cell cycle regulation 39 Somatostatin adrenocorticotropic hormone somatostatin modulation, adrenocorticotropic hormone release 245 somatostatin receptor expression 244, 245 analogs 237 angiogenesis inhibition, s 139, 140 cortistatin homology 236, 237 gonadotroph somatostatin modulation, gonadotropin release 246 somatostatin receptor expression 245 growth hormone somatostatin analog treatment somatostatin receptor expression 238, 239 prolactinoma prolactin secretion modulation, somatostatin 243, 244 somatostatin analog treatment 244 somatostatin receptor expression 242, 243 receptors binding potency, analogs 237 deficiency, somatotroph 75, 76 expression and functional significance, subtypes, pituitary 237, 238 scintigraphy, diagnostics 247 subtypes 236 structure 236 thyrotroph somatostatin analog treatment 246, 247 somatostatin receptor expression 246 Somatotroph DNA microarray analysis 158 in situ hybridization studies 147, 148 somatostatin analog treatment somatostatin receptor expression 238, 239 E-cadherin/catenin downregulation, genetic alterations 130, 131 immunohistochemistry 129, 130 excess growth hormone secretion mechanisms, tumorigenesis cyclic AMP response element binding protein activation 74 ghrelin dysregulation 75 growth hormone receptor deficiency 76 growth hormone-releasing hormone and receptor overactivity 71, 72 growth hormone secretagogue receptor overactivity 74, 75 G s mutations 72, 73 insulin-like growth factor I receptor deficiency 76, 77 overview 70, 71 Pit-1 activation 74 protein kinase A regulatory subunit inactivation 73, 74 somatostatin receptor deficiency 75, 76 thyrotropin-releasing hormone receptor abnormalities 74 familial isolated somatotropinoma 275 intermediate filament/adhesion molecule abnormalities, 129 lineage development 6 9 ultrastructural classification, s 127, 128 Sonic hedgehog (Shh), pituitary development, role 3 Southern blot, clonality assay 190, 191 Steroidogenic factor-1 (SF-1), gonadotroph differentiation, role 9, 10 Thyroid hormone, receptor defects, thyrotroph tumorigenesis 84 Subject Index 299

8 Thyroid-stimulating hormone (TSH), see Thyrotroph defects, thyrotroph tumorigenesis 83, 84 Thyrotroph DNA microarray analysis 158, 159 somatostatin analog treatment 246, 247 somatostatin receptor expression 246 hormonal derangement, tumorigenesis overview 82, 83 thyroid hormone receptor defects 84 thyroid-stimulating hormone 83, 84 thyrotropin-releasing hormone 82, 83 lineage development 6 9 Thyrotroph embryonic factor (TEF), thyroid-stimulating hormone expression activation 9 Thyrotropin-releasing hormone (TRH) defects, thyrotroph tumorigenesis 82, 83 receptor abnormalities, somatotroph 74 Tissue microarray (TMA) pituitary tumor studies 161 principles 160, 161 validation 161 Tissue plasminogen activator (tpa), pituitary expression 119 Tpit, corticotroph differentiation, role 5 Transforming growth factor alpha (TGF- ), pituitary tumorigenesis, role Transforming growth factor beta (TGF- ), pituitary tumorigenesis, role Ubiquitin-proteasome system, overview, p27 regulation Urokinase, pituitary expression, receptor 119 Vascular endothelial growth factor (VEGF), angiogenesis regulation, s Vasoactive intestinal polypeptide (VIP), lactotroph tumorigenesis, role 82 Wnt, pituitary development, role 3 X chromosome inactivation analysis, clonality assay 189 Zn-15, Pit-1 synergism 7 Subject Index 300