Abstract
During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors.
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References
Abbud RA, Takumi I, Barker EM, Ren SG, Chen DY, Wawrowsky K, Melmed S (2005) Early multipotential pituitary focal hyperplasia in the alpha-subunit of glycoprotein hormone-driven pituitary tumor-transforming gene transgenic mice. Mol Endocrinol 19:1383–1391. doi:10.1210/me.2004-0403
Aflorei ED, Korbonits M (2014) Epidemiology and etiopathogenesis of pituitary adenomas. J Neurooncol 117:379–394. doi:10.1007/s11060-013-1354-5
Alexander JM (2001) Tumor suppressor loss in pituitary tumors. Brain Pathol 11:342–355
Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold A, Klibanski A (1990) Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Investig 86:336–340. doi:10.1172/JCI114705
Alexandraki KI, Munayem Khan M, Chahal HS, Dalantaeva NS, Trivellin G, Berney DM, Caron P, Popovic V, Pfeifer M, Jordan S, Korbonits M, Grossman AB (2012) Oncogene-induced senescence in pituitary adenomas and carcinomas. Hormones (Athens) 11:297–307
Arzt E (2001) gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine-neuro-endocrine pathways. J Clin Investig 108:1729–1733. doi:10.1172/JCI14660
Arzt E, Buric R, Stelzer G, Stalla J, Sauer J, Renner U, Stalla GK (1993) Interleukin involvement in anterior pituitary cell growth regulation: effects of IL-2 and IL-6. Endocrinology 132:459–467. doi:10.1210/endo.132.1.8419142
Arzt E, Pereda MP, Castro CP, Pagotto U, Renner U, Stalla GK (1999) Pathophysiological role of the cytokine network in the anterior pituitary gland. Front Neuroendocrinol 20:71–95. doi:10.1006/frne.1998.0176
Arzt E, Chesnokova V, Stalla GK, Melmed S (2009) Pituitary adenoma growth: a model for cellular senescence and cytokine action. Cell Cycle 8:677–678
Asa SL, Ezzat S (2002) The pathogenesis of pituitary tumours. Nat Rev Cancer 2:836–849. doi:10.1038/nrc926
Asa SL, Ezzat S (2009) The pathogenesis of pituitary tumors. Annu Rev Pathol 4:97–126. doi:10.1146/annurev.pathol.4.110807.092259
Borg SA, Kerry KE, Baxter L, Royds JA, Jones TH (2003) Expression of interleukin-6 and its effects on growth of HP75 human pituitary tumor cells. J Clin Endocrinol Metab 88:4938–4944. doi:10.1210/jc.2002-022044
Bottoni A, Piccin D, Tagliati F, Luchin A, Zatelli MC, Degli Uberti EC (2005) miR-15a and miR-16-1 down-regulation in pituitary adenomas. J Cell Physiol 204:280–285. doi:10.1002/jcp.20282
Bottoni A, Zatelli MC, Ferracin M, Tagliati F, Piccin D, Vignali C, Calin GA, Negrini M, Croce CM, Degli Uberti EC (2007) Identification of differentially expressed microRNAs by microarray: a possible role for microRNA genes in pituitary adenomas. J Cell Physiol 210:370–377. doi:10.1002/jcp.20832
Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665. doi:10.1038/nature03841
Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671. doi:10.1210/jcem.86.12.8070
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529. doi:10.1073/pnas.242606799
Campisi J (2001) Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 11:S27–S31
Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522. doi:10.1016/j.cell.2005.02.003
Castro CP, Giacomini D, Nagashima AC, Onofri C, Graciarena M, Kobayashi K, Paez-Pereda M, Renner U, Stalla GK, Arzt E (2003) Reduced expression of the cytokine transducer gp130 inhibits hormone secretion, cell growth, and tumor development of pituitary lactosomatotrophic GH3 cells. Endocrinology 144:693–700. doi:10.1210/en.2002-220891
Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730. doi:10.1038/nature03918
Chesnokova V, Kovacs K, Castro AV, Zonis S, Melmed S (2005) Pituitary hypoplasia in Pttg−/− mice is protective for Rb+/− pituitary tumorigenesis. Mol Endocrinol 19:2371–2379. doi:10.1210/me.2005-0137
Chesnokova V, Zonis S, Rubinek T, Yu R, Ben-Shlomo A, Kovacs K, Wawrowsky K, Melmed S (2007) Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. Cancer Res 67:10564–10572. doi:10.1158/0008-5472.CAN-07-0974
Chesnokova V, Zonis S, Kovacs K, Ben-Shlomo A, Wawrowsky K, Bannykh S, Melmed S (2008) p21(Cip1) restrains pituitary tumor growth. Proc Natl Acad Sci USA 105:17498–17503. doi:10.1073/pnas.0804810105
Chesnokova V, Zonis S, Zhou C, Ben-Shlomo A, Wawrowsky K, Toledano Y, Tong Y, Kovacs K, Scheithauer B, Melmed S (2011) Lineage-specific restraint of pituitary gonadotroph cell adenoma growth. PLoS One 6:e17924. doi:10.1371/journal.pone.0017924
Cichowski K, Hahn WC (2008) Unexpected pieces to the senescence puzzle. Cell 133:958–961. doi:10.1016/j.cell.2008.05.027
Clayton RN, Farrell WE (2004) Pituitary tumour clonality revisited. Front Horm Res 32:186–204
Clayton RN, Pfeifer M, Atkinson AB, Belchetz P, Wass JA, Kyrodimou E, Vanderpump M, Simpson D, Bicknell J, Farrell WE (2000) Different patterns of allelic loss (loss of heterozygosity) in recurrent human pituitary tumors provide evidence for multiclonal origins. Clin Cancer Res 6:3973–3982
Colao A, Ochoa AS, Auriemma RS, Faggiano A, Pivonello R, Lombardi G (2010) Pituitary carcinomas. Front Horm Res 38:94–108. doi:10.1159/000318499
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642. doi:10.1038/436642a
Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233. doi:10.1016/j.cell.2007.07.003
Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K (2006) A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10:459–472. doi:10.1016/j.ccr.2006.10.003
Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704–714. doi:10.1038/nrg2634
Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A (2006) High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91:4769–4775. doi:10.1210/jc.2006-1668
Daly AF, Tichomirowa MA, Beckers A (2009) The epidemiology and genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 23:543–554. doi:10.1016/j.beem.2009.05.008
Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M (2007) A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21:379–384. doi:10.1101/gad.1516407
Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27. doi:10.1016/j.cell.2012.06.013
Deng S, Calin GA, Croce CM, Coukos G, Zhang L (2008) Mechanisms of microRNA deregulation in human cancer. Cell Cycle 7:2643–2646
Di Ieva A, Rotondo F, Syro LV, Cusimano MD, Kovacs K (2014) Aggressive pituitary adenomas–diagnosis and emerging treatments. Nat Rev Endocrinol 10:423–435. doi:10.1038/nrendo.2014.64
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367
Donangelo I, Gutman S, Horvath E, Kovacs K, Wawrowsky K, Mount M, Melmed S (2006) Pituitary tumor transforming gene overexpression facilitates pituitary tumor development. Endocrinology 147:4781–4791. doi:10.1210/en.2006-0544
Dworakowska D, Grossman AB (2009) The pathophysiology of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 23:525–541. doi:10.1016/j.beem.2009.05.004
Elston MS, McDonald KL, Clifton-Bligh RJ, Robinson BG (2009) Familial pituitary tumor syndromes. Nat Rev Endocrinol 5:453–461. doi:10.1038/nrendo.2009.126
Farnoud MR, Kujas M, Derome P, Racadot J, Peillon F, Li JY (1994) Interactions between normal and tumoral tissues at the boundary of human anterior pituitary adenomas. An immunohistochemical study. Virchows Arch 424:75–82
Farrell WE (2005) Epigenetic mechanisms of tumorigenesis. Horm Metab Res 37:361–368. doi:10.1055/s-2005-870153
Farrell WE (2006) Pituitary tumours: findings from whole genome analyses. Endocr Relat Cancer 13:707–716. doi:10.1677/erc.1.01131
Farrell WE, Clayton RN (2003) Epigenetic change in pituitary tumorigenesis. Endocr Relat Cancer 10:323–330
Fedele M, Fusco A (2010) Role of the high mobility group A proteins in the regulation of pituitary cell cycle. J Mol Endocrinol 44:309–318. doi:10.1677/JME-09-0178
Fernandez A, Karavitaki N, Wass JA (2010) Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 72:377–382. doi:10.1111/j.1365-2265.2009.03667.x
Filippella M, Galland F, Kujas M, Young J, Faggiano A, Lombardi G, Colao A, Meduri G, Chanson P (2006) Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin Endocrinol (Oxf) 65:536–543. doi:10.1111/j.1365-2265.2006.02630.x
Gloddek J, Pagotto U, Paez Pereda M, Arzt E, Stalla GK, Renner U (1999) Pituitary adenylate cyclase-activating polypeptide, interleukin-6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells. J Endocrinol 160:483–490
Gray-Schopfer VC, Cheong SC, Chong H, Chow J, Moss T, Abdel-Malek ZA, Marais R, Wynford-Thomas D, Bennett DC (2006) Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 95:496–505. doi:10.1038/sj.bjc.6603283
Ha L, Ichikawa T, Anver M, Dickins R, Lowe S, Sharpless NE, Krimpenfort P, Depinho RA, Bennett DC, Sviderskaya EV, Merlino G (2007) ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc Natl Acad Sci USA 104:10968–10973. doi:10.1073/pnas.0611638104
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013
Hanisch A, Dieterich KD, Dietzmann K, Ludecke K, Buchfelder M, Fahlbusch R, Lehnert H (2000) Expression of members of the interleukin-6 family of cytokines and their receptors in human pituitary and pituitary adenomas. J Clin Endocrinol Metab 85:4411–4414. doi:10.1210/jcem.85.11.7122
Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S (1999) Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat Med 5:1317–1321. doi:10.1038/15275
Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S (1990) Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 71:1427–1433. doi:10.1210/jcem-71-6-1427
Hofler H, Walter GF, Denk H (1984) Immunohistochemistry of folliculo-stellate cells in normal human adenohypophyses and in pituitary adenomas. Acta Neuropathol 65:35–40
Ishikawa H, Heaney AP, Yu R, Horwitz GA, Melmed S (2001) Human pituitary tumor-transforming gene induces angiogenesis. J Clin Endocrinol Metab 86:867–874. doi:10.1210/jcem.86.2.7184
Jones TH, Daniels M, James RA, Justice SK, McCorkle R, Price A, Kendall-Taylor P, Weetman AP (1994) Production of bioactive and immunoreactive interleukin-6 (IL-6) and expression of IL-6 messenger ribonucleic acid by human pituitary adenomas. J Clin Endocrinol Metab 78:180–187. doi:10.1210/jcem.78.1.8288702
Kim D, Pemberton H, Stratford AL, Buelaert K, Watkinson JC, Lopes V, Franklyn JA, McCabe CJ (2005) Pituitary tumour transforming gene (PTTG) induces genetic instability in thyroid cells. Oncogene 24:4861–4866. doi:10.1038/sj.onc.1208659
Kim DS, Franklyn JA, Smith VE, Stratford AL, Pemberton HN, Warfield A, Watkinson JC, Ishmail T, Wakelam MJ, McCabe CJ (2007) Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity. Carcinogenesis 28:749–759. doi:10.1093/carcin/bgl202
Kirsch M, Morz M, Pinzer T, Schackert HK, Schackert G (2009) Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas. Genes Chromosomes Cancer 48:143–154. doi:10.1002/gcc.20621
Lazzerini Denchi E, Helin K (2005) E2F1 is crucial for E2F-dependent apoptosis. EMBO Rep 6:661–668. doi:10.1038/sj.embor.7400452
Levy A, Lightman S (2003) Molecular defects in the pathogenesis of pituitary tumours. Front Neuroendocrinol 24:94–127
Liu N, Chen NY, Cui RX, Li WF, Li Y, Wei RR, Zhang MY, Sun Y, Huang BJ, Chen M, He QM, Jiang N, Chen L, Cho WC, Yun JP, Zeng J, Liu LZ, Li L, Guo Y, Wang HY, Ma J (2012) Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. Lancet Oncol 13:633–641. doi:10.1016/S1470-2045(12)70102-X
Mao ZG, He DS, Zhou J, Yao B, Xiao WW, Chen CH, Zhu YH, Wang HJ (2010) Differential expression of microRNAs in GH-secreting pituitary adenomas. Diagn Pathol 5:79. doi:10.1186/1746-1596-5-79
Marx SJ, Agarwal SK, Kester MB, Heppner C, Kim YS, Skarulis MC, James LA, Goldsmith PK, Saggar SK, Park SY, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree J, Erdos MR, Collins FS, Chandrasekharappa SC (1999) Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent Prog Horm Res 54:397–438 (discussion 438-399)
Melmed S (1994) Pituitary neoplasia. Endocrinol Metab Clin North Am 23:81–92
Melmed S (2003) Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Investig 112:1603–1618. doi:10.1172/JCI20401
Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7:257–266. doi:10.1038/nrendo.2011.40
Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724. doi:10.1038/nature03890
Mooi WJ, Peeper DS (2006) Oncogene-induced cell senescence–halting on the road to cancer. N Engl J Med 355:1037–1046. doi:10.1056/NEJMra062285
Nugent M, Miller N, Kerin MJ (2011) MicroRNAs in colorectal cancer: function, dysregulation and potential as novel biomarkers. Eur J Surg Oncol 37:649–654. doi:10.1016/j.ejso.2011.05.005
Ogino A, Yoshino A, Katayama Y, Watanabe T, Ota T, Komine C, Yokoyama T, Fukushima T (2005) The p15(INK4b)/p16(INK4a)/RB1 pathway is frequently deregulated in human pituitary adenomas. J Neuropathol Exp Neurol 64:398–403
Paez-Pereda M, Giacomini D, Echenique C, Stalla GK, Holsboer F, Arzt E (2005) Signaling processes in tumoral neuroendocrine pituitary cells as potential targets for therapeutic drugs. Curr Drug Targets Immune Endocr Metab Disord 5:259–267
Pease M, Ling C, Mack WJ, Wang K, Zada G (2013) The role of epigenetic modification in tumorigenesis and progression of pituitary adenomas: a systematic review of the literature. PLoS One 8:e82619. doi:10.1371/journal.pone.0082619
Pei L, Melmed S (1997) Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol 11:433–441. doi:10.1210/mend.11.4.9911
Peltomaki P (2012) Mutations and epimutations in the origin of cancer. Exp Cell Res 318:299–310. doi:10.1016/j.yexcr.2011.12.001
Pereda MP, Goldberg V, Chervin A, Carrizo G, Molina A, Andrada J, Sauer J, Renner U, Stalla GK, Arzt E (1996) Interleukin-2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants. Mol Cell Endocrinol 124:33–42
Perez Castro C, Nagashima AC, Pereda MP, Goldberg V, Chervin A, Largen P, Renner U, Stalla GK, Arzt E (2000) The gp130 cytokines interleukin-11 and ciliary neurotropic factor regulate through specific receptors the function and growth of lactosomatotropic and folliculostellate pituitary cell lines. Endocrinology 141:1746–1753. doi:10.1210/endo.141.5.7442
Perez Castro C, Carbia Nagashima A, Paez Pereda M, Goldberg V, Chervin A, Carrizo G, Molina H, Renner U, Stalla GK, Arzt E (2001) Effects of the gp130 cytokines ciliary neurotropic factor (CNTF) and interleukin-11 on pituitary cells: CNTF receptors on human pituitary adenomas and stimulation of prolactin and GH secretion in normal rat anterior pituitary aggregate cultures. J Endocrinol 169:539–547
Perez-Castro C, Renner U, Haedo MR, Stalla GK, Arzt E (2012) Cellular and molecular specificity of pituitary gland physiology. Physiol Rev 92:1–38. doi:10.1152/physrev.00003.2011
Quereda V, Malumbres M (2009) Cell cycle control of pituitary development and disease. J Mol Endocrinol 42:75–86. doi:10.1677/JME-08-0146
Raappana A, Koivukangas J, Ebeling T, Pirila T (2010) Incidence of pituitary adenomas in Northern Finland in 1992-2007. J Clin Endocrinol Metab 95:4268–4275. doi:10.1210/jc.2010-0537
Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33:49–54. doi:10.1038/ng1060
Ray D, Melmed S (1997) Pituitary cytokine and growth factor expression and action. Endocr Rev 18:206–228. doi:10.1210/edrv.18.2.0297
Renner U, Pagotto U, Arzt E, Stalla GK (1996) Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review. Eur J Endocrinol 135:515–532
Renner U, Gloddek J, Arzt E, Inoue K, Stalla GK (1997) Interleukin-6 is an autocrine growth factor for folliculostellate-like TtT/GF mouse pituitary tumor cells. Exp Clin Endocrinol Diabetes 105:345–352. doi:10.1055/s-0029-1211777
Renner U, Gloddek J, Pereda MP, Arzt E, Stalla GK (1998) Regulation and role of intrapituitary IL-6 production by folliculostellate cells. Domest Anim Endocrinol 15:353–362
Renner U, Paez-Pereda M, Arzt E, Stalla GK (2004) Growth factors and cytokines: function and molecular regulation in pituitary adenomas. Front Horm Res 32:96–109
Saez C, Japon MA, Ramos-Morales F, Romero F, Segura DI, Tortolero M, Pintor-Toro JA (1999) hpttg is over-expressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene 18:5473–5476. doi:10.1038/sj.onc.1202914
Salehi F, Kovacs K, Scheithauer BW, Lloyd RV, Cusimano M (2008) Pituitary tumor-transforming gene in endocrine and other neoplasms: a review and update. Endocr Relat Cancer 15:721–743. doi:10.1677/ERC-08-0012
Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T, Riehle DL, Laws ER Jr (2006) Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59:341–353. doi:10.1227/01.NEU.0000223437.51435.6E (discussion 341-353)
Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–346
Serrano M, Blasco MA (2001) Putting the stress on senescence. Curr Opin Cell Biol 13:748–753
Tateno T, Zhu X, Asa SL, Ezzat S (2010) Chromatin remodeling and histone modifications in pituitary tumors. Mol Cell Endocrinol 326:66–70. doi:10.1016/j.mce.2009.12.028
Ueta Y, Levy A, Chowdrey HS, Lightman SL (1995) S-100 antigen-positive folliculostellate cells are not the source of IL-6 gene expression in human pituitary adenomas. J Neuroendocrinol 7:467–474
Vajtai I, Kappeler A, Sahli R (2007) Folliculo-stellate cells of “true dendritic” type are involved in the inflammatory microenvironment of tumor immunosurveillance of pituitary adenomas. Diagn Pathol 2:20. doi:10.1186/1746-1596-2-20
Vandeva S, Jaffrain-Rea ML, Daly AF, Tichomirowa M, Zacharieva S, Beckers A (2010) The genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 24:461–476. doi:10.1016/j.beem.2010.03.001
Vlotides G, Eigler T, Melmed S (2007) Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev 28:165–186. doi:10.1210/er.2006-0042
Yacqub-Usman K, Richardson A, Duong CV, Clayton RN, Farrell WE (2012) The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nat Rev Endocrinol 8:486–494. doi:10.1038/nrendo.2012.54
Yoshino A, Katayama Y, Ogino A, Watanabe T, Yachi K, Ohta T, Komine C, Yokoyama T, Fukushima T (2007) Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas. J Neurooncol 83:153–162. doi:10.1007/s11060-006-9316-9
You JS, Jones PA (2012) Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22:9–20. doi:10.1016/j.ccr.2012.06.008
Yu R, Melmed S (2010) Pathogenesis of pituitary tumors. Prog Brain Res 182:207–227. doi:10.1016/S0079-6123(10)82009-6
Yu R, Heaney AP, Lu W, Chen J, Melmed S (2000) Pituitary tumor transforming gene causes aneuploidy and p53-dependent and p53-independent apoptosis. J Biol Chem 275:36502–36505. doi:10.1074/jbc.C000546200
Yu R, Lu W, Chen J, McCabe CJ, Melmed S (2003) Overexpressed pituitary tumor-transforming gene causes aneuploidy in live human cells. Endocrinology 144:4991–4998. doi:10.1210/en.2003-0305
Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S (1999a) Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 84:761–767. doi:10.1210/jcem.84.2.5432
Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, Melmed S (1999b) Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol 13:156–166. doi:10.1210/mend.13.1.0225
Zhao L, Sun Y, Hou Y, Peng Q, Wang L, Luo H, Tang X, Zeng Z, Liu M (2012) MiRNA expression analysis of cancer-associated fibroblasts and normal fibroblasts in breast cancer. Int J Biochem Cell Biol 44:2051–2059. doi:10.1016/j.biocel.2012.08.005
Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3:245–252. doi:10.1038/35060032
Zhou C, Wawrowsky K, Bannykh S, Gutman S, Melmed S (2009) E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors. Mol Endocrinol 23:2000–2012. doi:10.1210/me.2009-0161
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This work was supported by grants from the Max Planck Society, Germany; the University of Buenos Aires; the Consejo Nacional de Investigaciones Científicas y Técnicas; the Agencia Nacional de Promoción Científica y Tecnológica, Argentina; and Fondo para la Convergencia Estructural de Mercosur (COF 03/11).
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Sapochnik, M., Nieto, L.E., Fuertes, M. et al. Molecular Mechanisms Underlying Pituitary Pathogenesis. Biochem Genet 54, 107–119 (2016). https://doi.org/10.1007/s10528-015-9709-6
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DOI: https://doi.org/10.1007/s10528-015-9709-6