, Volume 21, Issue 2, pp 130–137 | Cite as

Pathogenesis of non-functioning pituitary adenomas

  • Maria Chiara Zatelli


The pathogenesis of non functioning pituitary adenomas (NFPA) is a complex process involving several factors, from molecular to genetic and epigenetic modifications, where tumor suppressor genes, oncogenes, cell cycle derangements have been demonstrated to play an important role. MicroRNAs (miRNAs) have also been identified as possible players in NFPA tumorigenesis and pituitary stem cells have been investigated for their potential role in pituitary tumor initiation. However, a critical role for paracrine signalling has also been highlighted. This review focuses on the current knowledge on the involvement of these factors in NFPA pathogenesis.


Non functioning pituitary adenomas Pathogenesis Signalling pathway derangements 


  1. 1.
    Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7:257–266. CrossRefPubMedGoogle Scholar
  2. 2.
    Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) (2017) WHO classification of tumours of endocrine organs, 4th edn. IARC Press, LyonGoogle Scholar
  3. 3.
    Chanson P, Raverot G, Castinetti F, Cortet-Rudelli C, Galland F, Salenave S (2015) Management of clinically non-functioning pituitary adenoma. Ann Endocrinol 76:239–247CrossRefGoogle Scholar
  4. 4.
    Falchetti A (2017) Genetics of multiple endocrine neoplasia type 1 syndrome: what’s new and what’s old. F1000Research. PubMedPubMedCentralGoogle Scholar
  5. 5.
    Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML (2012) Endocrine society: clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97:2990–3011CrossRefPubMedGoogle Scholar
  6. 6.
    Corbetta S, Pizzocaro A, Peracchi M, Beck-Peccoz P, Faglia G, Spada A (1997) Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types. Clin Endocrinol 47:507–512CrossRefGoogle Scholar
  7. 7.
    Alrezk R, Hannah-Shmouni F, Stratakis CA (2017) MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr Relat Cancer 24:T195–T208. CrossRefPubMedGoogle Scholar
  8. 8.
    Beckers A, Aaltonen LA, Daly AF, Karhu A (2013) Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 34:239–277CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Daly AF, Beckers A (2017) The role of AIP mutations in pituitary adenomas: 10 years on. Endocrine 55:333–335CrossRefPubMedGoogle Scholar
  10. 10.
    Araujo PB, Kasuki L, de Azeredo Lima CH, Ogino L, Camacho AHS, Chimelli L, Korbonits M, Gadelha MR (2017) AIP mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation. Endocr Connect 6:914–925. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hu Y, Yang J, Chang Y, Ma S, Qi J (2016) SNPs in the aryl hydrocarbon receptor-interacting protein gene associated with sporadic non-functioning pituitary adenoma. Exp Ther Med 11:1142–1146CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lin Y, Jiang X, Shen Y, Li M, Ma H, Xing M, Lu Y (2009) Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocr Relat Cancer 16:301–310CrossRefPubMedGoogle Scholar
  13. 13.
    Simpson DJ, Bicknell JE, McNicol AM, Clayton RN, Farrell WE (1999) Hypermethylation of the p16/CDKN2A/MTSI gene and loss of protein expression is associated with nonfunctional pituitary adenomas but not somatotrophinomas. Genes Chrom Cancer 24:328–336CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B, Klibanski A (2002) Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis. J Clin Endocrinol Metab 87:1262–1267PubMedGoogle Scholar
  15. 15.
    Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, Klibanski A (2003) A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab 88:5119–5126CrossRefPubMedGoogle Scholar
  16. 16.
    Gentilin E, degli Uberti E, Zatelli MC (2016) Strategies to use microRNAs as therapeutic targets. Best Pract Res Clin Endocrinol Metab 30:629–639. CrossRefPubMedGoogle Scholar
  17. 17.
    Butz H, Likó I, Czirják S, Igaz P, Korbonits M, Rácz K, Patócs A (2011) MicroRNA profile indicates downregulation of the TGFβ pathway in sporadic non-functioning pituitary adenomas. Pituitary 14:112–124. CrossRefPubMedGoogle Scholar
  18. 18.
    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 204:280–285CrossRefPubMedGoogle Scholar
  19. 19.
    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 210:370–377CrossRefPubMedGoogle Scholar
  20. 20.
    Cheunsuchon P, Zhou Y, Zhang X, Lee H, Chen W, Nakayama Y, Rice KA, Hedley-Whyte ET, Swearingen B, Klibanski A (2011) Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas. Am J Pathol 179:2120–2130. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Butz H, Likó I, Czirják S, Igaz P, Khan MM, Zivkovic V, Bálint K, Korbonits M, Rácz K, Patócs A (2010) Down-regulation of Wee1 kinase by a specific subset of microRNA in human sporadic pituitary adenomas. J Clin Endocrinol Metab 95:E181–E191. CrossRefPubMedGoogle Scholar
  22. 22.
    Wu S, Gu Y, Huang Y, Wong TC, Ding H, Liu T, Zhang Y, Zhang X (2017) Novel biomarkers for non-functioning invasive pituitary adenomas were identified by using analysis of microRNAs expression profile. Biochem Genet 55:253–267. CrossRefPubMedGoogle Scholar
  23. 23.
    Michaelis KA, Knox AJ, Xu M, Kiseljak-Vassiliades K, Edwards MG, Geraci M, Kleinschmidt-DeMasters BK, Lillehei KO, Wierman ME (2011) Identification of growth arrest and DNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor in pituitary gonadotrope tumors. Endocrinology 152:3603–3613. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Qiao X, Wang H, Wang X, Zhao B, Liu J (2017) Microarray technology reveals potentially novel genes and pathways involved in non-functioning pituitary adenomas. Balkan J Med Genet 19:5–16. PubMedGoogle Scholar
  25. 25.
    Rubinfeld H, Shimon I (2012) PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways perturbations in non-functioning pituitary adenomas. Endocrine 42:285–291CrossRefPubMedGoogle Scholar
  26. 26.
    Zatelli MC, Minoia M, Filieri C, Tagliati F, Buratto M, Ambrosio MR, Lapparelli M, Scanarini M, degli Uberti EC (2010) Effect of everolimus on cell viability in nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 95:968–976. CrossRefPubMedGoogle Scholar
  27. 27.
    Levy A, Hall L, Yeudall A, Lightman S (1994) p53 gene mutations in pituitary adenomas: rare events. Clin Endocrinol 41:809–814CrossRefGoogle Scholar
  28. 28.
    Pei L, Melmed S, Scheithauer BW, Kovacs K, Prager D (1994) H-ras mutations in human pituitary carcinoma metastasis. J Clin Endocrinol Metab 78:842–846PubMedGoogle Scholar
  29. 29.
    Suliman M, Royds J, Cullen D, Timperley W, Powell T, Battersby R, Jones TH (2001) Mdm2 and the p53 pathway in human pituitary adenomas. Clin Endocrinol 54:317–325CrossRefGoogle Scholar
  30. 30.
    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:e17924CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chesnokova V, Zonis S, Wawrowsky K, Tani Y, Ben-Shlomo A, Ljubimov V, Mamelak A, Bannykh S, Melmed S (2012) Clusterin and FOXL2 act concordantly to regulate pituitary gonadotroph adenoma growth. Mol Endocrinol 26:2092–2103CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ruskyte K, Liutkevicienė R, Vilkeviciute A, Vaitkiene P, Valiulytė I, Glebauskiene B, Kriauciuniene L, Zaliuniene D (2016) MMP-14 and TGFβ-1 methylation in pituitary adenomas. Oncol Lett 12:3013–3017CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Valiulyte I, Steponaitis G, Skiriute D, Tamasauskas A, Vaitkiene P (2017) Signal transducer and activator of transcription 3 (STAT3) promoter methylation and expression in pituitary adenoma. BMC Med Genet 18:72. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Fukuoka H, Cooper O, Ben-Shlomo A, Mamelak A, Ren SG, Bruyette D, Melmed S (2011) EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest 121:4712–4721. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cooper O, Vlotides G, Fukuoka H, Greene MI, Melmed S (2011) Expression and function of ErbB receptors and ligands in the pituitary. Endocr Relat Cancer 18:R197–R211. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Chaidarun SS, Eggo MC, Sheppard MC, Stewart PM (1994) Expression of epidermal growth factor (EGF), its receptor, and related oncoprotein (erbB-2) in human pituitary tumors and response to EGF in vitro. Endocrinology 135:2012–2021. CrossRefPubMedGoogle Scholar
  37. 37.
    Kontogeorgos G, Stefaneanu L, Kovacs K, Cheng Z (1996) Localization of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFr) in human pituitary adenomas and nontumorous pituitaries: an immunocytochemical study. Endocr Pathol 7:63–70. CrossRefPubMedGoogle Scholar
  38. 38.
    Otsuka F, Tamiya T, Yamauchi T, Ogura T, Ohmoto T, Makino H (1999) Quantitative analysis of growth related factors in human pituitary adenomas. Lowered insulin-like growth factor-I and its receptor mRNA in growth hormone-producing adenomas. Regul Pep 83:31–38. CrossRefGoogle Scholar
  39. 39.
    Birman P, Michard M, Li JY, Peillon F, Bression D (1987) Epidermal growth factor-binding sites, present in normal human and rat pituitaries, are absent in human pituitary adenomas. J Clin Endocrinol Metab 65:275–281. CrossRefPubMedGoogle Scholar
  40. 40.
    Jaffrain-Rea ML, Petrangeli E, Lubrano C, Minniti G, Di Stefano D, Sciarra F, Frati L, Tamburrano G, Cantore G, Gulino A (1998) Epidermal growth factor binding sites in human pituitary macroadenomas. J Endocrinol 158:425–433. CrossRefPubMedGoogle Scholar
  41. 41.
    Onguru O, Scheithauer BW, Kovacs K, Vidal S, Jin L, Zhang S, Ruebel KH, Lloyd RV (2004) Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas. Mod Pathol 17:772–780. CrossRefPubMedGoogle Scholar
  42. 42.
    Theodoropoulou M, Arzberger T, Gruebler Y, Jaffrain-Rea ML, Schlegel J, Schaaf L, Petrangeli E, Losa M, Stalla GK, Pagotto U (2004) Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J Endocrinol 183:385–394. CrossRefPubMedGoogle Scholar
  43. 43.
    Renner U, Mojto J, Arzt E, Lange M, Stalla J, Muller OA, Stalla GK (1993) Secretion of polypeptide growth factors by human nonfunctioning pituitary adenoma cells in culture. Neuroendocrinology 57:825–834. CrossRefPubMedGoogle Scholar
  44. 44.
    Grosse R, Roelle S, Herrlich A, Hohn J, Gudermann T (2000) Epidermal growth factor receptor tyrosine kinase mediates Ras activation by gonadotropin-releasing hormone. J Biol Chem 275:12251–12260. CrossRefPubMedGoogle Scholar
  45. 45.
    Chaidarun SS, Klibanski A, Alexander JM (1997) Tumor specific expression of alternatively spliced estrogen receptor messenger ribonucleic acid variants in human pituitary adenomas. J Clin Endocrinol Metab 82:1058–1065PubMedGoogle Scholar
  46. 46.
    Nishioka H, Tamura K, Iida H, Kutsukake M, Endo A, Ikeda Y, Haraoka J (2011) Co-expression of somatostatin receptor subtypes and estrogen receptor-α mRNAs by non-functioning pituitary adenomas in young patients. Mol Cell Endocrinol 331:73–78. CrossRefPubMedGoogle Scholar
  47. 47.
    Drastikova M, Beranek M, Gabalec F, Netuka D, Masopust V, Cesak T, Marek J, Palicka V, Cap J (2016) Expression profiles of somatostatin, dopamine, and estrogen receptors in pituitary adenomas determined by means of synthetic multilocus calibrators. Biomed Pap 60:238–243. CrossRefGoogle Scholar
  48. 48.
    Greenman Y, Melmed S (1994) Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 78:398–403PubMedGoogle Scholar
  49. 49.
    Greenman Y, Melmed S (1994) Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 79:724–729PubMedGoogle Scholar
  50. 50.
    Bancalari RE, Gregory LC, McCabe MJ, Dattani MT (2012) Pituitary gland development: an update. Endocr Dev 23:1–15. CrossRefPubMedGoogle Scholar
  51. 51.
    McCabe MJ, Dattani MT (2014) Genetic aspects of hypothalamic and pituitary gland development. Handb Clin Neurol 124:3–15. CrossRefPubMedGoogle Scholar
  52. 52.
    Olson LE, Tollkuhn J, Scafoglio C, Krones A, Zhang J, Ohgi KA, Wu W, Taketo MM, Kemler R, Grosschedl R, Rose D, Li X, Rosenfeld MG (2006) Homeodomain-mediated beta-catenin-dependent switching events dictate cell-lineage determination. Cell 125:593–605CrossRefPubMedGoogle Scholar
  53. 53.
    Gaston-Massuet C, Andoniadou CL, Signore M, Sajedi E, Bird S, Turner JM, Martinez-Barbera JP (2008) Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development. Dev Biol 324:322–333CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Alatzoglou KS, Andoniadou CL, Kelberman D, Buchanan CR, Crolla J, Arriazu MC, Roubicek M, Moncet D, Martinez-Barbera JP, Dattani MT (2011) SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours. Hum Mutat 32:1376–1380. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Buslei R, Nolde M, Hofmann B, Meissner S, Eyupoglu IY, Siebzehnrubl F, Hahnen E, Kreutzer J, Fahlbusch R (2005) Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathol 109:589–597CrossRefPubMedGoogle Scholar
  56. 56.
    Elston MS, Gill AJ, Conaglen JV, Clarkson A, Shaw JM, Law AJ, Cook RJ, Little NS, Clifton-Bligh RJ, Robinson BG, McDonald KL (2008) Wnt pathway inhibitors are strongly down-regulated in pituitary tumors. Endocrinology 149:1235–1242CrossRefPubMedGoogle Scholar
  57. 57.
    Gonzalez-Meljem JM, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, Kaushal G, Virasami A, Panousopoulos L, Mousavy-Gharavy N, Guerrero S, Rashid A, Jani M, Goding N, Jacques CR, Adams TS, Gil DJ, Andoniadou J, Martinez-Barbera CL, Pedro Martinez-Barbera J (2017) Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat Commun 8:1819. CrossRefGoogle Scholar
  58. 58.
    Arzt E, Chesnokova V, Stalla GK, Melmed S (2009) Pituitary adenoma growth: a model for cellular senescence and cytokine action. Cell Cycle 8:677–678CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Carreno G, Gonzalez-Meljem JM, Haston S, Martinez-Barbera JP (2016) Stem cells and their role in pituitary tumorigenesis. Mol Cell Endocrinol 445:27–34. CrossRefPubMedGoogle Scholar
  60. 60.
    Manoranjan B, Mahendram S, Almenawer SA, Venugopal C, McFarlane N, Hallett R, Vijayakumar T, Algird A, Murty NK, Sommer DD, Provias JP, Reddy K, Singh SK (2016) The identification of human pituitary adenoma-initiating cells. Acta Neuropathol Commun 4:125CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Donangelo I, Ren SG, Eigler T, Svendsen C, Melmed S (2014) Sca1+ murine pituitary adenoma cells show tumor-growth advantage. Endocr Relat Cancer 21:203–216. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Martinez-Barbera JP, Andoniadou CL (2016) Concise review: paracrine role of stem cells in pituitary tumors: a focus on adamantinomatous craniopharyngioma. Stem Cells 34:268–276. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Peverelli E, Giardino E, Treppiedi D, Meregalli M, Belicchi M, Vaira V, Corbetta S, Verdelli C, Verrua E, Serban AL, Locatelli M, Carrabba G, Gaudenzi G, Malchiodi E, Cassinelli L, Lania AG, Ferrero S, Bosari S, Vitale G, Torrente Y, Spada A, Mantovani G (2017) Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem-like cells isolated from nonfunctioning pituitary tumors. Int J Cancer 140:1870–1880. CrossRefPubMedGoogle Scholar
  64. 64.
    Orciani M, Caffarini M, Sorgentoni G, Ricciuti RA, Arnaldi G, Di Primio R (2017) Effects of somatostatin and its analogues on progenitor mesenchymal cells isolated from human pituitary adenomas. Pituitary 20(2):251–260. CrossRefPubMedGoogle Scholar
  65. 65.
    Caffarini M, Orciani M, Trementino L, Di Primio R, Arnaldi G (2017) Pituitary adenomas, stem cells, and cancer stem cells: what’s new? J Endocrinol Invest. PubMedGoogle Scholar
  66. 66.
    Lu R, Gao H, Wang H, Cao L, Bai J, Zhang Y (2013) Overexpression of the Notch3 receptor and its ligand Jagged1 in human clinically non-functioning pituitary adenomas. Oncol Lett 5:845–851CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Miao Z, Miao Y, Lin Y, Lu X (2012) Overexpression of the Notch3 receptor in non-functioning pituitary tumours. J Clin Neurosci 19:107–110CrossRefPubMedGoogle Scholar
  68. 68.
    Perrone S, Zubeldia-Brenner L, Gazza E, Demarchi G, Baccarini L, Baricalla A, Mertens F, Luque G, Vankelecom H, Berner S, Becu-Villalobos D, Cristina C (2017) Notch system is differentially expressed and activated in pituitary adenomas of distinct histotype, tumor cell lines and normal pituitaries. Oncotarget 8:57072–57088. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Haston S, Manshaei S, Martinez-Barbera JP (2018) Stem/progenitor cells in pituitary organ homeostasis and tumourigenesis. J Endocrinol 236:R1-R13. CrossRefPubMedGoogle Scholar
  70. 70.
    Cristina C, Luque GM, Demarchi G, Lopez Vicchi F, Zubeldia-Brenner L, Perez Millan MI, Perrone S, Ornstein AM, Lacau-Mengido IM, Berner SI, Becu-Villalobos D (2014) Angiogenesis in pituitary adenomas: human studies and new mutant mouse models. Int J Endocrinol. PubMedPubMedCentralGoogle Scholar
  71. 71.
    McCabe CJ, Boelaert K, Tannahill LA, Heaney AP, Stratford AL, Khaira JS, Hussain S, Sheppard MC, Franklyn JA, Gittoes NJ (2002) Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. J Clin Endocrinol Metab 87:4238–4244CrossRefPubMedGoogle Scholar
  72. 72.
    Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M, Pontecorvi A, De Marinis L, Maira G, degli Uberti EC (2007) Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer 14:91–102CrossRefPubMedGoogle Scholar
  73. 73.
    Gagliano T, Filieri C, Minoia M, Buratto M, Tagliati F, Ambrosio MR, Lapparelli M, Zoli M, Frank G, degli Uberti EC, Zatelli MC (2013) Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Pituitary 16:91–100. CrossRefPubMedGoogle Scholar
  74. 74.
    Trovato M, Torre ML, Ragonese M, Simone A, Scarfì R, Barresi V, Giuffrè G, Benvenga S, Angileri FF, Tuccari G, Trimarchi F, Ruggeri RM, Cannavò S (2013) HGF/c-met system targeting PI3K/AKT and STAT3/phosphorylated-STAT3 pathways in pituitary adenomas: an immunohistochemical characterization in view of targeted therapies. Endocrine 44:735–743. CrossRefPubMedGoogle Scholar
  75. 75.
    Maniotis A, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155:739–752CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Di Michele J, Rotondo F, Kovacs K, Syro LV, Yousef GM, Cusimano MD, Di Ieva A (2017) Vasculogenic mimicry in clinically non-functioning pituitary adenomas: a histologic study. Pathol Oncol Res 23:803–809. CrossRefPubMedGoogle Scholar
  77. 77.
    Yao S, Zhu Y, Chen L (2013) Advances in targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov 12:130–146CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800CrossRefPubMedGoogle Scholar
  79. 79.
    Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Mei Y, Bi WL, Greenwald NF, Du Z, Agar NY, Kaiser UB, Woodmansee WW, Reardon DA, Freeman GJ, Fecci PE, Laws ER Jr, Santagata S, Dunn GP, Dunn IF (2016) Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget 7:76565–76576. PubMedPubMedCentralGoogle Scholar
  81. 81.
    Brilli L, Danielli R, Ciuoli C, Calabrò L, Di Giacomo AM, Cerase A, Paffetti P, Sestini F, Porcelli B, Maio M, Pacini F (2017) Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab. Endocrine 58:535–541. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Section of Endocrinology and Internal Medicine, Department of Medical SciencesUniversity of FerraraFerraraItaly

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