Exploring stem cell biology in pituitary tumors and derived organoids

in Endocrine-Related Cancer
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  • 1 Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), Leuven, Belgium
  • | 2 Department of Imaging and Pathology, UZ Leuven (University Hospitals Leuven), Leuven, Belgium
  • | 3 Department of Anatomy and Structural Science, Yamagata University Faculty of Medicine, Yamagata, Japan
  • | 4 Department of Endocrinology, UZ Leuven (University Hospitals Leuven), Leuven, Belgium
  • | 5 Department of Neurosurgery, UZ Leuven (University Hospitals Leuven), Leuven, Belgium

Correspondence should be addressed to H Vankelecom: hugo.vankelecom@kuleuven.be

*(Y-L Lee and H Roose contributed equally)

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Pituitary tumorigenesis is highly prevalent and causes major endocrine disorders. Hardly anything is known on the behavior of the local stem cells in this pathology. Here, we explored the stem cells’ biology in mouse and human pituitary tumors using transcriptomic, immunophenotyping and organoid approaches. In the prolactinoma-growing pituitary of dopamine receptor D2 knock-out mice, the stem cell population displays an activated state in terms of proliferative activity and distinct cytokine/chemokine phenotype. Organoids derived from the tumorous glands’ stem cells recapitulated these aspects of the stem cells’ activation nature. Upregulated cytokines, in particular interleukin-6, stimulated the stem cell-derived organoid development and growth process. In human pituitary tumors, cells typified by expression of stemness markers, in particular SOX2 and SOX9, were found present in a wide variety of clinical tumor types, also showing a pronounced proliferative status. Organoids efficiently developed from human tumor samples, displaying a stemness phenotype as well as tumor-specific expression fingerprints. Transcriptomic analysis revealed fading of cytokine pathways at organoid development and passaging, but their reactivation did not prove capable of rescuing early organoid expansion and passageability arrest. Taken together, our study revealed and underscored an activated phenotype of the pituitary-resident stem cells in tumorigenic glands and tumors. Our findings pave the way to defining the functional position of the local stem cells in pituitary tumor pathogenesis, at present barely known. Deeper insight can lead to more efficient and targeted clinical management, currently still not satisfactorily.

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  • Andoniadou CL, Signore M, Sajedi E, Gaston-Massuet C, Kelberman D, Burns AJ, Itasaki N, Dattani M & Martinez-Barnera JP 2007 Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development 134 14991508. (https://doi.org/10.1242/dev.02829)

    • Search Google Scholar
    • Export Citation
  • Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M, Gaston-Massuet C, Mollard P, Jacques TS & Le Tissier P et al.2013 Sox2+ stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell 13 433445. (https://doi.org/10.1016/j.stem.2013.07.004)

    • Search Google Scholar
    • Export Citation
  • Asa SL, Kelly MA, Grandy DK & Low MJ 1999 Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. Endocrinology 140 53485355. (https://doi.org/10.1210/endo.140.11.7118)

    • Search Google Scholar
    • Export Citation
  • Barbieri F, Bajetto A, Stumm R, Pattarozzi A, Porcile C, Zona G, Dorcaratto A, Ravetti JL, Minuto F & Spaziante R et al.2008 Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas. Clinical Cancer Research 14 50225032. (https://doi.org/10.1158/1078-0432.CCR-07-4717)

    • Search Google Scholar
    • Export Citation
  • Bi WL, Horowitz P, Greenwald NF, Abedalthagafi M, Agarwalla PK, Gibson WJ, Mei Y, Schumacher SE, Ben-David U & Chevalier A et al.2017 Landscape of genomic alterations in pituitary adenomas. Clinical Cancer Research 23 18411851. (https://doi.org/10.1158/1078-0432.CCR-16-0790)

    • Search Google Scholar
    • Export Citation
  • Boj SF, Hwang C-I, Baker LA, Chio IIC, Engle DD, Corbo V, Jager M, Ponz-sarvise M, Tiriac H & Spector MS et al.2015 Organoid model of human and mouse pancreatic ductal adenocarcinoma. Cell 160 324338. (https://doi.org/10.1016/j.cell.2014.12.021.Organoid)

    • Search Google Scholar
    • Export Citation
  • Boretto M, Cox B, Noben M, Hendriks N, Fassbender A, Roose H, Amant F, Timmerman D, Tomassetti C & Vanhie A et al.2017 Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development 144 17751786. (https://doi.org/10.1242/dev.148478)

    • Search Google Scholar
    • Export Citation
  • Boretto M, Maenhoudt N, Luo X, Hennes A, Boeckx B, Bui B, Heremans R, Perneel L, Kobayashi H & Van Zundert I et al.2019 Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nature Cell Biology 21 10411051. (https://doi.org/10.1038/s41556-019-0360-z)

    • Search Google Scholar
    • Export Citation
  • Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR, Allen GE, Arnes-Benito R, Sidorova O & Gaspersz MP et al.2017 Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nature Medicine 23 14241435. (https://doi.org/10.1038/nm.4438)

    • Search Google Scholar
    • Export Citation
  • Cano DA, Soto-moreno A & Leal-cerro A 2014 Genetically engineered mouse models of pituitary tumors. Frontiers in Oncology 4 203. (https://doi.org/10.3389/fonc.2014.00203)

    • Search Google Scholar
    • Export Citation
  • Carretero J, Martin-Clavijo A, Vazquez G, Somalo J, Rubio M, Sanchez F, Hernandez E, Montero MC, Torres JL & Vazquez R 1999 Effects of in vitro immunosuppression of interleukin-6 on the proliferation of rat hypophyseal cells. European Journal of Anatomy 3 137143.

    • Search Google Scholar
    • Export Citation
  • Chen J, Hersmus N, Van Duppen V, Caesens P, Denef C & Vankelecom H 2005 The adult pituitary contains a cell population displaying stem/progenitor cell and early-embryonic characteristics. Endocrinology 146 39853998. (https://doi.org/10.1210/en.2005-0185)

    • Search Google Scholar
    • Export Citation
  • Chen J, Crabbe A, Van Duppen V & Vankelecom H 2006 The Notch signaling system is present in the postnatal pituitary: marked expression and regulatory activity in the newly discovered side population. Molecular Endocrinology 20 32933307. (https://doi.org/10.1210/me.2006-0293)

    • Search Google Scholar
    • Export Citation
  • Chen J, Gremeaux L, Fu Q, Liekens D, Van Laere S & Vankelecom H 2009 Pituitary progenitor cells tracked down by side population dissection. Stem Cells 27 11821195. (https://doi.org/10.1002/stem.51)

    • Search Google Scholar
    • Export Citation
  • Chenlo M, Rodriguez-Gomez IA, Serramito R, Garcia-Rendueles AR, Villar-Taibo R, Fernandez-Rodriguez E, Perez-Romero S, Suarez-Fariña M, Garcia-Allut A & Cabezas-Agricola JM et al.2019 Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly. EBiomedicine 43 537552. (https://doi.org/10.1016/j.ebiom.2019.04.007)

    • Search Google Scholar
    • Export Citation
  • Clevers H 2011 The cancer stem cell: premises, promises and challenges. Nature Medicine 17 313319. (https://doi.org/10.1038/nm.2304)

  • Cox B, Laporte E, Vennekens A, Kobayashi H, Nys C, Van Zundert I, Ujii H, Drubbel AV, Beck B & Roose H et al.2019 Organoids from pituitary as a novel research model toward pituitary stem cell exploration. Journal of Endocrinology 240 287308. (https://doi.org/10.1530/JOE-18-0462)

    • Search Google Scholar
    • Export Citation
  • Cristina C, Rubinstein M, Low MJ & Becu-Villalobos D 2006 Dopaminergic D2 receptor knockout mouse: an animal model of prolactinoma. Frontiers of Hormone Research 35 5063. (https://doi.org/10.1159/000094308)

    • Search Google Scholar
    • Export Citation
  • Cui Y, Li C, Jiang Z, Zhang S, Li Q, Liu X, Zhou Y, Li R, Wei L & Li L et al.2021 Single-cell transcriptome and genome analyses of pituitary neuroendocrine tumors. Neuro-Oncology 23 18591871. (https://doi.org/10.1093/neuonc/noab102)

    • Search Google Scholar
    • Export Citation
  • Daly AF, Tichomirowa MA & Beckers A 2009 The epidemiology and genetics of pituitary adenomas. Best Practice and Research: Clinical Endocrinology and Metabolism 23 543554. (https://doi.org/10.1016/j.beem.2009.05.008)

    • Search Google Scholar
    • Export Citation
  • Dekkers JF, Alieva M, Wellens LM, Ariese HCR, Jamieson PR, Vonk AM, Amatngalim GD, Hu H, Oost KC & Snippert HJG et al.2019 High-resolution 3D imaging of fixed and cleared organoids. Nature Protocols 14 17561771. (https://doi.org/10.1038/s41596-019-0160-8)

    • Search Google Scholar
    • Export Citation
  • Diaz-Rodriguez E, Garcia-Rendueles AR, Ibáñez-Costa A, Gutierrez-Pascual E, Garcia-Lavandeira M, Leal A, Japon MA, Soto A, Venegas E & Tinahones FJ et al.2014 Somatotropinomas, but not nonfunctioning pituitary adenomas, maintain a functional apoptotic RET/Pit1/ARF/p53 pathway that is blocked by excess GDNF. Endocrinology 155 43294340. (https://doi.org/10.1210/en.2014-1034)

    • Search Google Scholar
    • Export Citation
  • Ellis P, Fagan BM, Magness ST, Hutton S, Taranova O, Hayashi S, McMahon A, Rao M & Pevny L 2004 SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Developmental Neuroscience 26 148165. (https://doi.org/10.1159/000082134)

    • Search Google Scholar
    • Export Citation
  • Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML & McCutcheon IE 2004 The prevalence of pituitary adenomas: a systematic review. Cancer 101 613619. (https://doi.org/10.1002/cncr.20412)

    • Search Google Scholar
    • Export Citation
  • Fatemi N, Dusick JR, Mattozo C, McArthur DL, Cohan P, Boscardin J, Wang C, Swerdloff RS & Kelly DF 2008 Pituitary hormonal loss and recovery after transsphenoidal adenoma removal. Neurosurgery 63 70971 8; discussion 718. (https://doi.org/10.1227/01.NEU.0000325725.77132.90)

    • Search Google Scholar
    • Export Citation
  • Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R & Robinson ICAF 2008 SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. PNAS 105 29072912. (https://doi.org/10.1073/pnas.0707886105)

    • Search Google Scholar
    • Export Citation
  • 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. Clinical Endocrinology 65 536543. (https://doi.org/10.1111/j.1365-2265.2006.02630.x)

    • Search Google Scholar
    • Export Citation
  • Fujii M & Sato T 2021 Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nature Materials 20 156169. (https://doi.org/10.1038/s41563-020-0754-0)

    • Search Google Scholar
    • Export Citation
  • Fusco A, Zatelli MC, Bianchi A, Cimino V, Tilaro L, Veltri F, Angelini F, Lauriola L, Vellone V & Doglietto F et al.2008 Prognostic significance of the Ki67 labeling index in growth hormone-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 93 27462750. (https://doi.org/10.1210/jc.2008-0126)

    • Search Google Scholar
    • Export Citation
  • Garcia-Lavandeira M, Quereda V, Flores I, Saez C, Diaz-rodriguez E, Japon MA, Ryan AK, Blasco MA, Dieguez C & Malumbres M et al.2009 A GRFa2/Prop1/stem (GPS) cell niche in the pituitary. PLoS ONE 4 e4815. (https://doi.org/10.1371/journal.pone.0004815)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-Meljem JM, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, Kaushal G, Virasami A, Panousopoulos L & Neda Mousavy-Gharavy S et al.2017 Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nature Communications 8 114. (https://doi.org/10.1038/s41467-017-01992-5)

    • Search Google Scholar
    • Export Citation
  • Hansen TM, Batra S, Lim M, Gallia GL, Burger PC, Salvatori R, Wand G, Quinones-Hinojosa A, Kleinberg L & Redmond KJ 2014 Invasive adenoma and pituitary carcinoma: a SEER database analysis. Neurosurgical Review 37 27928 5; discussion 285. (https://doi.org/10.1007/s10143-014-0525-y)

    • Search Google Scholar
    • Export Citation
  • Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben-Jonathan N & Grandy DK et al.1997 Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19 103113. (https://doi.org/10.1016/S0896-6273(0080351-7)

    • Search Google Scholar
    • Export Citation
  • Kim JM, Lee YH, Ku CR & Lee EJ 2011 The cyclic pentapeptide d-arg3FC131, a CXCR4 antagonist, induces apoptosis of somatotrope tumor and inhibits tumor growth in nude mice. Endocrinology 152 536544. (https://doi.org/10.1210/en.2010-0642)

    • Search Google Scholar
    • Export Citation
  • Kippin TE, Martens DJ & Van Der Kooy D 2005 p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes and Development 19 756767. (https://doi.org/10.1101/gad.1272305)

    • Search Google Scholar
    • Export Citation
  • Kishi S, Abe H, Akiyama H, Tominaga T, Murakami T, Mima A, Nagai K, Kishi F, Matsuura M & Matsubara T et al.2011 SOX9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy. Journal of Biological Chemistry 286 3216232169. (https://doi.org/10.1074/jbc.M111.244541)

    • Search Google Scholar
    • Export Citation
  • Laporte E, Nys C & Vankelecom H 2022 Development of organoids from mouse pituitary as in vitro model to explore pituitary stem cell biology. Journal of Visualized Experiments 180 e63431. (https://doi.org/10.3791/63431)

    • Search Google Scholar
    • Export Citation
  • López de Andrés J, Griñán-Lisón C, Jiménez G & Marchal JA 2020 Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. Journal of Hematology and Oncology 13 136. (https://doi.org/10.1186/s13045-020-00966-3)

    • Search Google Scholar
    • Export Citation
  • Love MI, Huber W & Anders S 2014 Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology 15 550. (https://doi.org/10.1186/s13059-014-0550-8)

    • Search Google Scholar
    • Export Citation
  • Manoranjan B, Mahendram S, Almenawer SA, Venugopal C, Mcfarlane N, Hallett R, Vijayakumar T, Algird A, Murty NK & Sommer DD et al.2016 The identification of human pituitary adenoma-initiating cells. Acta Neuropathologica Communications 4 125. (https://doi.org/10.1186/s40478-016-0394-4)

    • Search Google Scholar
    • Export Citation
  • Melmed S 2011 Pathogenesis of pituitary tumors. Nature Reviews: Endocrinology 7 257266. (https://doi.org/10.1038/nrendo.2011.40)

  • Melmed S 2020 Pituitary-tumor endocrinopathies. New England Journal of Medicine 382 937950. (https://doi.org/10.1056/NEJMra1810772)

  • Mertens F, Gremeaux L, Chen J, Fu Q, Willems C, Roose H, Govaere O, Roskams T, Cristina C & Becú-Villalobos D et al.2015 Pituitary tumors contain a side population with tumor stem cell-associated characteristics. Endocrine-Related Cancer 22 481504. (https://doi.org/10.1530/ERC-14-0546)

    • Search Google Scholar
    • Export Citation
  • Mete O & Lopes MB 2017 Overview of the 2017 WHO classification of pituitary tumors. Endocrine Pathology 28 228243. (https://doi.org/10.1007/s12022-017-9498-z)

    • Search Google Scholar
    • Export Citation
  • Peverelli E, Treppiedi D, Giardino E, Vitali E, Lania AG & Mantovani G 2015 Dopamine and somatostatin analogues resistance of pituitary tumors: focus on cytoskeleton involvement. Frontiers in Endocrinology 6 187. (https://doi.org/10.3389/fendo.2015.00187)

    • Search Google Scholar
    • Export Citation
  • Pietzsch T, Saalfeld S, Preibisch S & Tomancak P 2015 BigDataViewer: visualization and processing for large image data sets. Nature Methods 12 481483. (https://doi.org/10.1038/nmeth.3392)

    • Search Google Scholar
    • Export Citation
  • Rizzoti K, Akiyama H & Lovell-badge R 2013 Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand. Cell Stem Cell 13 419432. (https://doi.org/10.1016/j.stem.2013.07.006)

    • Search Google Scholar
    • Export Citation
  • Ronchi CL, Peverelli E, Herterich S, Weigand I, Mantovani G, Schwarzmayr T, Sbiera S, Allolio B, Honegger J & Appenzeller S et al.2016 Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas. European Journal of Endocrinology 174 363372. (https://doi.org/10.1530/EJE-15-1064)

    • Search Google Scholar
    • Export Citation
  • Roose H 2018 The Role of Pituitary Stem Cells in Homeostasis and Tumorigenesis of the Pituitary Gland. PhD Thesis. KU Leuven, Belgium.

  • Rose-John S 2018 Interleukin-6 family cytokines. Cold Spring Harbor Perspectives in Biology 10 117. (https://doi.org/10.1101/cshperspect.a028415)

    • Search Google Scholar
    • Export Citation
  • Sabatino ME, Petiti JP, Del Valle Sosa Ldel V, Pérez PA, Gutiérrez S, Leimgruber C, Latini A, Torres AI & De Paul AL 2015 Evidence of cellular senescence during the development of estrogen-induced pituitary tumors. Endocrine-Related Cancer 22 299317. (https://doi.org/10.1530/ERC-14-0333)

    • Search Google Scholar
    • Export Citation
  • Sapochnik M, Fuertes M & Arzt E 2017a Programmed cell senescence: role of IL-6 in the pituitary. Journal of Molecular Endocrinology 58 R241R253. (https://doi.org/10.1530/JME-17-0026)

    • Search Google Scholar
    • Export Citation
  • Sapochnik M, Haedo MR, Fuertes M, Ajler P, Carrizo G, Cervio A, Sevlever G, Stalla GK & Arzt E 2017b Autocrine IL-6 mediates pituitary tumor senescence. Oncotarget 8 46904702. (https://doi.org/10.18632/oncotarget.13577)

    • Search Google Scholar
    • Export Citation
  • Schindelin J, Arganda-carreras I, Frise E, Kaynig V, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B & Tinevez J et al.2019 Fiji – an open source platform for biological image analysis. Nature Methods 9 115. (https://doi.org/10.1038/nmeth.2019.Fiji)

    • Search Google Scholar
    • Export Citation
  • Schutgens F & Clevers H 2020 Human organoids: tools for understanding biology and treating diseases. Annual Review of Pathology 15 211234. (https://doi.org/10.1146/annurev-pathmechdis-012419-032611)

    • Search Google Scholar
    • Export Citation
  • Shirian FI, Ghorbani M, Khamseh ME, Imani M, Panahi M, Alimohammadi A, Nourbakhsh M, Salimi V & Tavakoli-Yaraki M 2021 Upregulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas. BMC Endocrine Disorders 21 50. (https://doi.org/10.1186/s12902-021-00720-x)

    • Search Google Scholar
    • Export Citation
  • Sierra A, Martín-Suárez S, Valcárcel-Martín R, Pascual-Brazo J, Aelvoet SA, Abiega O, Deudero JJ, Brewster AL, Bernales I & Anderson AE et al.2015 Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell 16 488503. (https://doi.org/10.1016/j.stem.2015.04.003)

    • Search Google Scholar
    • Export Citation
  • Soukup J, Česák T, Hornychová H, Michalová K, Michnová Ľ, Netuka D, Čáp J & Gabalec F 2020 Stem cell transcription factor sox2 is expressed in a subset of folliculo-stellate cells of growth hormone-producing pituitary neuroendocrine tumours and its expression shows no association with tumour size or IGF1 levels: a clinicopathological study of 109 cases. Endocrine Pathology 31 337347. (https://doi.org/10.1007/s12022-020-09634-1)

    • Search Google Scholar
    • Export Citation
  • Spoletini M, Taurone S, Tombolini M, Minni A, Altissimi G, Wierzbicki V, Giangaspero F, Parnigotto PP, Artico M & Bardella L et al.2017 Trophic and neurotrophic factors in human pituitary adenomas (Review). International Journal of Oncology 51 10141024. (https://doi.org/10.3892/ijo.2017.4120)

    • Search Google Scholar
    • Export Citation
  • Stark GR, Cheon H & Wang Y 2018 Responses to cytokines and interferons that depend upon JAKs and STATs. Cold Spring Harbor Perspectives in Biology 10 116. (https://doi.org/10.1101/cshperspect.a028555)

    • Search Google Scholar
    • Export Citation
  • Trouillas J, Jaffrain-Rea ML, Vasiljevic A, Dekkers O, Popovic V, Wierinckx A, McCormack A, Petersenn S, Burman P & Raverot G et al.2020 Are aggressive pituitary tumors and carcinomas two sides of the same coin? Pathologists reply to clinician’s questions. Reviews in Endocrine and Metabolic Disorders 21 243251. (https://doi.org/10.1007/s11154-020-09562-9)

    • Search Google Scholar
    • Export Citation
  • Van De Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, Van Houdt W, Van Gorp J, Taylor-Weiner A & Kester L et al.2015 Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161 933945. (https://doi.org/10.1016/j.cell.2015.03.053)

    • Search Google Scholar
    • Export Citation
  • Van der Klaauw AA, Kars M, Biermasz NR, Roelfsema F, Dekkers OM, Corssmit EP, Van Aken MO, Havekes B, Pereira AM & Pijl H et al.2008 Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas. Clinical Endocrinology 69 775784. (https://doi.org/10.1111/j.1365-2265.2008.03288.x)

    • Search Google Scholar
    • Export Citation
  • Vankelecom H & Roose H 2017 The stem cell connection of pituitary tumors. Frontiers in Endocrinology 8 339. (https://doi.org/10.3389/fendo.2017.00339)

    • Search Google Scholar
    • Export Citation
  • Vennekens A, Laporte E, Hermans F, Cox B, Modave E, Janiszewski A, Nys C, Kobayashi H, Malengier-Devlies B & Chappell J et al.2021 Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland. PNAS 118 111. (https://doi.org/10.1073/pnas.2100052118)

    • Search Google Scholar
    • Export Citation
  • Wu JL, Qiao JY & Duan QH 2016 Significance of TNF-α and IL-6 expression in invasive pituitary adenomas. Genetics and Molecular Research 15 19. (https://doi.org/10.4238/gmr.15017502)

    • Search Google Scholar
    • Export Citation
  • Würth R, Barbieri F, Pattarozzi A, Gaudenzi G, Gatto F, Fiaschi P, Ravetti JL, Zona G, Daga A & Persani L et al.2017 Phenotypical and pharmacological characterization of stem-like cells in human pituitary adenomas. Molecular Neurobiology 54 48794895. (https://doi.org/10.1007/s12035-016-0025-x)

    • Search Google Scholar
    • Export Citation
  • Zhang D, Hugo W, Redublo P, Miao H, Bergsneider M, Wang MB, Kim W, Yong WH & Heaney AP 2021 A human ACTH-secreting corticotroph tumoroid model. Novel human ACTH-secreting tumor cell in vitro model. EBiomedicine 66 103294. (https://doi.org/10.1016/j.ebiom.2021.103294)

    • Search Google Scholar
    • Export Citation
  • Zheng R, Chen G, Li X, Wei X, Liu C & Derwahl M 2019 Effect of IL-6 on proliferation of human thyroid anaplastic cancer stem cells. International Journal of Clinical and Experimental Pathology 12 39924001.

    • Search Google Scholar
    • Export Citation