{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:05:54Z","timestamp":1780391154580,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babes\u201d University of Medicine and Pharmacy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pituitary neuroendocrine tumors (PitNETs) represent a complex pathology based on numerous incompletely elucidated molecular mechanisms. Beyond tumor cells, analyzing the tumor microenvironment may help identify novel prognostic markers and therapies. A key component of this environment is the folliculo-stellate (FS) cell. We examined FS cells in 77 PitNETs obtained by transsphenoidal surgery, using glial fibrillary acidic protein (GFAP) as an immunohistochemical marker. Immunohistochemistry for anterior pituitary hormones and transcription factors was performed to accurately classify the tumors. Our study included 19 somatotroph, 16 mammosomatotroph, 5 plurihormonal PIT-1 positive, 7 corticotroph, 14 gonadotroph, 11 unusual plurihormonal, and 5 null cell PitNETs. FS cells were observed in 55 of the cases, distributed isolated, in small groups or diffuse networks. A considerable number of tumors immunopositive for more than one hormone (including associations between GH\/PRL, but also unusual combinations like GH\/ACTH) also contained FS cells (p &lt; 0.01), suggesting their involvement in tumor lineages differentiation. In 27 tumors, GFAP-positive cells clustered in highly vascularized areas. Additionally, in 11 of these cases a direct interaction between endothelial cells and FS cells was noted, sustaining their potential role in tumor angiogenesis. Given their complexity, FS cells may be crucial for understanding tumorigenesis mechanisms.<\/jats:p>","DOI":"10.3390\/cells14131019","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T10:45:11Z","timestamp":1751539511000},"page":"1019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An Old New Friend: Folliculo-Stellate Cells in Pituitary Neuroendocrine Tumors"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7623-3042","authenticated-orcid":false,"given":"Valeria-Nicoleta","family":"Nastase","sequence":"first","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Pius Branzeu\u201d County Emergency Hospital, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iulia Florentina","family":"Burcea","sequence":"additional","affiliation":[{"name":"\u201cC. I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"},{"name":"Endocrinology Department, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4568-2714","authenticated-orcid":false,"given":"Roxana Ioana","family":"Dumitriu-Stan","sequence":"additional","affiliation":[{"name":"\u201cC. I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"},{"name":"Endocrinology Department, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0067-8247","authenticated-orcid":false,"given":"Amalia Raluca","family":"Ceausu","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5755-179X","authenticated-orcid":false,"given":"Flavia","family":"Zara","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Municipal Emergency Hospital, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Poiana","sequence":"additional","affiliation":[{"name":"\u201cC. I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"},{"name":"Endocrinology Department, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Raica","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ilie, M.D., Vasiljevic, A., Raverot, G., and Bertolino, P. (2019). The Microenvironment of Pituitary Tumors-Biological and Therapeutic Implications. Cancers, 11.","DOI":"10.3390\/cancers11101605"},{"key":"ref_2","unstructured":"Lloyd, R.V., Osamura, R.Y., Kl\u00f6ppel, G., and Rosai, J. (2017). WHO Classification of Tumours of Endocrine Organs, International Agency for Research on Cancer IARC. [4th ed.]. print."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s10014-018-0314-3","article-title":"The 2017 who classification of pituitary adenoma: Overview and comments","volume":"35","author":"Inoshita","year":"2018","journal-title":"Brain Tumor Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1242\/jcs.116392","article-title":"The tumor microenvironment at a glance","volume":"125","author":"Balkwill","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1679\/aohc.62.205","article-title":"The structure and function of folliculo-stellate cells in the anterior pituitary gland","volume":"62","author":"Inoue","year":"1999","journal-title":"Arch. Histol. Cytol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1076\/apab.110.1.50.911","article-title":"Are folliculo-stellate cells in the anterior pituitary gland supportive cells or organ-specific stem cells?","volume":"110","author":"Inoue","year":"2002","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1177\/1.2.93","article-title":"Electron microscopic studies of the anterior pituitary gland","volume":"1","author":"Rinehart","year":"1953","journal-title":"J. Histochem. Cytochem. Off. J. Histochem. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1007\/BF00307293","article-title":"Le r\u00e9seau des cellules folliculo-stellaires et les follicules de l\u2019ad\u00e9nohypophyse du rat (Pars distalis)","volume":"129","year":"1972","journal-title":"Z. F\u00fcr Zellforsch Und Mikrosk. Anat"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/00005072-198203000-00005","article-title":"The presence of glial fibrillary acidic protein in the human pituitary gland","volume":"41","author":"Velasco","year":"1982","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/j.1365-2826.2008.01716.x","article-title":"An insight to pituitary folliculo-stellate cells","volume":"20","author":"Devnath","year":"2008","journal-title":"J. Neuroendocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/BF00222177","article-title":"Pituitary folliculo-stellate cells immunostained with S-100 protein antiserum in postnatal, castrated and thyroidectomized rats","volume":"231","author":"Shirasawa","year":"1983","journal-title":"Cell Tissue Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1242\/jcs.108.6.2369","article-title":"Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor","volume":"108","author":"Roberts","year":"1995","journal-title":"J. Cell Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000126346","article-title":"Apoptosis in the anterior pituitary gland of the rat: Studies with estrogen and bromocriptine","volume":"57","author":"Drewett","year":"1993","journal-title":"Neuroendocrinology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1507\/endocrj1954.24.301","article-title":"Relationship between the follicular cells and marginal layer cells of the anterior pituitary","volume":"24","author":"Yoshimura","year":"1977","journal-title":"Endocrinol. Jpn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/BF02915456","article-title":"Immunohistochemical study of folliculostellate cells in pituitary lesions","volume":"2","author":"Nishioka","year":"1991","journal-title":"Endocr. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.humpath.2021.05.002","article-title":"Follicular cells in pituitary neuroendocrine tumors","volume":"114","author":"Delfin","year":"2021","journal-title":"Hum. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Trouillas, J., Jaffrain-Rea, M.L., Vasiljevic, A., Raverot, G., Roncaroli, F., and Villa, C.C. (2020). How to classify the pituitary neuroendocrine tumors (PitNET)s in 2020. Cancers, 12.","DOI":"10.3390\/cancers12020514"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"C5","DOI":"10.1530\/ERC-17-0004","article-title":"From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): An International Pituitary Pathology Club proposal","volume":"24","author":"Asa","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1007\/s12020-019-02029-1","article-title":"Mammosomatotroph and mixed somatotroph-lactotroph adenoma in acromegaly: A retrospective study with long-term follow-up","volume":"66","author":"Lv","year":"2019","journal-title":"Endocrine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","article-title":"Overview of the 2022 WHO Classification of Pituitary Tumors","volume":"33","author":"Asa","year":"2022","journal-title":"Endocr Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0344-0338(99)80026-0","article-title":"Folliculo-stellate cells in pituitary adenomas of patients with acromegaly","volume":"195","author":"Voit","year":"1999","journal-title":"Pathol. Res. Pract."},{"key":"ref_22","first-page":"16","article-title":"Development of folliculo-stellate cells in the human pituitary","volume":"119","author":"Coates","year":"1988","journal-title":"Acta Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/BF02921341","article-title":"S-100 protein immunopositivity in human nontumorous hypophyses and pituitary adenomas","volume":"3","author":"Marin","year":"1992","journal-title":"Endocr. Pathol."},{"key":"ref_24","first-page":"338","article-title":"Analysis of S-100 protein positive folliculo-stellate cells in rat pituitary tissues","volume":"133","author":"Lloyd","year":"1988","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s12022-008-9015-5","article-title":"Clusterin expression in non-neoplastic adenohypophyses and pituitary adenomas: Cytoplasmic clusterin localization in adenohypophysis is related to aging","volume":"19","author":"Ekici","year":"2008","journal-title":"Endocr. Pathol."},{"key":"ref_26","first-page":"912","article-title":"Clusterin: A double-edged sword in cancer and neurological disorders","volume":"23","author":"Sultana","year":"2024","journal-title":"EXCLI J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chesnokova, V., Zonis, S., Zhou, C., Ben-Shlomo, A., Wawrowsky, K., Toledano, Y., Tong, Y., Kovacs, K., Scheithauer, B., and Melmed, S. (2011). Lineage-specific restraint of pituitary gonadotroph cell adenoma growth. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017924"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1210\/me.2012-1158","article-title":"Clusterin and FOXL2 act concordantly to regulate pituitary gonadotroph adenoma growth","volume":"26","author":"Chesnokova","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s12022-024-09841-0","article-title":"Multilineage Pituitary Neuroendocrine Tumors Expressing TPIT and SF1: A Clinicopathological Series of Six Tumors","volume":"35","author":"Asa","year":"2024","journal-title":"Endocr. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.5858\/arpa.2023-0543-OA","article-title":"Clinicopathologic Correlates of PIT1 and SF1-Multilineage Pituitary Neuroendocrine Tumors and the Diagnostic Utility of NKX2.2 Immunohistochemistry in Pituitary Pathology","volume":"149","author":"Karatay","year":"2025","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ccell.2019.11.002","article-title":"Pangenomic Classification of Pituitary Neuroendocrine Tumors","volume":"37","author":"Neou","year":"2020","journal-title":"Cancer Cell."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"810","DOI":"10.3171\/2022.12.JNS222118","article-title":"Pituitary adenomas with multiple cell lineage combinations: Clinicopathological features and short-term prognosis","volume":"139","author":"Tang","year":"2023","journal-title":"J. Neurosurg."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Roca, E., Mattogno, P.P., Porcelli, T., Poliani, L., Belotti, F., Schreiber, A., Maffezzoni, F., Fontanella, M.M., and Doglietto, F. (2018). Plurihormonal ACTH-GH Pituitary Adenoma: Case Report and Systematic Literature Review. World Neurosurg., 114.","DOI":"10.1016\/j.wneu.2018.02.120"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s12022-020-09634-1","article-title":"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","volume":"31","author":"Soukup","year":"2020","journal-title":"Endocr. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.yexcr.2003.09.018","article-title":"Differentiation of skeletal muscle from pituitary folliculo-stellate cells and endocrine progenitor cells","volume":"292","author":"Mogi","year":"2004","journal-title":"Exp. Cell Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e13053","DOI":"10.1111\/jne.13053","article-title":"Renewing an old interest: Pituitary folliculostellate cells","volume":"33","author":"Mollard","year":"2021","journal-title":"J. Neuroendocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mce.2016.10.005","article-title":"Stem cells and their role in pituitary tumorigenesis","volume":"445","author":"Carreno","year":"2017","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"W\u00fcrth, R., Thellung, S., Corsaro, A., Barbieri, F., and Florio, T. (2020). Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00054"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s11102-024-01385-0","article-title":"Pituitary tumours without distinct lineage differentiation express stem cell marker SOX2","volume":"27","author":"Lenders","year":"2024","journal-title":"Pituitary"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/BF02914990","article-title":"Pituitary Folliculo-Stellate-Like Cells Stimulate Somatotroic Pituitary Tumor Growth in Nude Mice","volume":"6","author":"Koyama","year":"1995","journal-title":"Endocr. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/01913120290104476","article-title":"Folliculo-stellate cells of the human pituitary: A type of adult stem cell?","volume":"26","author":"Horvath","year":"2002","journal-title":"Ultrastruct. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/PL00008809","article-title":"Expression of Ptx1 in the adult rat pituitary glands and pituitary cell lines: Hormone-secreting cells and folliculo-stellate cells","volume":"298","author":"Kurotani","year":"1999","journal-title":"Cell Tissue Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Horiguchi, K., Fujiwara, K., Yoshida, S., Nakakura, T., Arae, K., Tsukada, T., Hasegawa, R., Takigami, S., Ohsako, S., and Yashiro, T. (2018). Isolation and characterisation of CD9-positive pituitary adult stem\/progenitor cells in rats. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-23923-0"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s00418-020-01862-0","article-title":"CX3CL1\/CX3CR1-signalling in the CD9\/S100\u03b2\/SOX2-positive adult pituitary stem\/progenitor cells modulates differentiation into endothelial cells","volume":"153","author":"Horiguchi","year":"2020","journal-title":"Histochem. Cell Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/1019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:04:10Z","timestamp":1760033050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/1019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":44,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["cells14131019"],"URL":"https:\/\/doi.org\/10.3390\/cells14131019","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,3]]}}}