Phenotypic and functional characteristics of pituitary adenoma stem cells

Table 1 Summary of the studies included in the systematic literature review

Ref.	Cell lines	Identification marker	Pathway	Molecular agent	Effects on tumor behavior
Yokoyama et al[37], 2007	MtT/S and MtT/E cells derived from rat prolactinoma	NA	GH-IGF1	IGF-1	Paracrine IGF-1 from GH+ cells promotes progenitor proliferation
Xu et al[23], 2009	Human PA samples	Nestin, CD133	NA	NA	Tumorigenesis, self-renewal, chemoresistance
Yunoue et al[24], 2011	Human PA samples	CD133	NA	CD133, CD34, VEGFR2, nestin	CD133+ cells are implicated as endothelial progenitors in PAs
Ma et al[38], 2013	Human PA samples	NA	Nucleostemin-p53; ASPP2-p53	Nucleostemin and ASPP2	Tumorigenesis, tumor progression, self-renewal
Zhao et al[39], 2015	Human PA samples	Nestin, CD133	NA	NA	Sphere-formation, self-renewal, chemoresistance
Mathioudakis et al[40], 2015	Human PA samples	GFRa2	GFRa2-RET	GFRa2	Tumorigenesis
Lampichler et al[30], 2015	Human PA samples; mouse pituitary adenoma cell line AtT-20	SOX2, TP53, MKI67, SOD1	Hh signaling	GLI1	Tumorigenesis
Manoranjan et al[31], 2016	Human PA samples	CD15, CD133, SOX2	NA	Pax7, SOX2	Tumorigenesis, self-renewal, tumor progression
Peverelli et al[32], 2017	Human PA samples	SOX2, POU5F1/OCT4, KLF4 and EGR1	DRD2 and SSTR2 associated inhibitory pathways	DA, SSA	Sphere-formation, tumor proliferation and invasion of CS
Mezzomo et al[41], 2017	Human PA samples	Underexpressed TP63 isoforms (TAp63, ∆Np63)	NA	NA	Tumorigenesis, tumor progression
Orciani et al[42], 2017	Human PA samples	OCT4, NANOG, KLF4, SOX2, TGFbRII, E-CADHERIN	EMT, Somatostatin signaling	SST, SSA	EMT
Gao et al[43], 2017	MMQ cells (rat), human PA samples	CD133, Nestin, OCT4, SOX2, D2R	D2R	DA	DA resistance
Würth et al[27], 2017	Human PA samples	SOX2, Oct4, CD133, Nestin, NANOG.	SSTR2, SSTR5, D2R	Somatostatin/dopamine chimera BIM-23A760	Tumorigenesis, self-renewal, angiogenesis
Horiguchi et al[44], 2018	Rat anterior pituitary CD9+ cells	CD9, SOX2, S100β	BMP signaling	NA	Self-renewal
Tamura et al[45], 2019	Human PA samples	PITX2, SNAIL1	NA	PITX2	Tumor progression, invasion of CS
Tang et al[26], 2019	HP75 cells	SOX2	Wnt/beta-catenin, SHH	SOX2	Tumor proliferation
Zubeldía-Brenner et al[46], 2019	GH3 (rat)	NA	Notch	γ-secretase inhibitor (Notch blockade)	Sphere-formation
Soukup et al[47], 2020	Human PA samples	SOX2	NA	SOX2	NA
Taniguchi-Ponciano et al[48], 2020	Human PA samples	NR5A1, TBX19, POU1F1	NA	NA	Tumorigenesis
Cai et al[49], 2021	MMQ cells (rat)	CD133, Nestin, HCAM, OCT4, SCA1	D2R	CD133	DA resistance
Chen et al[50], 2020	Human PA samples, GH3 (rat), MMQ cells (rat), mouse pituitary adenoma cell line AtT-20	DLK1/MEG3	PI3K/AKT/mTOR	DLK1	Tumorigenesis, self-renewal, tumor progression, angiogenesis
Guido et al[33], 2021	Rat (F344)	GFRa2, SOX2, SOX9, Nestin, CD133, CD44	NA	NA	Self-renewal
Xiao et al[51], 2021	Human PA samples, MMQ cells (rat)	CD133, Nestin, SOX2S	JAK2/STAT5	DA, Pimozine	Tumorigenesis, DA resistance
Nys et al[52], 2022	Human PA samples, Mouse PA samples (DRD2-/-)	SOX2, SOX9, TACSTD, KRT8, KRT18	NF-κB, IFN-γ, JAK/STAT	IL-6	Tumorigenesis
Saksis et al[53], 2023	GH3 (rat), Human PA samples	OCT4, CD133, Nestin, SOX2, CXCR4	NA	NA	Self-renewal, chemoresistance
Yuan et al[54], 2023	Human PA samples	SOX2, OCT4, Nestin, CD133	NA	ANXA2	Tumorigenesis, self-renewal, angiogenesis
Zhang et al[34], 2023	Human PA samples	SOX2, S100β, SOX9, VIM, CLDN4	NA	SREBF1	Tumorigenesis, recurrence
Li et al[55], 2024	Human PA samples, GH3 (rat).	NA	Wnt/beta-catenin	KMT5A	Apoptosis, tumor progression
Jotanovic et al[56], 2024	Human PA samples	NA	NF-κB, WnT/EMT, mTOR	NA	Bone invasion, tumor progression
Øystese et al[29], 2024	Human PA samples	SOX2, SOX9, PROP1	Wnt/beta-catenin, Notch, FGF, SHH, TGF- β/BMP	SOX2, SOX9, PROP1	Self-renewal
Lenders et al[57], 2024	Human PA samples	SF-1, PIT-1, T-PIT, SOX2, Nestin, CD133	NA	NA	Tumorigenesis of WLDL tumors
Peng et al[58], 2024	Human PA samples	Nestin, CD133, SOX2, OCT4	PI3K/Akt, Wnt/beta-catenin, calcium signaling, cAMP signaling, RAS	NA	Tumorigenesis, self-renewal, chemoresistance
Lang et al[59], 2025	Human PA samples	PIT-1, CK8/18	NA	NA	Tumor progression
Chaudhary et al[60], 2025	Human and mouse PA samples	DPPA4, SOX2, OCT4, NANOG	Wnt/beta-catenin, Histone methylation	DPPA4	Tumor progression, cell migration, EMT

NA: Not available; GH-IGF1: Growth hormon-insulin-like growth factor-1; PA: Pituitary adenoma; VEGFR2: Vascular endothelial growth factor receptor 2; ASPP2-p53: Tumor protein P53 binding protein 2; GFRa2: Glial-cell-line-derived neurotrophic factor family receptor alpha 2; GFRa2-RET: Glial-cell-line-derived neurotrophic factor family receptor alpha 2-rearranged during transfection; SOX2: SRY-related HMG-box transcription factor 2; GLI1: Glioma-associated oncogene homolog 1 (Zinc finger protein); MKI67: Marker of proliferation; SOD1: Superoxide dismutase 1; Pax7: Paired box 7; POU5F1: POU domain, class 5, transcription factor 1; OCT4: Octamer-binding transcription factor 4; KLF4: KLF transcription factor 4; EGR1 Early growth response 1:; DRD2: Dopamine agonist receptor subtype 2; SSTR2: Somatostatin receptor 2; RAS: Rat sarcoma; DA: Dopamine agonist; SSA: Somatostatin receptor agonist; CS: Cavernous sinus; TP63: Tumor protein P63; TGFbRII: Transforming growth factor beta receptor 2; D2R: Dopamine receptor D2; SSTR5: Somatostatin receptor 5; PITX2: Paired Like homeodomain 2; SNAIL1: Snail family transcriptional repressor 1; SHH: Sonic hedgehog; NR5A1: Nuclear receptor subfamily 5 group A member 1; TBX19: T-Box transcription factor 19; POU1F1: POU class 1 homeobox 1; HCAM: Homing cell adhesion molecule; SCA1: Stem cell antigen 1; DLK1: Delta like non-canonical Notch ligand 1; MEG3: Maternally expressed 3; PI3K/AKT/mTOR: Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; JAK2/STAT5: Janus kinase 2/signal transducer and activator of transcription 5A; NF-κB: Nuclear factor kappa B; IFN-γ: Interferon gamma; TACSTD: Tumor associated calcium signal transducer 2; KRT8: Keratin 8; VIM: Vimentin; CLDN4: Claudin 4; TGF- β/BMP: Transforming growth factor beta 1/bone morphogenetic protein; SF-1: Splicing factor 1; PIT-1: Pituitary-specific positive transcription factor 1; T-PIT: Pituitary T-box transcription factor TPI; WLDL: Very-low density lipoprotein; DPPA4: Developmental pluripotency associated 4; TMZ: Temozolomide.

Table 2 Pituitary adenoma stem cells: Markers, pathways, models, phenotypes, and translational targets

Domain	Key elements	Representative examples/notes	Translational implications
Markers of stemness	Transcription factors; surface markers	SOX2, OCT4, NANOG; CD133, Nestin	Facilitate the identification of PASC and the prospective categorization of patients based on biomarkers
Experimental models	In vitro; in vivo; ex vivo	Sphere-forming assays, organoids, xenografts	Simulate tumor-propagating cell dynamics and evaluate pathway inhibitors
Signaling pathways	Core developmental cascades	Wnt/beta-catenin, Notch, SHH-GLI, PI3K/AKT/mTOR, JAK/STAT	Facilitate self-renewal, plasticity, invasion, and therapeutic resistance
Associated phenotypes	Cellular functions	Self-renewal, multipotency, epithelial–mesenchymal transition (EMT), drug resistance	Phenotypic characteristics of aggressive PitNETs
Therapeutic targets	Current and emerging strategies	Somatostatin receptor ligands (SRLs), dopamine agonists, temozolomide, PRRT; experimental Notch or Wnt inhibitors	Integrate endocrine regulation with therapies aimed at stemness
Clinical context	Disease entities and therapies	Acromegaly: Oral SST2 agonist paltusotine, oral octreotide capsules; Cushing’s: Osilodrostat, relacorilant; Aggressive PitNETs: TMZ, PRRT, ICIs	Exhibit the expanding translational pipeline and justification for combinatorial approaches

SOX2: SRY-related HMG-box transcription factor 2; OCT4: Octamer-binding transcription factor 4; SHH-GLI: Sonic hedgehog signaling molecule/glioma-associated oncogene homolog 1 (Zinc finger protein); PI3K/AKT/mTOR: Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; EMT: Epithelial–mesenchymal transition; SRLs: Somatostatin receptor ligands; SST2: Somatostatin receptor 2; JAK/STAT: Janus kinase/signal transducer and activator of transcription; PASC: Pituitary adenoma stem cells; PitNET: Pituitary neuroendocrine tumor; SRL: Somatostatin receptor ligand; TMZ: Temozolomide; PRRT: Peptide receptor radionuclide therapy; ICI: Immune checkpoint inhibitor.