Phenotypic and functional characteristics of pituitary adenoma stem cells

BACKGROUND Pituitary neuroendocrine tumors (PitNETs), formerly referred to as pituitary adenomas, are prevalent intracranial neoplasms that, although often benign histologically, can demonstrate invasive growth, therapeutic resistance, and recurrence. Emerging evidence supports the presence of a subpopulation of tumor-initiating cells with stem-like properties - pituitary adenoma stem cells (PASCs) - that may drive these aggressive features. This systematic review aims to critically examine the evidence on PASCs, their phenotypic and functional characteristics, and their role in PitNET pathophysiology. AIM To study the molecular markers, signaling pathways, research models, and phenotypic traits of PASCs, and to assess their potential significance for future translational and clinical applications. METHODS A comprehensive literature search was conducted in PubMed, Scopus, and Ovid MEDLINE in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-four studies were included based on predefined eligibility criteria. Data were extracted regarding PASC isolation methods (e.g., neurosphere formation, side population sorting), marker expression [e.g., SRY-related HMG-box transcription factor (SOX) 2, octamer-binding transcription factor 4, CD133, Nestin], pathway involvement (e.g., Wnt/beta-catenin, Notch, Sonic hedgehog), and functional behaviors such as self-renewal, differentiation, tumorigenicity, and therapy resistance. RESULTS Following duplicate removal, 315 unique articles were screened, with 47 full texts assessed for eligibility. Ultimately, 34 studies published between 2007 and 2025 met the inclusion criteria. The majority utilized human PitNET samples (83%), with a subset employing rat-derived cell lines (28%) or murine models (15%). PASCs were identified and characterized using various in vitro and in vivo approaches. Commonly reported stemness markers included SOX2 (59%), CD133 (38%), Nestin (35%), and octamer-binding transcription factor 4 (26%), with others such as SOX9, paired-like homeobox 1, and C-X-C chemokine receptor type 4 also frequently cited. Wnt/beta-catenin (18%) and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (9%) signaling pathways were most implicated, followed by Notch, Sonic hedgehog, and janus kinase/signal transducer and activator of transcription cascades. Functional assays revealed consistent findings of tumor initiation (44%), self-renewal (35%), and tumor progression or invasion (35%). Notably, a minority of studies explored therapeutic interventions targeting PASCs, including gamma-secretase inhibitors and possible novel combinations of molecular agents. CONCLUSION The accumulating evidence on PASCs highlights their pivotal role in PitNET tumorigenesis, progression, and therapy resistance. Their molecular and functional overlap with normal pituitary stem cells underscores the need for further lineage-tracing and in vivo validation.