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.
Department of Imaging and Pathology, UZ Leuven (University Hospitals Leuven), Leuven, Belgium.
Endocr Relat Cancer. 2022 Jun 17;29(7):427-450. doi: 10.1530/ERC-21-0374.
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.
垂体肿瘤的发生非常普遍，会导致严重的内分泌紊乱。但对于这种疾病中局部干细胞的行为，人们几乎一无所知。在这里，我们使用转录组学、免疫表型和类器官方法探索了小鼠和人类垂体肿瘤中的干细胞生物学。在多巴胺受体 D2 敲除小鼠的生长催乳素腺瘤的垂体中，干细胞群在增殖活性和独特的细胞因子/趋化因子表型方面显示出激活状态。源自肿瘤腺体干细胞的类器官再现了这些干细胞激活特性的方面。上调的细胞因子，特别是白细胞介素 6，刺激了干细胞源性类器官的发育和生长过程。在人类垂体肿瘤中，表达干细胞标志物（特别是 SOX2 和 SOX9）的细胞存在于多种临床肿瘤类型中，也表现出明显的增殖状态。类器官能够有效地从人类肿瘤样本中发展而来，显示出干细胞表型和肿瘤特异性表达特征。转录组分析显示，细胞因子途径在类器官发育和传代过程中逐渐减弱，但它们的重新激活并不能证明能够挽救早期类器官的扩张和传代能力的停滞。总之，我们的研究揭示并强调了肿瘤发生腺体和肿瘤中垂体驻留干细胞的激活表型。我们的发现为定义局部干细胞在垂体肿瘤发病机制中的功能地位铺平了道路，目前对此知之甚少。更深入的了解可以导致更有效和有针对性的临床管理，目前仍不理想。
