Abstract
Classified as benign central nervous system (CNS) tumors, pituitary adenomas account for 10% of diagnosed intracranial neoplasms. Although surgery is often curative, patients with invasive macroadenomas continue to experience significant morbidity and are prone to tumor recurrence. Given the identification of human brain tumor-initiating cells (TICs) that initiate and maintain tumor growth while promoting disease progression and relapse in multiple CNS tumors, we investigated whether TICs also drive the growth of human pituitary adenomas. Using a nanoString-based 80-gene custom codeset specific for developmental pathways, we identified a differential stem cell gene expression profile within human pituitary adenomas. Prospective functional characterization of stem cell properties in patient-derived adenomas representing all hormonal subtypes yielded a subtype-dependent self-renewal profile, which was enriched within the CD15+ cell fraction. The tumor-initiating capacity of CD15high adenoma cells was assayed in comparison to CD15low adenomas using in vivo limiting dilutions, which maintained the rare frequency of TICs. Repeated analyses using sorted cell populations for CD15+ TICs compared to CD15- adenoma cells provided further evidence of xenograft tumor formation to support CD15+ cells as putative pituitary adenoma-initiating cells (PAICs). The clinical utility of our findings was established through in silico analyses and comparative gene expression profiling of primary and recurrent pituitary adenomas. CD15 was enriched in recurrent adenomas, which was validated using routine clinical immunohistochemistry in a limited number of samples. Our work reports the first prospective identification of human PAICs using CD15. Patients with CD15high adenomas may therefore benefit from more aggressive surgical interventions and chemo/radiotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0394-4) contains supplementary material, which is available to authorized users.
Highlights
Inter- and intratumoral heterogeneity are hallmark features of human central nervous system (CNS) tumors, as distinct molecular subgroups and cell populations have been described in tumors that otherwise appear histologically homogeneous [9, 29, 31]
The successful detection of stemness genes in pituitary adenomas has previously been hampered by limitations in robust, costeffective gene expression platforms capable of detecting genes expressed at the resolution of a single transcript, as might be the case with stemness genes, which are exclusively expressed in rare tumor-initiating cells (TICs) [15]
Given the presence of a differential stemness gene expression profile, coupled with the capacity for sphere formation and expression of putative TIC markers, our data supports the application of the TIC model for investigating the biological heterogeneity observed in human Pituitary adenomas (PAs)
Summary
Inter- and intratumoral heterogeneity are hallmark features of human central nervous system (CNS) tumors, as distinct molecular subgroups and cell populations have been described in tumors that otherwise appear histologically homogeneous [9, 29, 31]. Whereas TICs have been reliably isolated and characterized in murine models of PA [1, 5, 7, 10], our insight into human PAICs has been limited to observational studies in which adenoma cells are cultured as tumor spheres in serum-free media or immunohistochemical staining for the expression of putative regulators of self-renewal [3, 19, 35, 36]. A functional validation of putative markers of human PAICs may yield a robust profile of these cells within treatmentrefractory adenomas
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