The identification of human pituitary adenoma-initiating cells

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.

Pituitary stem cell regulation: who is pulling the strings?

“…However, these cells were sensitive to the antiproliferative effect of drugs (in this case, dopamine/somatostatin chimeric agonists), which does not fit with the general concept of therapy resistance of TSC. In another recent study, CD15 + cells were identified in pituitary adenomas exhibiting higher sphere-forming capacity than the remaining cells, and upregulated expression of SOX2 (Manoranjan et al 2016). The latter finding is in agreement with an earlier report that showed SOX2 expression in a candidate TSC population as identified by SP efflux capacity (Mertens et al 2015).…”

Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells

“…Similar results were obtained by the intracranial injection in nude mice of 10,000 CD133 + /nestin + PA cells, which gave rise to tumors, detectable after 6 weeks from the graft (83). In another study, one PASC culture from a null PA, sorted for CD15 expression, was pseudo-orthotopically injected in the brain of three mice (84). In agreement with the CSC theory, 50,000 CD15 + cells generated tumors when injected in the mouse brain, while up to 500,000 CD15 − cells were not tumorigenic.…”

“…Comparing the original tumor with the xenograft, both specimens were negative for GFAP, alphasmooth muscle actin, EMA, and TTF1, and, according to the neuroendocrine derivation, both expressed synaptophysin and CD56. Interestingly, desmin and myogenin were unexpectedly expressed only in the xenograft but not in the original PA, suggesting that CD15 + PASCs possess a microenvironmentdependent multi-lineage potential (84).…”

“…Moreover, indirect immunofluorescence analysis revealed the nuclear co-expression of the pituitary specific transcription factor PROP1 and SOX2 in about 2-10% of cells, while PROP1 was cytoplasmic in SOX2 − cells, highlighting the presence, within the culture, of heterogeneous populations of stem (PROP1 + /SOX2 + /) and precursor (PROP1 + /SOX2 − ) cells Finally, the analysis of cells from 22 PAs of different subtypes showed a preferential high expression of CD15, as compared to CD133. Moreover, by comparative analysis within each tumor cell culture, of CD15 high and CD15 low subpopulations, it was reported that CD15 high cells are also associated to higher SOX2 and PAX7 expression, and were detected in higher percentage in recurrent PAs as compared to the matched primary tumor (84).…”

Pituitary Adenomas and Invasiveness from Anatomo-Surgical, Radiological, and Histological Perspectives: A Systematic Literature Review

“…It is well known that primary central nervous system tumors contain tumor-initiating cells (TICs) with tumorigenic properties that contribute to maintainence of tumor growth and promote disease progression. A recent report investigated whether TICs also contribute to the growth of human pituitary tumors [177]. Using nanoString-based technology, the authors identified a differential stem cell gene expression profile within human pituitary adenomas of all hormonal subtypes that indicated CD15 as a putative pituitary adenoma-initiating cell marker.…”