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Phenotypical and Pharmacological Characterization of Stem-Like Cells in Human Pituitary Adenomas

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Abstract

The presence and functional role of tumor stem cells in benign tumors, and in human pituitary adenomas in particular, is a debated issue that still lacks a definitive formal demonstration. Fifty-six surgical specimens of human pituitary adenomas were processed to establish tumor stem-like cultures by selection and expansion in stem cell-permissive medium or isolating CD133-expressing cells. Phenotypic and functional characterization of these cells was performed (1) ex vivo, by immunohistochemistry analysis on paraffin-embedded tissues; (2) in vitro, attesting marker expression, proliferation, self-renewal, differentiation, and drug sensitivity; and (3) in vivo, using a zebrafish model. Within pituitary adenomas, we identified rare cell populations expressing stem cell markers but not pituitary hormones; we isolated and expanded in vitro these cells, obtaining fibroblast-free, stem-like cultures from 38 pituitary adenoma samples. These cells grow as spheroids, express stem cell markers (Oct4, Sox2, CD133, and nestin), show sustained in vitro proliferation as compared to primary cultures of differentiated pituitary adenoma cells, and are able to differentiate in hormone-expressing pituitary cells. Besides, pituisphere cells, apparently not tumorigenic in mice, engrafted in zebrafish embryos, inducing pro-angiogenic and invasive responses. Finally, pituitary adenoma stem-like cells express regulatory pituitary receptors (D2R, SSTR2, and SSTR5), whose activation by a dopamine/somatostatin chimeric agonist exerts antiproliferative effects. In conclusion, we provide evidence that human pituitary adenomas contain a subpopulation fulfilling biological and phenotypical signatures of tumor stem cells that may represent novel therapeutic targets for therapy-resistant tumors.

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Acknowledgments

The authors are thankful to M. Culler (Ipsen Inc.) for providing us with BIM-23A760, and to Dr. E. Mannino for her contribution in the early phases of the study. This work was supported by grants from the Italian Association for Cancer Research (AIRC) to TF and the Italian Ministry of University and Research (FIRB RBAP11884M) to GV.

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    Authors and Affiliations

    1. Pharmacology Section, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132, Genoa, Italy

      Roberto Würth, Federica Barbieri, Alessandra Pattarozzi, Federico Gatto, Diego Ferone & Tullio Florio

    2. Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy

      Federica Barbieri, Federico Gatto, Diego Ferone & Tullio Florio

    3. Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy

      Germano Gaudenzi, Luca Persani & Giovanni Vitale

    4. Department of Neurosciences, University of Genova, Genoa, Italy

      Pietro Fiaschi & Gianluigi Zona

    5. Department of Neurosurgery, IRCCS-AOU San Martino-IST, Genoa, Italy

      Pietro Fiaschi & Gianluigi Zona

    6. Department of Pathology, IRCCS-AOU San Martino-IST, Genoa, Italy

      Jean-Louis Ravetti

    7. Laboratory of Gene Transfer, IRCCS-AOU San Martino-IST, Genoa, Italy

      Antonio Daga

    8. Endocrine and Metabolic Research Laboratory, Istituto Auxologico Italiano-IRCCS, Milan, Italy

      Luca Persani & Giovanni Vitale

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    Roberto Würth and Federica Barbieri contributed equally to this work.

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    Würth, R., Barbieri, F., Pattarozzi, A. et al. Phenotypical and Pharmacological Characterization of Stem-Like Cells in Human Pituitary Adenomas. Mol Neurobiol 54, 4879–4895 (2017). https://doi.org/10.1007/s12035-016-0025-x

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