Multicellular spheroids from normal and neoplastic thyroid tissues as a suitable model to test the effects of multikinase inhibitors
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Valentina Cirello1,2, Valentina Vaira3, Elisa Stellaria Grassi4, Valeria Vezzoli4, Dario Ricca3, Carla Colombo1,5, Silvano Bosari2,3, Leonardo Vicentini6, Luca Persani4,5, Stefano Ferrero3,7, Laura Fugazzola1,2
1Endocrine Unit, Fondazione IRCCS Ca’ Granda, 20122 Milan
2Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan
3Division of Pathology, Fondazione IRCCS Ca’ Granda, 20122 Milan
4Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, 20149 Milan
5Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan
6Endocrine Surgery Unit, Fondazione IRCCS Ca’ Granda, 20122 Milan
7Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
Laura Fugazzola, email: [email protected]
Keywords: multicellular spheroids, thyroid cancer, multi-tyrosine kinase inhibitors, SP600125, ROCK
Received: August 26, 2016 Accepted: November 22, 2016 Published: December 26, 2016
Multicellular three-dimensional (3D) spheroids represent an experimental model that is intermediate in its complexity between monolayer cultures and patients’ tumor. In the present study, we characterize multicellular spheroids from papillary (PTC) and follicular (FTC) thyroid cancers and from the corresponding normal tissues. We show that these 3D structures well recapitulate the features of the original tissues, in either the differentiated and “stem-like” components. As a second step, we were aimed to test the effects of a small multikinase inhibitor, SP600125 (SP), previously shown to efficiently induce cell death in undifferentiated thyroid cancer monolayer cultures. We demonstrate the potent effect of SP on cell growth and survival in our 3D multicellular cultures. SP exerts its main effects through direct and highly significant inhibition of the ROCK pathway, known to be involved in the regulation of cell migration and β-catenin turnover. Consistently, SP treatment resulted in a significant decrease in β-catenin levels with respect to basal conditions in tumor but not in normal spheroids, indicating that the effect is promisingly selective on tumor cells.
In conclusion, we provide the morphological and molecular characterization of thyroid normal and tumor spheroids. In this 3D model we tested in vitro the effects of the multikinase inhibitor SP and further characterized its mechanism of action in both normal and tumor spheroids, thus making it an ideal candidate for developing new drugs against thyroid cancer.
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