Abstract
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.
Highlights
Multicellular three-dimensional spheroids represent an experimental model that is intermediate in its complexity between monolayer cultures and patients’ tumor, and are successfully used in cancer research [1, 2]
This mechanism of action may be important in anticancer therapy considering that Rho/Rho-associated Kinase (ROCK) pathway is hyperactivated in different human neoplasia and its activity correlates with metastatic disease [9,10,11]
Spheroids obtained from 17 papillary thyroid cancers (PTCs) showed a variable morphology and size, whereas spheroids from 4 follicular thyroid cancers (FTCs) and contralateral normal thyroid tissues had a more regular shape and well-defined borders
Summary
Multicellular three-dimensional spheroids represent an experimental model that is intermediate in its complexity between monolayer cultures and patients’ tumor, and are successfully used in cancer research [1, 2]. In normal and cancer thyroid derived cell lines, cultured in monolayer, that the kinase inhibitor SP600125 (SP) is highly effective in blocking cell growth and migration and in the induction of mitotic catastrophe through direct inhibition of ROCK, a kinase involved in the regulation of cell migration, microtubule dynamics and β-catenin turnover [8]. This mechanism of action may be important in anticancer therapy considering that Rho/ROCK pathway is hyperactivated in different human neoplasia and its activity correlates with metastatic disease [9,10,11]. SP was found to be effective against poorly differentiated cancer cells and, at a lesser extent, on papillary thyroid cancer derived cells [8]
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