Multicellular spheroids as a tumor model in differentiated thyroid cancer

Prof. Laura Fugazzola  and coworkers from the University of Milan and Istituto Auxologico Italiano, Division of Endocrinology, reported data on multicellular spheroids  obtained  from neoplastic and normal thyroid tissues as a suitable model to test the effects of multikinase inhibitors. They showed that spheroids are morphologically different according to the tissue of origin (papillary, follicular thyroid cancer or normal contralateral tissue). The expression of thyroid differentiation markers was found to be maintained in spheroids, being lower in tumor compared to normal thyroid spheroids. Among those “stem-like” markers tested, OCT4 was found to harbor the highest expression in both tumor tissues and spheroids and was expressed in the core of tumor spheroids, whereas the thyroid differentiation marker Thyroglobulin was found to be mostly expressed at the periphery. This is consistent with the notion that stem-like cells and endothelial cells preferentially reside in the core of thyroid spheroids, which is known to be characterized by hypoxia and low nutrients. Thus, investigators concluded that multicellular 3D spheroids well recapitulate the features of the original tissues, in regard to both the differentiated and “stem-like” components.

Immunohistochemistry analysis for the stem cell marker OCT4 and the thyroid differentiation marker thyroglobulin on consecutive paraffin-embedded tumor spheroids sections.  The panels demonstrate that these antigens do not co-localize; OCT4 cells were principally located in the centre and thyroglobulin-staining cells at the periphery of the spheres.

This model allowed testing of the in vitro effects of the kinase inhibitor SP600125 which was found to be highly and selectively effective on both PTC and FTC derived spheroids, without any impact on spheroids obtained from normal tissues. In particular, after 96 hours with SP600125 treatment, tumor spheroids became smaller, inhomogeneous and irregular, with a significant reduction in the protein content. The effect of SP600125 was found to be mediated by the direct inhibition of the ROCK/β-catenin pathway.

These results indicate that the use of 3D spheroids can disclose different effects of multikinase inhibitors in conditions that resemble tumor tissue and also support SP600125 as a promising therapeutic compound for thyroid cancer.

 

These findings were originally published in the following articles:
Oncotarget. 2017 Feb 7;8(6):9752-9766
Oncotarget. 2015 Nov 3; 6(34): 36383-99
Minerva Endocrinologica. 2017 Jan 31.  epub ahead of print

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