Tumor-stroma crosstalk leads to a tumor-promoting microenvironment. In this milieu, extracellular vesicles (EVs) are protagonists in cell-cell communication. Despite thyroid cancer being the most common endocrine malignancy, the contribution of the tumor microenvironment to thyroid cancer progression is still largely underexplored. We focused on the role of thyroid tumor cell-fibroblast interaction and EVs as mediators of tumor-stroma interplay, in the promotion of thyroid tumor aggressiveness. Thyroid tumor (TPC-1, 8505c) or non-tumor thyroid cells (NThyOri) were co-cultured with human fibroblasts (Fb). Thyroid cell migration was investigated by the wound-healing assay and actin-network staining. Cell-CD147 expression was characterized by flow cytometry. EVs, obtained by ultracentrifugation of conditioned media (CMs), were characterized by transmission electron-microscopy and CD81 and CD147 expression. Metalloproteinases (MMPs) were evaluated by zymography in CMs. A migratory phenotype was triggered in thyroid tumor cells treated with CMs from Fb or from Fb-thyroid tumor cell co-cultures. Fb-thyroid cell co-cultures induced the secretion of proMMP9 and proMMP2 and led to a significant MMP2 activation in CMs. Fb, thyroid cells and Fb-thyroid cell co-cultures released EVs, and remarkably, EVs released by Fb-thyroid tumor cell co-cultures induced the secretion of proMMP2 and the expression of MMP2 from normal Fb. A significant CD147 expression was demonstrated in Fb-thyroid tumor cell-derived EVs. These findings reveal the role of Fb and thyroid tumor cell-Fb interaction in the promotion of a microenvironment suitable for thyroid tumor progression. Moreover, they highlight, for the first time, the role of thyroid tumor cell-Fb interaction in the production of specialized EVs.

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