Dexamethasone Selectively Inhibits Detachment of Metastatic Thyroid Cancer Cells during Random Positioning

Simple Summary Metastasis is the most dangerous feature of advanced cancers. In vitro models of this process could help us to study and understand mechanisms that are not readily accessible in the human body. In our approach, we used random positioning cell cultures to induce cancer cells to spread and form tumor spheroids. In this experimental setup, we show that dexamethasone is able to specifically inhibit the detachment of metastatic thyroid cancer cells. Our results not only show how differently healthy and malignant thyroid cells act and react in this in vitro metastasis model system, but also provide valuable insights into its functioning, possibilities and limitations. We recently reported that synthetic glucocorticoid dexamethasone (DEX) is able to suppress metastasis-like spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells cultured under random positioning. We now show that this inhibition was selective for two metastatic thyroid carcinoma cells, FTC-133 and WRO, whereas benign Nthy-ori 3-1 thyrocytes and recurrent ML-1 follicular thyroid cancer cells were not affected by DEX. We then compare Nthy-ori 3-1 and FTC-133 cells concerning their adhesion and mechanosignaling. We demonstrate that DEX disrupts random positioning-triggered p38 stress signaling in FTC-133 cells, thereby antagonizing a variety of biological functions. Thus, DEX treatment of FTC-133 cells is associated with increased adhesiveness, which is mainly caused by the restored, pronounced formation of a normal number of tight junctions. Moreover, we show that Nthy-ori 3-1 and ML-1 cells upregulate the anti-adhesion protein mucin-1 during random positioning, presumably as a protection against mechanical stress. In summary, mechanical stress seems to be an important component in this metastasis model system that is processed differently by metastatic and healthy cells. The balance between adhesion, anti-adhesion and cell-cell connections enables detachment of adherent human cells on the random positioning machine-or not, allowing selective inhibition of thyroid in vitro metastasis by DEX.