Tumor necrosis factor α induces three‐dimensional cytomorphologic differentiation of human anaplastic thyroid carcinoma cells through activation of nuclear factor κB

BACKGROUND Anaplastic thyroid carcinoma is almost uniformly fatal. Microvilli are an important three-dimensional (3-D) cytomorphologic feature of thyrocyte differentiation, because fewer microvilli are seen in less differentiated tumors. Differentiation therapies, such as retinoic acid and somatostatin, have been tested previously in experimental models of differentiated thyroid carcinoma but not in anaplastic thyroid carcinoma. The objective of this study was to determine whether tumor necrosis factor α (TNF-α) is capable of inducing 3-D cytomorphologic differentiation of anaplastic thyroid carcinoma cells, and, if so, to investigate the mechanism involved. METHODS Anaplastic thyroid carcinoma cells were treated with TNF-α and examined for evidence of cytomorphologic differentiation using electron microscopy. To study the mechanism of differentiation, immunoblotting was used to analyze inhibitory κB (I-κB) proteins and electrophoretic mobility shift assays to analyze nuclear factor κB (NF-κB) activation. The effect of NF-κB SN50, a NF-κB translocation inhibitor, on cytomorphologic changes induced in anaplastic thyroid carcinoma cells by TNF-α also was studied. In addition, levels of thyroglobulin and vascular endothelial growth factor (VEGF) secreted into the culture medium were measured. RESULTS The results showed that TNF-α can induce activation of NF-κB and that the activation and translocation of NF-κB into the nucleus is responsible for promoting the 3-D cytomorphologic differentiation of anaplastic thyroid carcinoma cells, which was inhibited by the NF-κB translocation inhibitor, NF-κB SN50. TNF-α also induced increased thyroglobulin secretion and reduced VEGF secretion by anaplastic tumor cells. CONCLUSIONS The current data suggest that TNF-α can induce thyrocyte differentiation in anaplastic thyroid carcinoma cells through NF-κB and that it merits investigation as differentiation therapy for the treatment of patients with anaplastic thyroid carcinoma. The authors also found that microvilli were useful markers for studying thyrocyte differentiation in anaplastic thyroid carcinoma cells. Cancer 2002;95:1827–33. © 2002 American Cancer Society. DOI 10.1002/cncr.10857