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[Cancer Research 63, 6784-6790, October 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Thyroid Cancer Resistance to Chemotherapeutic Drugs via Autocrine Production of Interleukin-4 and Interleukin-101

Giorgio Stassi2, Matilde Todaro, Monica Zerilli, Lucia Ricci-Vitiani, Diana Di Liberto, Mariella Patti, Adamaria Florena, Francesca Di Gaudio, Giuseppe Di Gesù and Ruggero De Maria

Department of Surgical and Oncological Sciences [G. S., M. T., M. Z., D. D. L., M. P., G. D. G.], Pathology Institute [A. F.], and Department of Medical Biotechnologies and Forensic Medicine [F. D. G.], University of Palermo, 90127 Palermo, Italy; Department of Hematology and Oncology, Istituto Superiore di Sanità 00161, Rome, Italy [L. R-V., R. D. M.]; and Department of Experimental Oncology, Istituto Oncologico del Mediterraneo, 95029 Catania, Italy [R. D. M.]

We investigated the mechanisms responsible for the widespread refractoriness to chemotherapeutic drugs observed in thyroid cancers. We show that malignant epithelial cells from papillary, follicular, and anaplastic thyroid carcinomas express high levels of Bcl-2 and Bcl-xL. Exogenous expression of either Bcl-2 or Bcl-xL in normal thyrocytes was sufficient to prevent chemotherapeutic drug-induced cytotoxicity. All of the histological thyroid cancer variants examined produced interleukin-4 (IL-4) and interleukin-10 (IL-10), which increased Bcl-2 and Bcl-xL levels and protected thyroid cells from chemotherapeutic agents. Exposure to neutralizing antibodies against IL-4 and IL-10 resulted in down-modulation of Bcl-2 and Bcl-xL, death of a considerable percentage of thyroid cancer cells, and sensitization of the residual tumor population to cytotoxic drug-induced apoptosis. In conclusion, autocrine production of IL-4 and IL-10 promotes thyroid tumor cell progression and resistance to chemotherapy through the up-regulation of antiapoptotic proteins. Thus, IL-4 and IL-10 may represent new therapeutic targets for the treatment of thyroid cancer.




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