Editors' ChoiceThyroid Cancer

Restoration of Function by Gene Induction

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Science Translational Medicine  10 Mar 2010:
Vol. 2, Issue 22, pp. 22ec38
DOI: 10.1126/scitranslmed.3001026

Thyroid cancer usually has a good long-term prognosis. This optimistic view stems from an effective combination therapy, which includes surgical thyroid removal followed by radioactive iodine ablation of any remaining thyroid tissue. Thyroid cells normally store iodide that they grasp from the circulation, but when radioactive iodine is taken up, the cells die. Problem solved. But cancerous thyroid cells sometimes lose their ability to take up iodide, rendering the radioactive iodine unable to destroy the cells. This loss of function causes the 10-year survival rate for thyroid cancer patients to plummet from 80 to 95% to ~10%. There currently is no solution to the dilemma of how to kill thyroid cancer cells that do not ingest radioactive iodine. Now, Hou et al. have unearthed an exciting cellular response that may pave the way to better treatments.

The authors take advantage of the fact that molecules involved in the thyroid’s iodide uptake ability—the sodium/iodide symporter, thyroid-stimulating hormone receptor, thyroperoxidase, and thyroglobulin—are inactivated in poorly differentiated and undifferentiated thyroid cancers. Conversely, studies in rats have suggested that enhanced stimulation of key biological components, such as the phosphatidylinositol 3-kinase/Akt and MAP kinase signaling pathways and the histone deactylase enzyme, may impair the expression of genes that encode the iodide-uptake molecules. Therefore, Hou et al. tested a large panel of human thyroid cancer cell lines to determine whether they could restore gene expression and, ultimately, the normal thyroid iodide-uptake function. In fact, they found that by treating the cells with inhibitors of either of the signaling pathways or histone deactylase, expression of the iodide-handling genes was stimulated and iodide uptake was detected in most of the cell lines tested. The inhibitors tested in this study have acceptable safety profiles and display activity in clinical trials for drugs to treat other cancers.

This work beautifully demonstrates how a clinical problem identified in humans was dissected further in a rat model, leading to a hypothesis that was tested in an in vitro study in human cells. These findings may drive clinical trials that test the ability of these inhibitors to treat poorly differentiated and undifferentiated thyroid cancers, with the hope of assigning the “good prognosis” label to all thyroid malignancies.

P. Hou et al., Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways. J. Clin. Endocrinol. Metab. 95, 820–828 (2010). [Abstract]

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