Contributions of Thyroid Hormone to Cancer Metastasis

Abstract

Acting at a cell surface receptor on the extracellular domain of integrin αvβ3, thyroid hormone analogues regulate downstream the expression of a large panel of genes relevant to cancer cell proliferation, to cancer cell survival pathways, and to tumor-linked angiogenesis. Because αvβ3 is involved in the cancer cell metastatic process, we examine here the possibility that thyroid hormone as l-thyroxine (T4) and the thyroid hormone antagonist, tetraiodothyroacetic acid (tetrac), may respectively promote and inhibit metastasis. Actions of T4 and tetrac that are relevant to cancer metastasis include the multitude of synergistic effects on molecular levels such as expression of matrix metalloproteinase genes, angiogenesis support genes, receptor tyrosine kinase (EGFR/ERBB2) genes, specific microRNAs, the epithelial⁻mesenchymal transition (EMT) process; and on the cellular level are exemplified by effects on macrophages. We conclude that the thyroid hormone-αvβ3 interaction is mechanistically linked to cancer metastasis and that modified tetrac molecules have antimetastatic activity with feasible therapeutic potential.

Keywords: T4; angiogenesis; cancer; cancer cell genes; epithelial-to-mesenchymal transition (EMT); integrin αvβ3; l-thyroxine; matrix metalloproteinases; metastasis; tetrac; thyroid hormone.

Figure 1

Tetrac covalently linked to polyethylene glycol (PEG) (named P-bi-TAT) was used as treatment in a breast cancer mouse model compared to control and shows the elimination of limb bone metastasis, implicating αvβ3 in the thyroid hormone-metastasis pathway [19]. Images shown were obtained with an In Vitro Imaging System (IVIS); vertical luminescence color bar estimates viability, ranging from nonviable (blue) to fully viable (red). (a) Metastatic luminescent signals of (MCF7-luc) breast cancer control (phosphate buffered saline) in mouse limbs (bones) in an orthotopic mouse model (female nude mice); (b) Metastatic luminescent signals of (MCF7-luc) breast cancer after P-bi-TAT subcutaneous treatment with 3 mg/kg TAT equivalent daily for 18 days shows the elimination of metastasis.