Contributions of Thyroid Hormone to Cancer Metastasis.

Shaker Mousa,Gennadi Glinsky,Osnat Ashur-Fabian,Paul Davis,Kelly Keating,Aleck Hercbergs,Hung-Yun Lin

doi:10.3390/biomedicines6030089

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.

Highlights

Evidence that is preclinical [1,2,3,4,5,6] and clinical [7,8,9,10] indicates that thyroid hormone can support tumor cell proliferation, antiapoptosis, and cancer-associated angiogenesis
A nanopharmaceutical formulation of tetrac as chemically modified nanoparticles cancer cells or blood vessel cells, and it has been shown that noted that modified tetrac (NDAT) administration potently (Nano-diamino-tetrac, NDAT) was engineered to extend its life in the pericellular microenvironment downregulates expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 genes [13,23]
Angiogenesis and Metastasis and much attention in cancer treatment has been directed at vascular targets, such as vascular growth factors (vascular endothelial growth factor, VEGF; basic fibroblast growth factor) or their receptors on endothelial cells

Summary

Introduction

Evidence that is preclinical [1,2,3,4,5,6] and clinical [7,8,9,10] indicates that thyroid hormone can support tumor cell proliferation, antiapoptosis, and cancer-associated angiogenesis. Certain of these actions of the hormone are initiated at a thyroid hormone–tetraiodothyroacetic acid (tetrac) receptor on the extracellular domain of integrin αvβ3 [11,12,13]. Integrin αvβ and its T4 receptor have been implicated in the process of cancer metastasis [16–. Treatment with 3 mg/kg TAT equivalent daily for 18 days shows the elimination of metastasis

Matrix

Angiogenesis

Fibronectin and Metastasis

Discussion

Conclusions