Endocrine Abstracts

In 2005, Bergh et al. first described a cell surface receptor for thyroid hormones (TH) T3 and T4 on integrin αvβ3 that is expressed on tumour cells and dividing endothelial cells. The deaminated T4 derivative tetraiodothyroacetic acid (tetrac) is a specific inhibitor of integrin-mediated TH action. Building on Paul Davis’ pioneer studies, we are investigating the effects of TH and tetrac on mesenchymal stem cells (MSCs), important progenitor cells of the tumour’s fibrovascular network, in the context of tumour angiogenesis. We were the first to show that recruitment and invasion of MSCs into tumours is significantly enhanced by TH stimulation and blocked by tetrac. In addition, we demonstrated that tetrac reverses the differentiation of MSCs towards a cancer-associated fibroblast-like and pro-angiogenic phenotype that occurs under tumour cell-conditioned medium and TH stimulation. Moreover, tetrac inhibited TH-stimulated endothelial cell tube formation, as did supernatant from MSCs stimulated with tumour cell-conditioned medium and TH in the presence of tetrac. Further, we established a reporter gene system by transfecting MSCs with the sodium iodide symporter (NIS) under control of the promoter for the vascular endothelial growth factor (VEGF), a critical angiogenesis mediator, leading to enhanced NIS-mediated iodide uptake activity after stimulation with tumour cell-conditioned medium and TH that was blocked by tetrac. In an orthotopic hepatocellular carcinoma xenograft mouse model, tumoural radioiodide uptake, measured by iodide-124 PET, demonstrated successful tumoural recruitment of MSCs followed by VEGF promoter-driven NIS expression. In hyperthyroid animals, tumoural radioiodide uptake was strongly enhanced compared to euthyroid and hypothyroid mice, while treatment with tetrac markedly reduced uptake, confirming inhibition of TH-mediated stimulation of VEGF by tetrac. Our data suggest that tetrac blocks the pro-angiogenic signalling of TH in MSCs via integrin αvβ3, providing further evidence of the anti-angiogenic activity of tetrac in the context of tumour stroma formation.