Plasma membrane-mediated non-genomic effects of T4, T3 and thyroid hormone metabolite tetrac on the tumor microenvironment

There is now growing evidence that the thyroid hormones T3 and T4 play a critical role in tumor progression through the stimulation of tumor cell proliferation and survival, as well as angiogenesis and inflammation. These effects are thought to be mediated mainly by non-classical mechanisms initiated at the cell surface receptor integrin αvβ3, which can be effectively inhibited by tetrac, a deaminated T4 derivative. Integrin αvβ3 is abundantly expressed on most cancer cells and the growing endothelium associated with tumors, but also on mesenchymal stem cells (MSCs). These multipotent progenitor cells actively home to growing tumors where they support the tumor’s fibrovascular network by differentiating into carcinoma-associated fibroblast (CAF)-like cells and blood vessel-stabilizing pericytes. Integrin αvβ3 expression on MSCs makes them susceptible to thyroid hormone stimulation.

In the DFG Schwerpunktprogramm 1629 THYROID TRANS ACT (http://www.thyroidtransact.de) we have shown that thyroid hormones stimulate the differentiation of MSCs towards a CAF-/pericyte-like and hypoxia-responsive, pro-angiogenic phenotype, characterized by the secretion of numerous paracrine pro-angiogenic factors, in addition to driving their migration, invasion, and recruitment to the tumor microenvironment. We have thus characterized MSCs as novel thyroid hormone-dependent targets, significantly improving our understanding of the critical role of thyroid hormones T3 and T4 in the regulation of MSC biology in the context of cancer as well as the anti-tumor activity of tetrac.