Analysis of the effects of T3 and T4 on the hypoxia response network of mesenchymal stem cells

[08:30 – 08:40]
Mesenchymal stem cells (MSCs) are actively recruited into growing tumour stroma, where they support the tumour's fibrovascular network. Thyroid hormones influence the hypoxia response network by stimulating hypoxia inducible factor- (HIF-) 1α expression through non-genomic mechanisms via integrin αvβ3. To improve our understanding of thyroid hormone action in the tumour microenvironment, we examined the effects of T3, T4 and the integrin-specific inhibitor tetrac on the hypoxia response of MSCs.

Immortalised MSCs stably transfected with a HIF-specific sodium-iodide-symporter (NIS) reporter gene system (HIF-NIS-MSCs) were established and showed stimulation of NIS expression under hypoxic conditions in vitro. After injection of these cells into nude mice bearing subcutaneous hepatocellular carcinoma (HCC) xenografts, ¹²³I-scintigraphy and ¹²⁴I-/¹⁸F-tetrafluoroborate-PET-imaging revealed tumour hypoxia-induced radionuclide accumulation mediated by HIF-driven NIS expression. Treatment with T3 or T4 in the presence of HCC cell-conditioned medium (CM) for 24 hours resulted in stimulation of HIF-driven functional NIS expression in a concentration-dependent manner. In primary MSCs, this treatment led to a tetrac-dependent increase in expression of HIF-1α as determined by qPCR and Western blot, and HIF-responsive genes CXCL12, IL-6, VEGF and TGF-β1 as determined by qPCR. No effects were observed in the absence of CM.

Our data suggest that in the presence of tumour signals thyroid hormones stimulate the hypoxia response of MSCs in a tetrac-dependent and therefore integrin αvβ3-mediated manner. The establishment of HIF-NIS-MSCs opens the prospect of investigating thyroid hormone action on the hypoxia response network in tumour stroma in vivo. These studies will increase our understanding of thyroid hormone action in hypoxia-induced angiogenesis in tumours.