Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3

    1. Christine Spitzweg1
    1. 1Department of Internal Medicine II, University Hospital of Munich, Munich, Germany
      2Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Munich, Germany
      3Department of Biology II, Ludwig‐Maximilians‐University, Munich, Germany
      4Leibniz Institute for Environmental Medicine, Düsseldorf, Germany
      5Department of Nuclear Medicine, University Hospital of Munich, Munich, Germany
      6University Medical Center Hamburg‐Eppendorf, Hamburg, Germany
    1. Correspondence should be addressed to C Spitzweg; Email: christine.spitzweg{at}


    To improve our understanding of non-genomic, integrin αvβ3-mediated thyroid hormone action in tumour stroma formation, we examined the effects of triiodo-l-thyronine (T3), l-thyroxine (T4) and integrin-specific inhibitor tetrac on differentiation, migration and invasion of mesenchymal stem cells (MSCs) that are an integral part of the tumour's fibrovascular network. Primary human bone marrow-derived MSCs were treated with T3 or T4 in the presence of hepatocellular carcinoma (HCC) cell-conditioned medium (CM), which resulted in stimulation of the expression of genes associated with cancer-associated fibroblast-like differentiation as determined by qPCR and ELISA. In addition, T3 and T4 increased migration of MSCs towards HCC cell-CM and invasion into the centre of three-dimensional HCC cell spheroids. All these effects were tetrac-dependent and therefore integrin αvβ3-mediated. In a subcutaneous HCC xenograft model, MSCs showed significantly increased recruitment and invasion into tumours of hyperthyroid mice compared to euthyroid and, in particular, hypothyroid mice, while treatment with tetrac almost completely eliminated MSC recruitment. These studies significantly improve our understanding of the anti-tumour activity of tetrac, as well as the mechanisms that regulate MSC differentiation and recruitment in the context of tumour stroma formation, as an important prerequisite for the utilisation of MSCs as gene delivery vehicles.

    • Revision received 21 August 2015
    • Accepted 25 August 2015
    • Made available online as an Accepted Preprint 25 August 2015
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