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

Endocr Relat Cancer. 2015 Dec;22(6):941-52. doi: 10.1530/ERC-15-0245. Epub 2015 Aug 25.


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.

Keywords: integrin αvβ3; mesenchymal stem cells; tetrac; thyroid hormones; tumour stroma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Movement
  • Culture Media, Conditioned
  • Heterografts
  • Humans
  • Hyperthyroidism / chemically induced
  • Hyperthyroidism / complications
  • Hypothyroidism / chemically induced
  • Hypothyroidism / complications
  • Integrin alphaVbeta3 / physiology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms, Experimental / complications
  • Liver Neoplasms, Experimental / pathology
  • Male
  • Mesenchymal Stem Cells / drug effects*
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Proteins / physiology*
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / physiopathology
  • Specific Pathogen-Free Organisms
  • Spheroids, Cellular
  • Stromal Cells / pathology*
  • Thyroxine / analogs & derivatives*
  • Thyroxine / pharmacology*
  • Thyroxine / therapeutic use
  • Thyroxine / toxicity
  • Triiodothyronine / pharmacology*
  • Triiodothyronine / therapeutic use
  • Triiodothyronine / toxicity
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Culture Media, Conditioned
  • Integrin alphaVbeta3
  • Neoplasm Proteins
  • Triiodothyronine
  • tetraiodothyroacetic acid
  • Thyroxine