Integrin αvβ3-dependent thyroid hormone effects on tumour proliferation and vascularisation

in Endocrine-Related Cancer
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  • 1 Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
  • | 2 Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
  • | 3 Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
  • | 4 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Correspondence should be addressed to C Spitzweg: Christine.Spitzweg@med.uni-muenchen.de
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Thyroid hormones are emerging as critical regulators of tumour growth and progression. To assess the contribution of thyroid hormone signalling via integrin αvβ3, expressed on many tumour cells, endothelial cells, and stromal cells, to tumour growth, we compared the effects of thyroid hormones vs tetrac, a specific inhibitor of thyroid hormone action at integrin αvβ3, in two murine xenograft tumour models with and without integrin αvβ3 expression. Integrin αvβ3-positive human anaplastic thyroid cancer cells SW1736 and integrin αvβ3-negative human hepatocellular carcinoma cells HuH7 were injected into the flanks of nude mice. Tumour growth was monitored in euthyroid, hyperthyroid, hypothyroid, and euthyroid tetrac-treated mice. In SW1736 xenografts, hyperthyroidism led to a significantly increased tumour growth resulting in a decreased survival compared to euthyroid mice, while tumour growth was significantly reduced and, hence, survival prolonged in hypothyroid and tetrac-treated mice. Both proliferation and vascularisation, as determined by Ki67 and CD31 immunofluorescence staining, respectively, were significantly increased in tumours from hyperthyroid mice as compared to hypothyroid and tetrac-treated mice. No differences in tumour growth, survival, or Ki67 staining were observed between the different groups in integrin αvβ3-negative HuH7 xenografts. Vascularisation, however, was significantly decreased in hypothyroid and tetrac-treated mice compared to euthyroid and hyperthyroid mice. Apoptosis was not affected in either tumour model, nor were cell proliferation or apoptosis in vitro. Tumour growth regulation by thyroid hormones in αvβ3-positive tumours has important implications for cancer patients, especially those with thyroid dysfunctions and thyroid cancer patients treated with thyrotropin-suppressive L-thyroxine doses.

Supplementary Materials

    • Supplementary Figure S1: Cell proliferation and apoptosis in vitro. SW176 and HuH7 were treated with 1-10 nM T3, or 100 nM-1000 nM T4, with or without 100 nM tetrac. Cell viability relative to untreated controls was assessed by MTT assay after 24, 48, 72, and 96 h of hormone stimulation for (A) SW1736 (n=4, mean &#x00B1; SEM; one-way ANOVA, n/s not significant) and (B) HuH7 (n=3, mean &#x00B1; SEM; one-way ANOVA, n/s not significant). Average mRNA concentrations of proliferation and apoptosis markers were determined by qRT-PCR for (C) SW1736 and (D) HuH7 (n=3, mean &#x00B1; SEM; one-way ANOVA, *p<0.05, n/s not significant).
    • Supplementary Figure S2: Ex vivo analysis of apoptosis. Apoptosis was assessed by TUNEL assay and cleaved caspase 3-staining on frozen tumour sections. Representative fluorescence images after TUNEL staining are shown for SW1736 (A) and HuH7 (B) tumours. Magnification: 20&#x00D7;. A minimum of seven visual fields was quantified per SW1736 (C) or HuH7 (E) tumour (mean &#x00B1; SEM; one-way ANOVA, n/s not significant). The total number of cleaved caspase 3-positive pixels was evaluated by immunohistochemical staining of SW1736 (D) and HuH7 (F) tumours (mean &#x00B1; SEM; one-way ANOVA, n/s not significant).

 

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