Tumor Biology

, Volume 35, Issue 6, pp 5519–5526 | Cite as

Effect of thyroid hormone–nitric oxide interaction on tumor growth, angiogenesis, and aminopeptidase activity in mice

  • Javier Carmona-Cortés
  • Isabel Rodríguez-Gómez
  • Rosemary Wangensteen
  • Inmaculada Banegas
  • Ángel M. García-Lora
  • Andrés Quesada
  • Antonio Osuna
  • Félix Vargas
Research Article


This study evaluated the effects of thyroid hormone–NO interaction on tumor development, vascularization, vascular endothelial growth factor (VEGF), and aminopeptidase (AP) activity in a murine model of implanted Lewis’s carcinoma. Experiments were performed in male CBA-C57 mice. Animals were untreated (controls) or treated with: T4, the antithyroid drug methimazole, the NO inhibitor L-NAME, T4 + L-NAME, methimazole + NAME, the αvß3 integrin antagonist tetrac, T4 + tetrac, the iNOS inhibitor aminoguanidine (AG), and T4 + AG; all treatments were for 6 weeks except for tetrac, administered for the last 11 days. Mice were subcutaneously inoculated with 1 × 106 exponentially growing Lewis carcinoma 3LL cells into the dorsum. Study variables 9 days later were tumor weight (TW), Hb content, an index of tumor vascularization, VEGF, and AP activity. T4 produced parallel increases in TW and angiogenesis. L-NAME reduced TW and angiogenesis in control, hyperthyroid, and hypothyroid mice, whereas AG had no effect on these variables. Tetrac arrested TW in normal and T4-treated mice but did not decrease angiogenesis in T4-treated animals. Negative correlations were found between TW and AP activity in tumors from control hyper- and hypothyroid groups and an inverse relationship was observed between TW and AP activities in tetrac-treated mice. T4 enhances TW and angiogenesis, in which NO participates, but requires activation of integrin αvß3 to promote carcinogenesis. NO blockade reduces TW, regardless of the thyroid status. Thyroid hormone negatively modulates AP activity in the tumor. Accordingly, blockade of the membrane TH receptor αvß3 integrin reduces TW associated with an increase in AP activity.


Tumor growth Hemoglobin Thyroxine Methimazole Aminopeptidases 


Coflicts of interest



This study was supported by a grant (SAF2009-12294) from the Ministry of Education and Science and from the Carlos III Health Institute of the Spanish Ministry of Health and Consumer Affairs (Red de Investigación Renal, REDinREN 012/0021) “FEDER una manera de hacer Europa”.


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Javier Carmona-Cortés
    • 1
  • Isabel Rodríguez-Gómez
    • 2
  • Rosemary Wangensteen
    • 1
  • Inmaculada Banegas
    • 1
  • Ángel M. García-Lora
    • 3
  • Andrés Quesada
    • 4
  • Antonio Osuna
    • 4
  • Félix Vargas
    • 2
  1. 1.Departamento de Ciencias de la SaludUniversidad de JaénJaénSpain
  2. 2.Departamento de FisiologíaFacultad de MedicinaGranadaSpain
  3. 3.Servicio de Análisis Clínicos, InmunologíaHospital Virgen de las NievesGranadaSpain
  4. 4.Servicio de NefrologíaHospital Virgen de las NievesGranadaSpain

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