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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

Abstract

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.

Keywords

Tumor growth Hemoglobin Thyroxine Methimazole Aminopeptidases 

Notes

Coflicts of interest

None

Funding

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”.

References

  1. 1.
    Moeller LC, Führer D. Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer. 2013;20:R19–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Hellevik AI, Asvold BO, Bjoro T, Romundstad PR, Nilsen TIL, Vatten LJ. Thyroid function and cancer risk: a prospective population study. Cancer Epidemiol Biomarkers Prev. 2009;18:570–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Barrera-Hernandez G, Park KS, Dace A, Zhan Q, Cheng SY. Thyroid hormone-induced cell proliferation in GC cells is mediated by changes in G1 cyclin/cyclin-dependent kinase levels and activity. Endocrinology. 1999;140:5267–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Hall LC, Salazar EP, Kane SR, Liu N. Effects of thyroid hormones on human breast cancer cell proliferation. J Steroid Biochem Mol Biol. 2008;109:57–66.CrossRefPubMedGoogle Scholar
  5. 5.
    Tsui KH, Hsieh WC, Lin MH, Chang PL, Juang HH. Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2. Prostate. 2008;68:610–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Kumar MS, Chiang T, Deodhar SD. Enhancing effect of thyroxine on tumor growth and metastases in syngeneic mouse tumor systems. Cancer Res. 1979;39:3515–8.PubMedGoogle Scholar
  7. 7.
    Shoemaker JP, Bradley RL, Hoffman RV. Increased survival and inhibition of mammary tumors in hypothyroid mice. J Surg Res. 1976;21:151–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Mishkin SY, Pollack R, Yalovsky MA, Morris HP, Mishkin S. Inhibition of local and metastatic hepatoma growth and prolongation of survival after induction of hypothyroidism. Cancer Res. 1981;41:3040–5.PubMedGoogle Scholar
  9. 9.
    Theodossiou C, Schwarzenberger P. Propylthiouracil reduces xenograft tumor growth in an athymic nude mouse prostate cancer model. Am J Med Sci. 2000;319:96–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Vargas F, Moreno JM, Rodríguez-Gómez I, Wangensteen R, Osuna A, Alvarez-Guerra M, et al. Vascular and renal function in experimental thyroid disorders. Eur J Endocrinol. 2006;154:197–212.CrossRefPubMedGoogle Scholar
  11. 11.
    Carrillo-Sepúlveda MA, Ceravolo GS, Bruno-Fortes Z, Carvalho MH, Tostes RC, Laurindo FR, et al. Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes. Cardiovasc Res. 2010;85:560–70.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Lind DS. Arginine and cancer. J Nutr. 2004;134:2837S–41.PubMedGoogle Scholar
  13. 13.
    Morbidelli L, Donnini S, Ziche M. Role of nitric oxide in tumor angiogenesis. Cancer Treat Res. 2004;117:155–67.CrossRefPubMedGoogle Scholar
  14. 14.
    Cianchi F, Cortesini C, Fantappie O, Messerini L, Sardi I, Lasagna N. Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clin Cancer Res. 2004;10:2694–704.CrossRefPubMedGoogle Scholar
  15. 15.
    Schlossmann J, Feil R, Hofmann F. Signaling through NO and cGMP-dependent protein kinases. Ann Med. 2003;35:21–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen T, Nines RG, Peschke SM, Kresty LA, Stoner GD. Chemopreventive effects of a selective nitric oxide synthase inhibitor on carcinogen-induced rat esophageal tumorigenesis. Cancer Res. 2004;64:3714–24.CrossRefPubMedGoogle Scholar
  17. 17.
    Jadeski LC, Chakraborty C, Lala PK. Nitric oxide mediated promotion of mammary tumour cell migration requires sequential activation of nitric oxide synthase, guanylate cyclase and mitogen-activated protein kinase. Int J Cancer. 2003;106:496–504.CrossRefPubMedGoogle Scholar
  18. 18.
    Schleiffer R, Duranton B, Gosse F, Bergmann C, Raul F. Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats. Nitric Oxide. 2000;4:583–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Ardaillou R, Chansel D. Synthesis and effects of active fragments of angiotensin II. Kidney Int. 1997;52:1458–68.CrossRefPubMedGoogle Scholar
  20. 20.
    Nanus DM, Bogenrieder T, Papandreou CN, Finstad CL, Lee A, Vlamis V, et al. Aminopeptidase A expression and enzymatic activity in primary human renal cancers. Int J Oncol. 1998;13:261–7.PubMedGoogle Scholar
  21. 21.
    Gullbo J, Wickstrom M, Larsson R, Nygren P. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci. 2011;102:501–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Khakoo AY, Sidman RL, Pasqualini R, Arap W. Does the renin–angiotensin system participate in regulation of human vasculogenesis and angiogenesis? Cancer Res. 2008;68:9112–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Segarra AB, Ramirez M, Banegas I, Hermoso F, Vargas F, Vives F, et al. Influence of thyroid disorders on kidney angiotensinase activity. Horm Metab Res. 2006;38:48–52.CrossRefPubMedGoogle Scholar
  24. 24.
    Segarra AB, Wangensteen R, Ramirez M, Banegas I, Hermoso F, Vargas F, et al. Atrial angiotensinase activity in hypothyroid, euthyroid, and hyperthyroid rats. J Cardiovasc Pharmacol. 2006;48:117–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Mousa SA, Bergh JJ, Dier E, Rebbaa A, O’Connor LJ, Yalcin M, et al. Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis. 2008;11:183–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Griffiths MJ, Messent M, MacAllister RJ, Evans TW. Aminoguanidine selectively inhibits inducible nitric oxide synthase. Br J Pharmacol. 1993;110:963–8.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Misko TP, Moore WM, Kasten TP, Nickols GA, Corbett JA, Milton RG, et al. Selective inhibition of inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993;233:119–25.CrossRefPubMedGoogle Scholar
  28. 28.
    Ortiz MC, Fortepiani LA, Martínez C, Atucha NM, García-Estañ J. Renal and pressor effects of aminoguanidine in cirrhotic rats with ascites. J Am Soc Nephrol. 1996;7:2694–9.PubMedGoogle Scholar
  29. 29.
    Tan DY, Meng S, Cason GW, Manning Jr RD. Mechanisms of salt sensitive hypertension: role of inducible nitric oxide synthase. Am J Physiol Reg Integr Comp Physiol. 2000;279:R2297–303.Google Scholar
  30. 30.
    Düwel A, Eleno N, Jerkic M, Arevalo M, Bolaños JP, Bernabeu C, et al. Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice. Tumour Biol. 2007;28:1–8.PubMedGoogle Scholar
  31. 31.
    Yalcin M, Dyskin E, Lansing L, Bharali DJ, Mousa SS, Bridoux A, et al. Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid. J Clin Endocrinol Metab. 2010;95:1972–80.CrossRefPubMedGoogle Scholar
  32. 32.
    Mousa SA, Yalcin M, Bharali DJ, Meng R, Tang H-Y, Lin H-Y, et al. Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts. Lung Cancer. 2012;76:39–45.CrossRefPubMedGoogle Scholar
  33. 33.
    Aranda A, Martínez-Iglesias O, Ruiz-Llorente L, García-Carpizo V, Zambrano A. Thyroid receptor: roles in cancer. Trends Endocrinol Metab. 2009;20:319–24.CrossRefGoogle Scholar
  34. 34.
    Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31:139–70.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Luidens MK, Mousa SA, Davis FB, Lin HY, Davis PJ. Thyroid hormone and angiogenesis. Vasc Pharmacol. 2010;52:142–5.CrossRefGoogle Scholar
  36. 36.
    Deshayes F, Nahmias C. Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab. 2005;16:293–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Frank S, Stallmeyer B, Kampfer H, Schaffner C, Pfeilschifter J. Differential regulation of vascular endothelial growth factor and its receptor fms-like tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells. Biochem J. 1999;338:367–74.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Davis FB, Tang HY, Shih A, Keating T, Lansing L, Hercbergs A, et al. Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells. Cancer Res. 2006;66:7270–5.CrossRefPubMedGoogle Scholar
  39. 39.
    Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S. Integrin αvß3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology. 2005;146:2864–71.CrossRefPubMedGoogle Scholar
  40. 40.
    Masson-Gadais B, Houle F, Laferriére J, Huot J. Integrin αvß3 requirement for VEGFR2-mediated activation of SAPK2/p38 and Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF. Cell Stress Chaperones. 2003;8:37–52.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Sahni A, Francis CW. Stimulation of endothelial cell proliferation by FGF-2 in the presence of fibrinogen requires αvß3. Blood. 2004;104:3635–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Jadeski LC, Hum KO, Chakraborty C, Lala PK. Nitric oxide promotes murine mammary tumour growth and metastasis by stimulating tumour cell migration, invasiveness and angiogenesis. Int J Cancer. 2000;86:30–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, et al. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not fibroblast growth factor-induced angiogenesis. J Clin Invest. 1997;99:2625–34.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Edwards P, Cendan JC, Topping DB, Moldawer LL, Mackay S, Copeland EM, et al. Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J Surg Res. 1996;63:49–52.CrossRefPubMedGoogle Scholar
  45. 45.
    Thomsen LL, Miles DW. Role of nitric oxide in tumor progression: lessons from human tumors. Cancer Metastasis Rev. 1998;17:107–18.CrossRefPubMedGoogle Scholar
  46. 46.
    Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, et al. Roles of nitric oxide in tumor growth. Proc Natl Acad Sci U S A. 1995;92:4392–6.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Mayas MD, Ramírez-Expósito MJ, Carrera MP, Cobo M, Martínez-Martos JM. Renin–angiotensin system-regulating aminopeptidases in tumor growth of rat C6 gliomas implanted at the subcutaneous region. Anticancer Res. 2012;32:3675–82.PubMedGoogle Scholar
  48. 48.
    Del Pilar CM, Ramírez-Expósito MJ, Mayas MD, García MJ, Martínez-Martos JM. Mammary renin–angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer. Tumor Biol. 2010;31:583–8.CrossRefGoogle Scholar
  49. 49.
    Mawrin C, Wolke C, Haase D, Krüger S, Firsching R, Keilhoff G, et al. Reduced activity of CD13/aminopeptidase N (APN) in aggressive meningiomas is associated with increased levels of SPARC. Brain Pathol. 2010;20:200–10.CrossRefPubMedGoogle Scholar

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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