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Modulation of angiogenesis by thyroid hormone and hormone analogues: implications for cancer management

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Abstract

Acting via a cell surface receptor on integrin αvβ3, thyroid hormone is pro-angiogenic. Nongenomic mechanisms of actions of the hormone and hormone analogues at αvβ3 include modulation of activities of multiple vascular growth factor receptors and their ligands (vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor), as well as of angiogenic chemokines (CX3 family). Thyroid hormone also may increase activity of small molecules that support neovascularization (bradykinin, angiotensin II) and stimulate endothelial cell motility. Therapeutic angio-inhibition in the setting of cancer may be opposed by endogenous thyroid hormone, particularly when a single vascular growth factor is the treatment target. This may be a particular issue in management of aggressive or recurrent tumors. It is desirable to have access to chemotherapies that affect multiple steps in angiogenesis and to examine as alternatives in aggressive cancers the induction of subclinical hypothyroidism or use of antagonists of the αvβ3 thyroid hormone receptor that are under development.

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References

  1. Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18

    Article  CAS  PubMed  Google Scholar 

  2. Ebos JM, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8:210–221

    Article  CAS  PubMed  Google Scholar 

  3. Eklund L, Bry M, Alitalo K (2013) Mouse models for studying angiogenesis and lymphangiogenesis in cancer. Mol Oncol 7:259–282

    Article  CAS  PubMed  Google Scholar 

  4. Sun QM, Miao ZH, Lin LP, Gui M, Zhu CH, Xie H, Duan WH, Ding J (2009) BB, a new EGFR inhibitor, exhibits prominent anti-angiogenesis and antitumor activities. Cancer Biol Ther 8:1640–1647

    Article  CAS  PubMed  Google Scholar 

  5. Bertrand-Duchesne MP, Grenier D, Gagnon G (2010) Epidermal growth factor released from platelet-rich plasma promotes endothelial cell proliferation in vitro. J Periodontal Res 45:87–93

    Article  CAS  PubMed  Google Scholar 

  6. Ozkan EE (2011) Plasma and tissue insulin-like growth factor-1 receptor (IGF-1R) as a prognostic marker for prostate cancer and anti-IGF-1R agents as novel therapeutic strategy for refractory cases: a review. Mol Cell Endocrinol 344:1–24

    Article  CAS  PubMed  Google Scholar 

  7. Haleagrahara N, Chakravarthi S, Mathews L (2011) Insulin like growth factor-1 (IGF-1) causes overproduction of IL-8, an angiogenic cytokine, and stimulates neovascularization in isoproterenol-induced myocardial infarction in rats. Int J Mol Sci 12:8562–8574

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Piecewicz SM, Pandey A, Roy B, Xiang SH, Zetter BR, Sengupta S (2012) Insulin-like growth factors promote vasculogenesis in embryonic stem cells. PLoS One 7(2):e32191

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Schneller M, Vuori K, Ruoslahti E (1997) Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. EMBO J 16:5600–5607

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Tsou R, Isik FF (2001) Integrin activation is required for VEGF and FGF receptor protein presence on human microvascular endothelial cells. Mol Cell Biochem 224:81–89

    Article  CAS  PubMed  Google Scholar 

  11. De S, Razornova O, McCabe NP, O’Toole T, Qin J, Byzova TV (2005) VEGF-integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci USA 102:7589–7594

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Montenegro CF, Salla-Pontes CL, Ribeiro JU, Machado AZ, Ramos RF, Figueiredo CC, Morandi V, Selistre-de-Araujo HS (2012) Blocking αvβ3 integrin by a recombinant RGD disintegrin impairs VEGF signaling in endothelial cells. Biochimie 94:1812–1820

    Article  CAS  PubMed  Google Scholar 

  13. Plow EF, Haas TA, Zhang L, Loftus J, Smith JW (2000) Ligand binding to integrins. J Biol Chem 275:21785–21788

    Article  CAS  PubMed  Google Scholar 

  14. Wei S, Said-Al-Naief N, Hameed O (2009) Estrogen and progesterone receptor expression is not always specific for mammary and gynecologic carcinomas: a tissue microarray and pooled literature review study. Appl Immunohistochem Mol Morphol 17:393–402

    Article  CAS  PubMed  Google Scholar 

  15. Shimizu K, Hirami Y, Saisho S, Yukawa T, Maeda A, Yasuda K, Nakata M (2012) Membrane-bound estrogen receptor-α expression and epidermal growth factor receptor mutation are associated with a poor prognosis in lung adenocarcinoma patients. World J Surg Oncol 10:141

    Article  PubMed Central  PubMed  Google Scholar 

  16. Davis PJ, Davis FB, Mousa SA, Luidens MK, Lin HY (2011) Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu Rev Pharmacol Toxicol 51:99–115

    Article  CAS  PubMed  Google Scholar 

  17. Fagiani E, Christofori G (2013) Angiopoietins in angiogenesis. Cancer Lett 328:18–26

    Article  CAS  PubMed  Google Scholar 

  18. Lawler PR, Lawler J (2012) Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med 2(5):a006627

    Article  PubMed Central  PubMed  Google Scholar 

  19. Patiar S, Harris AL (2006) Role of hypoxia-inducible factor-1 alpha as a cancer therapy target. Endocr Relat Cancer 13(Suppl 1):S61–S75

    Article  CAS  PubMed  Google Scholar 

  20. Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, Rodriguez-Enriquez S, Moreno-Sanchez R (2009) Hif-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 9:1084–1101

    Article  CAS  PubMed  Google Scholar 

  21. Wilson PM, LaBonte MJ, Lenz HJ (2013) Assessing the in vivo efficacy of biological antiangiogenic therapies. Cancer Chemother Pharmacol 71:1–12

    Article  CAS  PubMed  Google Scholar 

  22. Majumder S, Piquet AC, Dufour JF, Chatterjee S (2013) Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis. Eur J Pharmacol 705:86–95

    Article  CAS  PubMed  Google Scholar 

  23. Davis FB, Mousa SA, O’Connor L, Mohamed S, Lin HY, Cao HJ, Davis PJ (2004) Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ Res 94:1500–1506

    Article  CAS  PubMed  Google Scholar 

  24. Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis PJ (2005) Integrin alphavbeta 3 contains a cell surface receptor for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146:2864–2871

    Article  CAS  PubMed  Google Scholar 

  25. Mousa SA, Bergh JJ, Dier E, Rebbaa A, O’Connor LJ, Yalcin M, Aljada A, Dyskin E, Davis FB, Lin HY, Davis PJ (2008) Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis 11:183–190

    Article  CAS  PubMed  Google Scholar 

  26. Wong VW, Crawford JD (2013) Vasculogenic cytokines in wound healing. Biomed Res Int 2013:190486

    PubMed Central  PubMed  Google Scholar 

  27. Lin HY, Sun M, Tang HY, Lin C, Luidens MK, Mousa SA, Incerpi S, Drusano GL, Davis FB, Davis PJ (2009) l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 296:C980–C991

    Article  CAS  PubMed  Google Scholar 

  28. Incerpi S, Lin HY, De Vito P, Fiore AM, Ahmed RG, Salvia R, Candelotti E, Luly P, Pedersen JZ, Davis FB, Davis PJ (2013) Thyroid hormone inhibition in L6 myoblasts of IGF-1-mediated glucose uptake and proliferation: new roles for integrin αvβ3. Manuscript submitted

  29. Shih A, Zhang S, Cao HJ, Tang HY, Davis FB, Davis PJ (2004) Disparate effects of thyroid hormone on actions of epidermal growth factor and transforming growth factor-α are mediated by 3′,5′-cyclic adenosine monophosphate-dependent protein kinase II. Endocrinology 145:1708–1717

    Article  CAS  PubMed  Google Scholar 

  30. Glinskii AB, Glinsky GV, Lin HY, Tang HY, Sun M, Davis FB, Luidens MK, Mousa SA, Hercbergs AH, Davis PJ (2009) Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac). Cell Cycle 8:3554–3562

    PubMed  Google Scholar 

  31. Bharali DJ, Yalcin M, Davis PJ, Mousa SA (2013) Tetraiodothyroacetic acid (tetrac) conjugated PLGA nanoparticles: a nanomedicine approach to treat drug-resistant breast cancer. Nanomedicine 8:1943–1954

    Google Scholar 

  32. Farwell AP (2013) Nonthyroidal illness syndrome. Thyroid 20:478–484

    CAS  Google Scholar 

  33. Leonard JL, Farwell AP (1997) Thyroid hormone-regulated actin polymerization in brain. Thyroid 7:147–151

    Article  CAS  PubMed  Google Scholar 

  34. Stefansson S, Su EJ, Ishigami S, Cale JM, Gao Y, Gorlatova N, Lawrence DA (2007) The contributions of integrin affinity and integrin-cytoskeletal engagement in endothelial and smooth muscle cell adhesion to vitronectin. J Biol Chem 282:15679–15689

    Article  CAS  PubMed  Google Scholar 

  35. Mousa SA, Davis FB, Mohamed S, Davis PJ, Feng X (2006) Pro-angiogenesis action of thyroid hormone and analogs in a three-dimensional in vitro microvascular endothelial sprouting model. Int Angiol 25:407–413

    CAS  PubMed  Google Scholar 

  36. El-Eter E, Rebbaa H, Alkayali A, Mousa SA (2007) Role of thyroid hormone analogues in angiogenesis and the development of collaterals in the rabbit hind limb ischemia model. J Thromb Thrombolysis 5(Suppl 1):375

    Google Scholar 

  37. Owen JL, Mohamadzadeh M (2013) Macrophages and chemokines as mediators of angiogenesis. Front Physiol 4:159

    Article  PubMed Central  PubMed  Google Scholar 

  38. Davis PJ, Glinsky GV, Lin HY, Incerpi S, Davis FB, Mousa SA, Tang HY, Hercbergs A, Luidens MK (2013) Molecular mechanisms of actions of formulations of the thyroid hormone analogue, tetrac, on the inflammatory response. Endocr Res 38:112–118

    Article  CAS  PubMed  Google Scholar 

  39. Kumar AH, Martin K, Turner EC, Buneker CK, Dorgham K, Deterre P, Caplice NM (2013) Role of CX3CR1 receptor in monocyte/macrophage driven neovascularization. PLoS One 8(2):e57230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Mousa SA, Yalcin M, Bharali DJ, Meng R, Tang HY, Lin HY, Davis FB, Davis PJ (2012) Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and their growth in xenografts. Lung Cancer 76:39–45

    Article  PubMed  Google Scholar 

  41. Yalcin M, Lin HY, Sudha T, Bharali DJ, Meng R, Tang HY, Davis FB, Stain SC, Davis PJ, Mousa SA (2013) Response of human pancreatic cancer cell xenografts to tetraiodothyroacetic acid nanoparticles. Horm Cancer 4:176–185

    Article  CAS  PubMed  Google Scholar 

  42. Yalcin M, Bharali DJ, Lansing L, Dyskin E, Mousa SS, Hercbergs A, Davis FB, Davis PJ, Mousa SA (2009) Tetraiodothyroacetic acid (tetrac) and tetrac nanoparticles inhibit growth of human renal cell carcinoma xenografts. Anticancer Res 29:3825–3831

    CAS  PubMed  Google Scholar 

  43. Yalcin M, Dyskin E, Lansing L, Bharadi DJ, Mousa SS, Bridoux A, Hercbergs AH, Lin HY, Davis FB, Glinsky GV, Glinskii AB, Ma J, Davis PJ, Mousa SA (2010) Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 95:1972–1980

    Article  CAS  PubMed  Google Scholar 

  44. Yalcin M, Bharali DJ, Dyskin E, Dier E, Lansing L, Mousa SS, Davis FB, Davis PJ, Mousa SA (2010) Tetraiodothyroacetic acid and tetraiodothyroacetic acid nanoparticle effectively inhibit the growth of human follicular thyroid cell carcinoma. Thyroid 20:281–286

    Article  CAS  PubMed  Google Scholar 

  45. Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, Cohen BH, Stevens GH, Reddy SK, Peereboom DM, Elson PJ, Gupta MK, Barnett GH (2003) Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II trial. Anticancer Res 23:617–626

    CAS  PubMed  Google Scholar 

  46. Aziz SA, Sznol J, Adeniran A, Colberg JW, Camp RL, Kluger HM (2013) Vascularity of primary and metastatic renal cell carcinoma specimens. J Transl Med 11:15

    Article  PubMed Central  PubMed  Google Scholar 

  47. Hercbergs AH, Ashur-Fabian O, Garfield D (2011) Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Current Opin Endocrinol Diabetes Obes 17:432–436

    Article  Google Scholar 

  48. Schmidinger M, Vogl UM, Bojic M, Lamm W, Heinzl H, Haitel A, Clodi M, Kramer G, Zielinski CC (2011) Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 117:534–544

    Article  PubMed  Google Scholar 

  49. Riesenbeck LM, Bierer S, Hoffmeister J, Kopke T, Papavasilis P, Hertle L, Thielen B, Hermann E (2011) Hypothyroidism correlates with a better prognosis in metastatic renal carcinoma patients treated with sorafenib or sunitinib. World J Urol 29:807–813

    Article  CAS  PubMed  Google Scholar 

  50. Okwan-Duodo D, Landry J, Shen XZ, Diaz R (2013) Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis. Am J Physiol Regul Integr Comp Physiol 305:R205–R215

    Article  Google Scholar 

  51. Stewart JM, Gera L, Chan DC, York EJ, Simkeviciene V, Bunn PA Jr, Taraseviciene-Stewart L (2005) Combination cancer chemotherapy with one compound: pluripotent bradykinin antagonists. Peptides 26:1288–1291

    Article  CAS  PubMed  Google Scholar 

  52. Song X, Chen Y, Sun Y, Lin B, Qin Y, Hui H, Li Z, You Q, Lu N, Guo Q (2012) Oroxylin A, a classical natural product, shows a novel inhibitory effect on angiogenesis induced by lipopolysaccharide. Pharmacol Rep 64:1189–1199

    Article  CAS  PubMed  Google Scholar 

  53. Rakhesh M, Cate M, Vijay R, Shrikant A, Shanjana A (2012) A TLR4-interacting peptide inhibits lipopolysaccharide-stimulated inflammatory responses, migration and invasion of colon cancer SW480 cells. Oncoimmunology 1:1495–1506

    Article  PubMed Central  PubMed  Google Scholar 

  54. Melkamu T, Qian X, Upadhyaya P, O’Sullivan MG, Kassie F (2013) Lipopolysaccharide enhances mouse lung tumorigenesis: a model for inflammation-driven cancer. Vet Pathol 50:895–902

    Article  CAS  PubMed  Google Scholar 

  55. Mousa SA, Mohamed S, Wexler EJ, Kerr JS (2005) Antiangiogenesis and anticancer efficiency of TA138, a novel alphavbeta3 antagonist. Anticancer Res 25:197–206

    CAS  PubMed  Google Scholar 

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA

    Shaker A. Mousa, Heng Yuan Tang & Paul J. Davis

  2. Taipei International Cancer Center, Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Technology, Taipei Medical University, Taipei, Taiwan

    Hung-Yun Lin

  3. Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA

    Aleck Hercbergs

  4. Department of Medicine, Albany Medical College, Albany, NY, USA

    Mary K. Luidens & Paul J. Davis

  5. Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rennselaer, NY, 12144, USA

    Shaker A. Mousa

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  1. Shaker A. Mousa
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  2. Hung-Yun Lin
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Correspondence to Shaker A. Mousa.

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Mousa, S.A., Lin, HY., Tang, H.Y. et al. Modulation of angiogenesis by thyroid hormone and hormone analogues: implications for cancer management. Angiogenesis 17, 463–469 (2014). https://doi.org/10.1007/s10456-014-9418-5

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  • DOI: https://doi.org/10.1007/s10456-014-9418-5

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