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Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells

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Abstract

Selenium (Se) has been widely reported to possess anti-tumor effects. Angiogenesis is the formation of new blood vessels and is required to supply oxygen, nutrients, and growth factors for tumor growth, progression, and metastasis. To explore whether the anti-tumor effect of Se was associated with angiogenesis in vivo, we studied the effects of sodium selenite (Sel) and methylseleninic acid (MSA) on tumors induced by canine mammary tumor cells (CMT1211) in mice; cyclophosphamide (CTX) served as a positive control. The results showed that the Se content was significantly increased in the Sel and MSA groups. Se significantly inhibited the tumor weights and volumes. Large necrotic areas and scattered and abnormal small necrotic areas were observed in the Se treatment group. Immunofluorescence double staining showed a reduction in the microvessel density (MVD) and increment in the vessel maturation index (VMI) compared with the untreated control group. As expected, the protein and mRNA levels of the angiogenesis factors angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) were decreased in the Se-treated tumors by IHC, as shown by western blotting and RT-QPCR. We also found that organic Se MSA provided stronger inhibition of tumor growth compared with inorganic sodium selenite (Sel). Altogether, our results indicated that Se exerted anti-tumor effects in vivo at least partially by inhibiting angiogenic factors.

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References

  1. Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE, Hurst R (2010) Selenium in human health and disease. Antioxid Redox Signal 14(7):1337–1383. doi:10.1089/ars.2010.3275

    Article  Google Scholar 

  2. Mistry HD, Broughton Pipkin F, Redman CW, Poston L (2012) Selenium in reproductive health. Am J Obstet Gynecol 206(1):21–30. doi:10.1016/j.ajog.2011.07.034

    Article  CAS  PubMed  Google Scholar 

  3. Chen YC, Prabhu KS, Das A, Mastro AM (2013) Dietary selenium supplementation modifies breast tumor growth and metastasis. Int J Cancer 133(9):2054–2064. doi:10.1002/ijc.28224

    Article  CAS  PubMed  Google Scholar 

  4. Rayman MP (2012) Selenium and human health. Lancet 379(9822):1256–1268. doi:10.1016/s0140-6736(11)61452-9

    Article  CAS  PubMed  Google Scholar 

  5. Hatfield DL, Tsuji PA, Carlson BA, Gladyshev VN (2014) Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem Sci 39(3):112–120. doi:10.1016/j.tibs.2013.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Westermarck T, Latvus A, Atroshi F (2014) The pharmacology and biochemistry of selenium in cancer. doi:10.5772/58425

  7. Cavallo F, De Giovanni C, Nanni P, Forni G, Lollini PL (2011) 2011: the immune hallmarks of cancer. Cancer Immunol Immunother: CII 60(3):319–326. doi:10.1007/s00262-010-0968-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wells A, Yates C, Shepard CR (2008) E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 25(6):621–628. doi:10.1007/s10585-008-9167-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bhattacharya A, Seshadri M, Oven SD, Toth K, Vaughan MM, Rustum YM (2008) Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs. Clin Cancer Res 14(12):3926–3932. doi:10.1158/1078-0432.CCR-08-0212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shojaei F (2012) Anti-angiogenesis therapy in cancer: current challenges and future perspectives. Cancer Lett 320(2):130–137. doi:10.1016/j.canlet.2012.03.008

    Article  CAS  PubMed  Google Scholar 

  11. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438(7070):932–936. doi:10.1038/nature04478

    Article  CAS  PubMed  Google Scholar 

  12. Auguste P, Lemiere S, Larrieu-Lahargue F, Bikfalvi A (2005) Molecular mechanisms of tumor vascularization. Critical Rev Oncol Hematol 54(1):53–61. doi:10.1016/j.critrevonc.2004.11.006

    Article  Google Scholar 

  13. Jonklaas J, Danielsen M, Wang H (2013) A pilot study of serum selenium, vitamin D, and thyrotropin concentrations in patients with thyroid cancer. Thyroid 23(9):1079–1086. doi:10.1089/thy.2012.0548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barrett CW, Singh K, Motley AK, Lintel MK, Matafonova E, Bradley AM, Ning W, Poindexter SV, Parang B, Reddy VK, Chaturvedi R, Fingleton BM, Washington MK, Wilson KT, Davies SS, Hill KE, Burk RF, Williams CS (2013) Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis. PLoS One 8(7):e67845. doi:10.1371/journal.pone.0067845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mashmouli B, Abdollah Pouri Hosseini SF (2013) Selenium as an effective element for lung cancer prevention and treatment. KAUMS J ((FEYZ)) 16(7):693–694

    Google Scholar 

  16. Zeng H, Combs GF Jr (2008) Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion. J Nutr Biochem 19(1):1–7. doi:10.1016/j.jnutbio.2007.02.005

    Article  PubMed  Google Scholar 

  17. Sanmartin C, Plano D, Sharma AK, Palop JA (2012) Selenium compounds, apoptosis and other types of cell death: an overview for cancer therapy. Int J Mol Sci 13(8):9649–9672. doi:10.3390/ijms13089649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rao L, Puschner B, Prolla TA (2001) Gene expression profiling of low selenium status in the mouse intestine: transcriptional activation of genes linked to DNA damage, cell cycle control and oxidative stress. J Nutr 131(12):3175–3181

    CAS  PubMed  Google Scholar 

  19. Jiang C, Jiang W, Ip C, Ganther H, Lu J (1999) Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake. Mol Carcinog 26(4):213–225. doi:10.1002/(SICI)1098-2744(199912)26:4<213::AID-MC1>3.0.CO;2-Z

    Article  CAS  PubMed  Google Scholar 

  20. Jiang C, Kim K-H, Wang Z, Lu J (2004) Methyl selenium-induced vascular endothelial apoptosis is executed by caspases and principally mediated by p38 MAPK pathway. Nutr Cancer 49(2):174–183

    Article  CAS  PubMed  Google Scholar 

  21. Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, Naldini L, De Palma M (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19(4):512–526. doi:10.1016/j.ccr.2011.02.005

    Article  CAS  PubMed  Google Scholar 

  22. Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos EK (2012) Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest 122(122 (6)):1991–2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307. doi:10.1038/nature10144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Carmeliet P (2004) VEGF as a key mediator of angiogenesis in cancer. Oncology 69:4–10

    Article  Google Scholar 

  25. Östman A (2004) PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 15(4):275–286. doi:10.1016/j.cytogfr.2004.03.002

    Article  PubMed  Google Scholar 

  26. Sleeckx N, Van Brantegem L, Fransen E, Van den Eynden G, Casteleyn C, Veldhuis Kroeze E, Van Ginneken C (2013) Evaluation of immunohistochemical markers of lymphatic and blood vessels in canine mammary tumours. J Comp Pathol 148(4):307–317. doi:10.1016/j.jcpa.2012.09.007

    Article  CAS  PubMed  Google Scholar 

  27. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731–3736. doi:10.1158/0008-5472.can-04-0074

    Article  CAS  PubMed  Google Scholar 

  28. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hagedorn NL, McCarville MB, Stewart CF, Davidoff AM (2007) Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 13(13):3942–3950. doi:10.1158/1078-0432.CCR-07-0278

    Article  CAS  PubMed  Google Scholar 

  29. Liu Y, Li W, Guo M, Li C, Qiu C (2015) Protective role of selenium compounds on the proliferation, apoptosis, and angiogenesis of a canine breast cancer cell line. Biol Trace Elem Res. doi:10.1007/s12011-015-0387-3

    Google Scholar 

  30. Li Z, Carrier L, Belame A, Thiyagarajah A, Salvo VA, Burow ME, Rowan BG (2009) Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis. Breast Cancer Res Treat 118(1):33–43. doi:10.1007/s10549-008-0216-x

    Article  CAS  PubMed  Google Scholar 

  31. Warrington JM, Kim JJM, Stahel P, Cieslar SRL, Moorehead RA, Coomber BL, Corredig M, Cant JP (2013) Selenized milk casein in the diet of BALB/c nude mice reduces growth of intramammary MCF-7 tumors. BMC Cancer 13:492–492. doi:10.1186/1471-2407-13-492

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hasunuma R, Ogawa T, Kawanishi Y (1982) Fluorometric determination of selenium in nanogram amounts in biological materials using 2, 3-diaminonaphthalene. Anal Biochem 126(2):242–245

    Article  CAS  PubMed  Google Scholar 

  33. Kakolyris S, Giatromanolaki A, Koukourakis M, Leigh IM, Georgoulias V, Kanavaros P, Sivridis E, Gatter KC, Harris AL (1999) Assessment of vascular maturation in Non-small cell lung cancer using a novel basement membrane component, LH39 correlation with p53 and angiogenic factor expression. Cancer Res 59(21):5602–5607

    CAS  PubMed  Google Scholar 

  34. Clark LC, Combs GF Jr, Turnbull BW et al (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: A randomized controlled trial. JAMA 276(24):1957–1963. doi:10.1001/jama.1996.03540240035027

    Article  CAS  PubMed  Google Scholar 

  35. Sleeman JP, Thiele W (2009) Tumor metastasis and the lymphatic vasculature. Int J Cancer 125(12):2747–2756. doi:10.1002/ijc.24702

    Article  CAS  PubMed  Google Scholar 

  36. Holopainen T, Bry M, Alitalo K, Saaristo A (2011) Perspectives on lymphangiogenesis and angiogenesis in cancer. J Surg Oncol 103(6):484–488. doi:10.1002/jso.21808

    Article  CAS  PubMed  Google Scholar 

  37. Thompson HJ, Wilson A, Lu J, Singh M, Jiang C, Upadhyaya P, El-Bayoumy K, Ip C (1994) Comparison of the effects of an organic and an inorganic form of selenium on a mammary carcinoma cell line. Carcinogenesis 15(2):183–186

    Article  CAS  PubMed  Google Scholar 

  38. Ip C (1998) Lessons from basic research in selenium and cancer prevention. J Nutr 128(11):1845–1854

    CAS  PubMed  Google Scholar 

  39. Grazul-Bilska AT, Caton JS, Arndt W, Burchill K, Thorson C, Borowczyk E, Bilski JJ, Redmer DA, Reynolds LP, Vonnahme KA (2009) Cellular proliferation and vascularization in ovine fetal ovaries: effects of undernutrition and selenium in maternal diet. Reproduction 137(4):699–707. doi:10.1530/REP-08-0375

    Article  CAS  PubMed  Google Scholar 

  40. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989

    Article  CAS  PubMed  Google Scholar 

  41. Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235(4787):442–447. doi:10.1126/science.2432664

    Article  CAS  PubMed  Google Scholar 

  42. Ahmad SA, Liu W, Jung YD, Fan F, Wilson M, Reinmuth N, Shaheen RM, Bucana CD, Ellis LM (2001) The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res 61(4):1255–1259

    CAS  PubMed  Google Scholar 

  43. Battegay EJ, Rupp J, Iruela-Arispe L, Sage EH, Pech M (1994) PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF beta-receptors. J Cell Biol 125(4):917–928. doi:10.1083/jcb.125.4.917

    Article  CAS  PubMed  Google Scholar 

  44. Ferrara N, Gerber H-P, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  CAS  PubMed  Google Scholar 

  45. Fagiani E, Christofori G (2013) Angiopoietins in angiogenesis. Cancer Lett 328(1):18–26. doi:10.1016/j.canlet.2012.08.018

    Article  CAS  PubMed  Google Scholar 

  46. Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y (1999) Hypoxia and vascular endothelial growth factor selectively Up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 274(22):15732–15739. doi:10.1074/jbc.274.22.15732

    Article  CAS  PubMed  Google Scholar 

  47. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18(1):4–25. doi:10.1210/edrv.18.1.0287

    Article  CAS  PubMed  Google Scholar 

  48. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13(1):9–22

    CAS  PubMed  Google Scholar 

  49. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21)):1182–1186. doi:10.1056/NEJM197111182852108

    CAS  PubMed  Google Scholar 

  50. Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nat Rev Mol Cell Biol 10(3):165–177

    Article  CAS  PubMed  Google Scholar 

  51. De Palma M, Venneri MA, Galli R, Sergi LS, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211–226. doi:10.1016/j.ccr.2005.08.002

    Article  PubMed  Google Scholar 

  52. McLeskey SW, Tobias CA, Vezza PR, Filie AC, Kern FG, Hanfelt J (1998) Tumor growth of FGF or VEGF transfected MCF-7 breast carcinoma cells correlates with density of specific microvessels independent of the transfected angiogenic factor. Am J Pathol 153(6):1993–2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Meeson AP, Argilla M, Ko K, Witte L, Lang RA (1999) VEGF deprivation-induced apoptosis is a component of programmed capillary regression. Development 126(7):1407–1415

    CAS  PubMed  Google Scholar 

  54. Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Investig 112(8):1142–1151. doi:10.1172/jci200318549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (NO. 4004-114060) and the Fundamental Research Funds for the Central Universities (NO. 2662015JC006).

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    1. College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province, 430070, People’s Republic of China

      Wenyu Li, Mengyao Guo, Yuzhu Liu, Weiwei Mu, Ganzhen Deng, Chengye Li & Changwei Qiu

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    Correspondence to Changwei Qiu.

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    All experiments were performed in accordance with protocols approved by the Animal Care and Use Committees of both the Chinese Academy of Medical Sciences and Huazhong Agricultural University.

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    Wenyu Li and Mengyao Guo contributed equally to this work.

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    Li, W., Guo, M., Liu, Y. et al. Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells. Biol Trace Elem Res 171, 371–379 (2016). https://doi.org/10.1007/s12011-015-0554-6

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