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Curcumin suppresses lymphatic vessel density in an in vivo human gastric cancer model

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Tumor Biology

Abstract

This study aimed to assess the effects of curcumin on lymphatic vessel density (LVD) in an in vivo model of gastric cancer using the gastric cancer cell line, SGC-7901. Gastric tumor-bearing nude mice were treated with saline or 40, 80, or 160 mg kg−1 day−1 curcumin for 8 weeks. The results indicated that the tumor volumes were significantly lower in mice treated with 80 and 160 mg kg−1 day−1 curcumin as compared with that of the control group (both P < 0.001). In addition, both 80 and 160 mg kg−1 day−1 curcumin significantly reduced LVD (both P < 0.01). Although immunohistochemical analysis showed that curcumin did not significantly alter the expression of prospero homeobox 1 (Prox-1), podoplanin, and vascular endothelial growth factor receptor 3 (VEGFR-3), 160 mg kg−1 day−1 curcumin significantly decreased the expression of Prox-1, podoplanin, and VEGFR-3 levels as detected by Western blot analysis (P ≤ 0.03). Downregulation of lymphatic vessel endothelial receptor 1 (LYVE-1), Prox-1, podoplanin, and VEGFR-3 mRNA expression by curcumin was also detected (all P < 0.05). Furthermore, the apoptosis rates of tumor cells increased with curcumin in a concentration-dependent manner (all P < 0.001). Thus, curcumin may inhibit gastric cancer lymph node metastasis. Our findings provide theoretical evidence and an experimental basis for further analysis of the clinical application of curcumin in the therapy of gastric cancer.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 2007;57:43–66.

    Article  PubMed  Google Scholar 

  2. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354–62.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Adachi Y, Shiraishi N, Suematsu T, Shiromizu A, Yamaguchi K, Kitano S. Most important lymph node information in gastric cancer: multivariate prognostic study. Ann Surg Oncol. 2000;7:503–7.

    Article  CAS  PubMed  Google Scholar 

  4. Coşkun U, Akyürek N, Dursun A, Yamaç D. Peritumoral lymphatic microvessel density associated with tumor progression and poor prognosis in gastric carcinoma. J Surg Res. 2010;164:110–5.

    Article  PubMed  Google Scholar 

  5. Ozmen F, Ozmen MM, Ozdemir E, Moran M, Seçkin S, Guc D, et al. Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer. World J Gastroenterol. 2011;17:3220–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Jüttner S, Wissmann C, Jöns T, Vieth M, Hertel J, Gretschel S, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol. 2006;24:228–40.

    Article  PubMed  Google Scholar 

  7. Mohandas KM, Desai DC. Epidemiology of digestive tract cancers in India. Indian J Gastroenterol. 1990;18:118–21.

    Google Scholar 

  8. Chung MY, Lim TG, Lee KW. Molecular mechanisms of chemopreventive phytochemicals against gastroenterological cancer development. World J Gastroenterol. 2013;19:984–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cai XZ, Huang WY, Qiao Y, Du SY, Chen Y, Chen D, et al. Inhibitory effects of curcumin on gastric cancer cells: a proteomic study of molecular targets. Phytomedicine. 2013;20:495–505.

    Article  CAS  PubMed  Google Scholar 

  10. Mahajanakatti AB, Murthy G, Sharma N, Skariyachan S. Exploring inhibitory potential of Curcumin against various cancer targets by in silico virtual screening. Interdiscip Sci. 2014;6:13–24.

    Article  CAS  PubMed  Google Scholar 

  11. Cai XZ, Wang J, Li XD, Wang GL, Liu FN, Cheng MS, et al. Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression. Cancer Biol Ther. 2009;8:1360–8.

    Article  CAS  PubMed  Google Scholar 

  12. Yu LL, Wu JG, Dai N, Yu HG, Si JM. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor. Oncol Rep. 2011;26:1197–203.

    CAS  PubMed  Google Scholar 

  13. Matsuo M, Sakurai H, Koizumi K, Saiki I. Curcumin inhibits the formation of capillary-like tubes by rat lymphatic endothelial cells. Cancer Lett. 2007;251:288–95.

    Article  CAS  PubMed  Google Scholar 

  14. Fujimoto A, Ishikawa Y, Akishima-Fukasawa Y, Ito K, Akasaka Y, Tamai S, et al. Significance of lymphatic invasion on regional lymph node metastasis in early gastric cancer using LYVE-1 immunohistochemical analysis. Am J Clin Pathol. 2007;127:82–8.

    Article  PubMed  Google Scholar 

  15. Yuanming L, Feng G, Lei T, Ying W. Quantitative analysis of lymphangiogenic markers in human gastroenteric tumor. Arch Med Res. 2007;38:106–12.

    Article  PubMed  Google Scholar 

  16. Zhang J, Ji J, Yuan F, Zhu L, Yan C, Yu YY, et al. Cyclooxygenase-2 expression is associated with VEGF-C and lymph node metastases in gastric cancer patients. Biomed Pharmacother. 2005;59:S285–8.

    Article  CAS  PubMed  Google Scholar 

  17. Chen FZ, Mo XM, Wang QP, Li J, Zhang L. Effects of rosiglitazone on the growth and lymphangiogenesis of human gastric cancer transplanted in nude mice. Oncol Rep. 2013;30:2705–12.

    CAS  PubMed  Google Scholar 

  18. Ma M, Zhang Y, Zhang L, et al. Establishment of a nude mouse model of human gastric cancer and characterization of its biological features. Acta Laboratorium Animalis Scientia Sinica. 2012;20:57–60.

    CAS  Google Scholar 

  19. Huang DS, Zhang L, Kuang HB. Study inhibitory effect of curcumin on angiogenesis of S180 sarcoma in mice. Modern Hospital. 2009;9:5–6.

    Google Scholar 

  20. Weidner N. Current pathologic methods for measuring in tratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat. 1996;36:169–80.

    Article  Google Scholar 

  21. Lee K, Park do J, Choe G, Kim HH, Kim WH, Lee HS. Increased intratumoral lymphatic vessel density correlates with lymph node metastasis in early gastric carcinoma. Ann Surg Oncol. 2010;17:73–80.

    Article  CAS  PubMed  Google Scholar 

  22. Nakamura KK. Importance of lymph vessels in gastric cancer: a prognostic indicator in general and a predictor for lymph node metastasis in early stage cancer. J Clin Pathol. 2006;59:77–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rudno-Rudzinska J, Kielan W, Grzebieniak Z, Dziegiel P, Donizy P, Mazur G, et al. High density of peritumoral lymphatic vessels measured by D2-40/podoplanin and LYVE-1 expression in gastric cancer patients: an excellent prognostic indicator or a false friend? Gastric Cancer. 2013;16:513–20.

    Article  CAS  PubMed  Google Scholar 

  24. Gordon EJ, Gale NW, Harvey NL. Expression of the hyaluronan receptor LYVE-1 is not restricted to the lymphatic vasculature: LYVE-1 is also expressed on embryonic blood vessels. Dev Dyn. 2008;237:1901–9.

    Article  CAS  PubMed  Google Scholar 

  25. Jackson DG. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. Acta Pathol Microbiol Immunol Scand. 2004;112:526–38.

    Article  CAS  Google Scholar 

  26. Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene. 2000;19:5598–605.

    Article  CAS  PubMed  Google Scholar 

  27. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–91.

    Article  CAS  PubMed  Google Scholar 

  28. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 2004;25:387–95.

    Article  CAS  PubMed  Google Scholar 

  29. Han FH, Li HM, Zheng DH, He YL, Zhan WH. The effect of the expression of vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 on the clinical outcome in patients with gastric carcinoma. Eur J Surg Oncol. 2010;36:1172–9.

    Article  PubMed  Google Scholar 

  30. Yashiro M, Shinto O, Nakamura K, Tendo M, Matsuoka T, Matsuzaki T, et al. Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model. Br J Cancer. 2009;101:1100–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hachisuka T, Narikiyo M, Yamada Y, Ishikawa H, Ueno M, Uchida H, et al. High lymphatic vessel density correlates with overexpression of VEGF-C in gastric cancer. Oncol Rep. 2005;13:733–7.

    CAS  PubMed  Google Scholar 

  32. Kigure W, Fujii T, Sutoh T, Morita H, Katoh T, Yajima RN, et al. The association of VEGF-C expression with tumor lymphatic vessel density and lymph node metastasis in patients with gastric cancer and gastrointestinal stromal tumor. Hepatogastroenterology. 2013;60:277–80.

    CAS  PubMed  Google Scholar 

  33. Agaimy A, Carney JA. Lymphatics and D2-40/podoplanin expression in gastrointestinal stromal tumours of the stomach with and without lymph node metastasis: an immunohistochemical study with special reference to the Carney triad. J Clin Pathol. 2010;63:229–34.

    Article  PubMed  Google Scholar 

  34. Brey EM, Lalani Z, Johnston C, Wong M, McIntire LV, Duke PJ, et al. Automated selection of DAB-labeled tissue for immunohistochemical quantification. J Histochem Cytochem. 2003;51(5):575–84.

    Article  CAS  PubMed  Google Scholar 

  35. Buchynska L, Kashuba E, Szekely L. Immunofluorescence staining of paraffin sections: creating DAB staining like virtual digital images using CMYK color conversion. Exp Oncol. 2008;30(4):327–9.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology, Sixth People’s Hospital Affiliated to Shanghai Jiaotong University, 600 Yishan Road, 200233, Shanghai, China

    Wei Da, Jinshui Zhu, Long Wang & Qun Sun

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  1. Wei Da
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  2. Jinshui Zhu
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  3. Long Wang
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Correspondence to Jinshui Zhu.

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Da, W., Zhu, J., Wang, L. et al. Curcumin suppresses lymphatic vessel density in an in vivo human gastric cancer model. Tumor Biol. 36, 5215–5223 (2015). https://doi.org/10.1007/s13277-015-3178-8

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  • DOI: https://doi.org/10.1007/s13277-015-3178-8

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