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Plasmid-encoding vasostatin inhibited the growth and metastasis of human hepatocellular carcinoma cells

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Abstract

The growth and metastasis of solid tumors depends on angiogenesis. Anti-angiogenesis therapy may represent a promising therapeutic option. Vasostatin, the N-terminal domain of calreticulin, is a very potent endogenous inhibitor of angiogenesis and tumor growth. In this study, we attempted to investigate whether plasmid-encoding vasostatin complexed with cationic liposome could suppress the growth and metastasis of hepatocellular carcinoma in vivo and discover its possible mechanism of action. Apoptosis induction of pSecTag2B-vasostatin plasmid on murine endothelial cells (MS1) was examined by flow cytometric analysis in vitro. Nude mice bearing HCCLM3 tumor received pSecTag2B-vasostatin, pSecTag2B-Null, and 0.9 % NaCl solution, respectively. Tumor net weight was measured and survival time was observed. Microvessel density within tumor tissues was determined by CD31 immunohistochemistry. H&E staining of lungs and TUNEL assay of primary tumor tissues were also conducted. The results displayed that pSecTag2B-vasostatin could inhibit the growth and metastasis of hepatocellular carcinoma xenografts and prolong survival time compared with the controls in vivo. Moreover, histologic analysis revealed that pSecTag2B-vasostatin treatment increased apoptosis and inhibited angiogenesis. The present data may be of importance to the further exploration of this new anti-angiogenesis approach in the treatment of hepatocellular cancer.

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References

  1. Pisani P, Parkin DM, Bray F, Ferlay J (1999) Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 83(1):18–29

    CAS  PubMed  Google Scholar 

  2. Tang ZY, Ye SL, Liu YK, Qin LX, Sun HC, Ye QH, Wang L, Zhou J, Qiu SJ, Li Y, Ji XN, Liu H, Xia JL, Wu ZQ, Fan J, Ma ZC, Zhou XD, Lin ZY, Liu KD (2004) A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 130(4):187–196. doi:10.1007/s00432-003-0511-1

    PubMed  Google Scholar 

  3. Yao L, Pike SE, Setsuda J, Parekh J, Gupta G, Raffeld M, Jaffe ES, Tosato G (2000) Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. Blood 96(5):1900–1905

    CAS  PubMed  Google Scholar 

  4. Xiao F, Wei Y, Yang L, Zhao X, Tian L, Ding Z, Yuan S, Lou Y, Liu F, Wen Y, Li J, Deng H, Kang B, Mao Y, Lei S, He Q, Su J, Lu Y, Niu T, Hou J, Huang MJ (2002) A gene therapy for cancer based on the angiogenesis inhibitor, vasostatin. Gene Ther 9(18):1207–1213. doi:10.1038/sj.gt.3301788

    Article  CAS  PubMed  Google Scholar 

  5. Pike SE, Yao L, Setsuda J, Jones KD, Cherney B, Appella E, Sakaguchi K, Nakhasi H, Atreya CD, Teruya-Feldstein J, Wirth P, Gupta G, Tosato G (1999) Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth. Blood 94(7):2461–2468

    CAS  PubMed  Google Scholar 

  6. Pike SE, Yao L, Jones KD, Cherney B, Appella E, Sakaguchi K, Nakhasi H, Teruya-Feldstein J, Wirth P, Gupta G, Tosato G (1998) Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J Exp Med 188(12):2349–2356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257. doi:10.1038/35025220

    Article  CAS  PubMed  Google Scholar 

  8. Zhang SZ, Pan FY, Xu JF, Yuan J, Guo SY, Dai G, Xue B, Shen WG, Wen CJ, Zhao DH, Li CJ (2005) Knockdown of c-Met by adenovirus-delivered small interfering RNA inhibits hepatocellular carcinoma growth in vitro and in vivo. Mol Cancer Ther 4(10):1577–1584. doi:10.1158/1535-7163.MCT-05-0106

    Article  CAS  PubMed  Google Scholar 

  9. Templeton NS, Lasic DD, Frederik PM, Strey HH, Roberts DD, Pavlakis GN (1997) Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol 15(7):647–652. doi:10.1038/nbt0797-647

    Article  CAS  PubMed  Google Scholar 

  10. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW (2003) Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 9(4):416–423. doi:10.1038/nm843

    Article  CAS  PubMed  Google Scholar 

  11. Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, Ren N, Qin LX (2008) Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology 48(6):1834–1842. doi:10.1002/hep.22531

    Article  CAS  PubMed  Google Scholar 

  12. Wu Y, Li ZY, Zhao X, Kan B, Wei YQ (2006) Inhibition of ovarian tumor growth by gene therapy with recombinant soluble vascular endothelial growth factor receptor 2. Hum Gene Ther 17(9):941–948. doi:10.1089/hum.2006.17.941

    Article  CAS  PubMed  Google Scholar 

  13. Oehler MK, Bicknell R (2000) The promise of anti-angiogenic cancer therapy. Br J Cancer 82(4):749–752. doi:10.1054/bjoc.1999.0991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82(1):4–6

    Article  CAS  PubMed  Google Scholar 

  15. Kinoshita S, Hirai R, Yamano T, Yuasa I, Tsukuda K, Shimizu N (2004) Angiogenesis inhibitor TNP-470 can suppress hepatocellular carcinoma growth without retarding liver regeneration after partial hepatectomy. Surg Today 34(1):40–46. doi:10.1007/s00595-003-2645-9

    Article  CAS  PubMed  Google Scholar 

  16. Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engstrom A, Timpl R, Welsh M, Claesson-Welsh L (2000) Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95(11):3403–3411

    CAS  PubMed  Google Scholar 

  17. Yao L, Pike SE, Pittaluga S, Cherney B, Gupta G, Jaffe ES, Tosato G (2002) Anti-tumor activities of the angiogenesis inhibitors interferon-inducible protein-10 and the calreticulin fragment vasostatin. Cancer Immunol Immunother 51(7):358–366. doi:10.1007/s00262-002-0294-2

    Article  CAS  PubMed  Google Scholar 

  18. Onn A, Isobe T, Itasaka S, Wu W, O’Reilly MS, Ki Hong W, Fidler IJ, Herbst RS (2003) Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice. Clin Cancer Res 9(15):5532–5539

    CAS  PubMed  Google Scholar 

  19. Camphausen K, Purow B, Sproull M, Scott T, Ozawa T, Deen DF, Tofilon PJ (2005) Influence of in vivo growth on human glioma cell line gene expression: convergent profiles under orthotopic conditions. Proc Natl Acad Sci USA 102(23):8287–8292. doi:10.1073/pnas.0502887102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Peng XC, Yang L, Yang LP, Mao YQ, Yang HS, Liu JY, Zhang DM, Chen LJ, Wei YQ (2008) Efficient inhibition of murine breast cancer growth and metastasis by gene transferred mouse survivin Thr34– > Ala mutant. J Exp Clin Cancer Res 27:46. doi:10.1186/1756-9966-27-46

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Ito I, Began G, Mohiuddin I, Saeki T, Saito Y, Branch CD, Vaporciyan A, Stephens LC, Yen N, Roth JA, Ramesh R (2003) Increased uptake of liposomal-DNA complexes by lung metastases following intravenous administration. Mol Ther 7(3):409–418

    Article  CAS  PubMed  Google Scholar 

  22. Thurston G, McLean JW, Rizen M, Baluk P, Haskell A, Murphy TJ, Hanahan D, McDonald DM (1998) Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J Clin Investig 101(7):1401–1413. doi:10.1172/JCI965

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Deol P, Khuller GK, Joshi K (1997) Therapeutic efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes against Mycobacterium tuberculosis infection induced in mice. Antimicrob Agents Chemother 41(6):1211–1214

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Taylor KM, Newton JM (1992) Liposomes for controlled delivery of drugs to the lung. Thorax 47(4):257–259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Xing-chen Peng, Ming Wang, Xu-xia Chen & Jing Liu

  2. Department of Pathology, Zunyi Medical College, Zunyi, 563003, People’s Republic of China

    Gui-hua Xiao

  3. Department of Pathology, Wenzhou Central Hospital, Wenzhou, 325000, People’s Republic of China

    Hong-li Liao

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  1. Xing-chen Peng
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  2. Ming Wang
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  3. Xu-xia Chen
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  4. Jing Liu
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  5. Gui-hua Xiao
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  6. Hong-li Liao
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Correspondence to Xing-chen Peng.

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Xing-chen Peng, Ming Wang, and Xu-xia Chen equally contributed to this work.

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Peng, Xc., Wang, M., Chen, Xx. et al. Plasmid-encoding vasostatin inhibited the growth and metastasis of human hepatocellular carcinoma cells. Mol Cell Biochem 395, 265–272 (2014). https://doi.org/10.1007/s11010-014-2135-y

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  • DOI: https://doi.org/10.1007/s11010-014-2135-y

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