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MTDH/AEG-1-based DNA vaccine suppresses lung metastasis and enhances chemosensitivity to doxorubicin in breast cancer

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Abstract

The gene MTDH/AEG-1 is overexpressed in more than 40% of breast cancer patients, and it is associated with poor clinical outcomes. Previous studies have indicated that MTDH/AEG-1 could promote metastatic lung-seeding and enhance chemoresistance. Therefore, MTDH/AEG-1 could be a candidate target against breast cancer lung metastasis. We demonstrated that MTDH/AEG-1-based DNA vaccine, delivered by attenuated Salmonella typhimurium, could evoke strong CD8+ cytotoxic-T-cell mediated immune responses against breast cancer. This vaccine showed anti-tumor growth and metastasis efficacy in a prophylactic setting. Importantly, in a therapeutic model, MTDH/AEG-1 vaccine was proved to increase chemosensitivity to doxorubicin and inhibit breast cancer lung metastasis. This vaccine could also prolong the life span of tumor-bearing mice without significant side effects in vivo. These results suggested that this novel DNA vaccine was effective in the inhibition of breast cancer growth and metastasis, and this vaccine in combination with chemotherapies offered new strategies for the clinical therapeutics of breast cancer metastasis.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  2. Berkowitz N, Gupta S, Silberman G (2000) Estimates of the lifetime direct costs of treatment for metastatic breast cancer. Value Health 3:23–30

    Article  PubMed  CAS  Google Scholar 

  3. Rice J, Ottensmeier CH, Stevenson FK (2008) DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 8:108–120

    Article  PubMed  CAS  Google Scholar 

  4. Xiang R, Lode HN, Chao TH, Ruehlmann JM, Dolman CS, Rodriguez F et al (2000) An autologous oral DNA vaccine protects against murine melanoma. Proc Natl Acad Sci USA 97:5492–5497

    Article  PubMed  CAS  Google Scholar 

  5. Luo Y, Zhou H, Mizutani M, Mizutani N, Reisfeld RA, Xiang R (2003) Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine. Proc Natl Acad Sci USA 100:8850–8855

    Article  PubMed  CAS  Google Scholar 

  6. Pertl U, Wodrich H, Ruehlmann JM, Gillies SD, Lode HN, Reisfeld RA (2003) Immunotherapy with a posttranscriptionally modified DNA vaccine induces complete protection against metastatic neuroblastoma. Blood 101:649–654

    Article  PubMed  CAS  Google Scholar 

  7. Xiang R, Mizutani N, Luo Y, Chiodoni C, Zhou H, Mizutani M et al (2005) A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res 65:553–561

    PubMed  CAS  Google Scholar 

  8. Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ et al (2002) Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 21:3592–3602

    Article  PubMed  CAS  Google Scholar 

  9. Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB (2005) Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene 353:8–15

    Article  PubMed  CAS  Google Scholar 

  10. Sarkar D, Emdad L, Lee SG, Yoo BK, Su ZZ, Fisher PB (2009) Astrocyte elevated gene-1: far more than just a gene regulated in astrocytes. Cancer Res 69:8529–8535

    Article  PubMed  CAS  Google Scholar 

  11. Britt DE, Yang DF, Yang DQ, Flanagan D, Callanan H, Lim YP et al (2004) Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells. Exp Cell Res 300:134–148

    Article  PubMed  CAS  Google Scholar 

  12. Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T et al (2009) Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci USA 106:12938–12943

    Article  PubMed  CAS  Google Scholar 

  13. Liu H, Song X, Liu C, Xie L, Wei L, Sun R (2009) Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. J Exp Clin Cancer Res 28:19

    Article  PubMed  Google Scholar 

  14. Yoo BK, Chen D, Su ZZ, Gredler R, Yoo J, Shah K et al (2010) Molecular mechanism of chemoresistance by astrocyte elevated gene-1. Cancer Res 70:3249–3258

    Article  PubMed  CAS  Google Scholar 

  15. Emdad L, Sarkar D, Lee SG, Su ZZ, Yoo BK, Dash R et al (2010) Astrocyte elevated gene-1: a novel target for human glioma therapy. Mol Cancer Ther 9:79–88

    Article  PubMed  CAS  Google Scholar 

  16. Emdad L, Lee SG, Su ZZ, Jeon HY, Boukerche H, Sarkar D et al (2009) Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis. Proc Natl Acad Sci USA 106:21300–21305

    Article  PubMed  CAS  Google Scholar 

  17. Brown DM, Ruoslahti E (2004) Metadherin a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5:365–374

    Article  PubMed  CAS  Google Scholar 

  18. Hu G, Wei Y, Kang Y (2009) The multifaceted role of MTDH/AEG-1 in cancer progression. Clin Cancer Res 15:5615–5620

    Article  PubMed  CAS  Google Scholar 

  19. Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F et al (2009) MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15:9–20

    Article  PubMed  CAS  Google Scholar 

  20. Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND et al (2009) Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 119:465–477

    Article  PubMed  CAS  Google Scholar 

  21. Yu C, Chen K, Zheng H, Guo X, Jia W, Li M et al (2009) Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 30:894–901

    Article  PubMed  CAS  Google Scholar 

  22. Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y et al (2007) Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 26:7647–7655

    Article  PubMed  CAS  Google Scholar 

  23. Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K et al (2006) Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66:1509–1516

    Article  PubMed  CAS  Google Scholar 

  24. Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB (2006) Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA 103:17390–17395

    Article  PubMed  CAS  Google Scholar 

  25. Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF, Fisher PB (2008) Astrocyte elevated gene-1 activates cell survival pathways through PI3 K-Akt signaling. Oncogene 27:1114–1121

    Article  PubMed  CAS  Google Scholar 

  26. Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ, Fisher PB (2008) Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res 68:1478–1484

    Article  PubMed  CAS  Google Scholar 

  27. Darji A, Guzman CA, Gerstel B, Wachholz P, Timmis KN, Wehland J et al (1997) Oral somatic transgene vaccination using attenuated S. typhimurium. Cell 91:765–775

    Article  PubMed  CAS  Google Scholar 

  28. Reisfeld RA, Niethammer AG, Luo Y, Xiang R (2004) DNA vaccines suppress tumor growth and metastases by the induction of anti-angiogenesis. Immunol Rev 199:181–190

    Article  PubMed  CAS  Google Scholar 

  29. Xiang R, Luo Y, Niethammer AG, Reisfeld RA (2008) Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 222:117–128

    Article  PubMed  CAS  Google Scholar 

  30. Luo Y, O’Hagan D, Zhou H, Singh M, Ulmer J, Reisfeld RA et al (2003) Plasmid DNA encoding human carcinoembryonic antigen (CEA) adsorbed onto cationic microparticles induces protective immunity against colon cancer in CEA-transgenic mice. Vaccine 21:1938–1947

    Article  PubMed  CAS  Google Scholar 

  31. Luo Y, Zhou H, Mizutani M, Mizutani N, Liu C, Xiang R et al (2005) A DNA vaccine targeting Fos-related antigen 1 enhanced by IL-18 induces long-lived T-cell memory against tumor recurrence. Cancer Res 65:3419–3427

    Article  PubMed  CAS  Google Scholar 

  32. Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C et al (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116:2132–2141

    Article  PubMed  CAS  Google Scholar 

  33. Cefai D, Morrison BW, Sckell A, Favre L, Balli M, Leunig M et al (1999) Targeting HER-2/neu for active-specific immunotherapy in a mouse model of spontaneous breast cancer. Int J Cancer 83:393–400

    Article  PubMed  CAS  Google Scholar 

  34. Esserman LJ, Lopez T, Montes R, Bald LN, Fendly BM, Campbell MJ (1999) Vaccination with the extracellular domain of p185neu prevents mammary tumor development in neu transgenic mice. Cancer Immunol Immunother 47:337–342

    Article  PubMed  CAS  Google Scholar 

  35. Granziero L, Krajewski S, Farness P, Yuan L, Courtney MK, Jackson MR et al (1999) Adoptive immunotherapy prevents prostate cancer in a transgenic animal model. Eur J Immunol 29:1127–1138

    Article  PubMed  CAS  Google Scholar 

  36. Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G et al (2002) A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 8:1369–1375

    PubMed  CAS  Google Scholar 

  37. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116:1955–1962

    Article  PubMed  CAS  Google Scholar 

  38. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059

    Article  PubMed  CAS  Google Scholar 

  39. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C et al (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15:1170–1178

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The attenuated S. typhimurium (dam − and AroA − ) strain RE88 and the murine 4T1 breast cancer cell line were kindly provided by Ralph A. Reisfeld (The Scripps Research Institute, La Jolla, CA). The cDNA encoding full-length murine MTDH was a gift from Erkki Ruoslahti (The Burnham Institute, La Jolla, CA). This study received financial support from Innotek Biopharmaceutical Co. Ltd. and Shanghai Advanced Research Institute (SARI), Chinese Academy of Sciences (CAS) (Research Fund No. 1105021000). This study was also supported by Grants from the Nature Science Foundation of Fujian, China (No. 2010J01372) and the National Nature Science Foundation of China (No. 30671938 to F. Guo, No. 81001177 to Y.H.Lin.). Thank Dr. Jian-Yong Wang, Ms. Shu-Qi Wang and Ms. Ying Yu for manuscript revision.

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Authors and Affiliations

  1. Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu’an, Fujian, 355000, China

    Ben-Jiang Qian, Chang-Ming Liu & Hui-Zhang Li

  2. Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), No. 225, South Chongqing Road, Shanghai, 200025, China

    Fei Yan, Na Li, Yi-Hui Lin & Fang Guo

  3. Center for Nanomedicine, Shanghai Advanced Research Institute of Chinese Academy of Sciences, Shanghai, China

    Qiao-Ling Liu & Fang Guo

  4. Department of Immunology, School of Basic Medicine, Peking Union Medical College, Beijing, China

    Yun-Ping Luo

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  1. Ben-Jiang Qian
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  2. Fei Yan
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  3. Na Li
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  8. Fang Guo
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  9. Hui-Zhang Li
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Correspondence to Fang Guo or Hui-Zhang Li.

Additional information

B.-J. Qian, F. Yan, these authors equally contributed to this work.

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Qian, BJ., Yan, F., Li, N. et al. MTDH/AEG-1-based DNA vaccine suppresses lung metastasis and enhances chemosensitivity to doxorubicin in breast cancer. Cancer Immunol Immunother 60, 883–893 (2011). https://doi.org/10.1007/s00262-011-0997-3

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  • DOI: https://doi.org/10.1007/s00262-011-0997-3

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