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Tagging staphylococcal enterotoxin B (SEB) with TGFaL3 for breast cancer therapy

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Tumor Biology

Abstract

Recent research has attempted to direct superantigens towards tumors by means of tumor-targeted superantigen (TTS) strategy. In this study, we explored the antitumor property of TTS by fusing the third loop of transforming growth factor α (TGFαL3) to staphylococcal enterotoxin type B (SEB) and investigated the possibility of the therapeutic application of TGFαL3-SEB as a novel antitumor candidate in mice bearing breast cancer. Treatment was performed through intratumoral and intravenous injection of TGFαL3-SEB. Tumor size/volume, long-term survival, and cytokine secretion were assessed. In addition, the toxicity of each treatment on liver and kidneys was examined. Our results indicated that the relative tumor volume significantly increased in the mice receiving intratumoral TGFaL3-SEB (p < 0.05). Surprisingly, 5 out of the 14 mice were cleared from the tumor thoroughly in 10–25 days after intratumoral administration of TGFaL3-SEB. Quantification of cytokines clearly showed that the mice receiving intratumoral SEB significantly secreted higher interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) compared with the other groups (p < 0.05). The antitumor effect was followed by inhibition of cell proliferation (Ki-67) and micro vascularization (CD31). The highest and lowest levels of tumor necrosis were observed in the intratumoral administration of TGFαL3-SEB (85 %) and PBS (14 %), respectively. Intratumoral injection of TGFαL3-SEB increased the lifespan of the mice so 37.5 % of them could survive for more than 6 months (p < 0.05). Overall, our findings indicated that intratumoral administration of TGFαL3-SEB effectively inhibited the growth of breast tumors through induction of necrosis and suppressing proliferation and angiogenesis without systemic toxicity.

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References

  1. Jamal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun M. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5–26.

    Article  Google Scholar 

  2. Akin S, Babacan T, Sarici F, Altundag K. A novel targeted therapy in breast cancer: cyclin dependent kinase inhibitors. J BUON. 2014;19:42.

    PubMed  Google Scholar 

  3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  4. Tinoco G, Warsch S, Glück S, Avancha K, Montero AJ. Treating breast cancer in the 21st century: emerging biological therapies. J Cancer. 2013;4:117.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mohamadabadi MA, Hassan ZM, Zavaran A, Hosseini MG, Noori S, Mahdavi M, et al. Arteether exerts antitumor activity and reduces cd4+ cd25+ foxp3+ t-reg cells. Iran J Immunol. 2013;10:139.

    Google Scholar 

  6. Soliman H. Immunotherapy strategies in the treatment of breast cancer. Cancer Control 2013;20(1):17–21.

  7. Fooladi AAI, Sattari M, Hassan ZM, Mahdavi M, Azizi T, Horii A. In vivo induction of necrosis in mice fibrosarcoma via intravenous injection of type B staphylococcal enterotoxin. Biotechnol Lett. 2008;30:2053–9.

    Article  CAS  PubMed  Google Scholar 

  8. Hedlund G, Eriksson H, Sundstedt A, Forsberg G, Jakobsen BK, Pumphrey N, et al. The tumor targeted superantigen ABR-217620 selectively engages TRBV7-9 and exploits TCR-pMHC affinity mimicry in mediating T cell cytotoxicity. PLoS One. 2013;8:e79082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li SC, Kabeer MH. Designer immunotherapy specific for cancer. J Cell Sci Ther. 2013;4:e116.

    Google Scholar 

  10. Dohlsten M, Lando P, Hedlund G, Trowsdale J, Kalland T. Targeting of human cytotoxic t lymphocytes to MHC class II-expressing cells by staphylococcal enterotoxins. Immunology. 1990;71:96.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Dohlsten M, Sundstedt A, Björklund M, Hedlund G, Kalland T. Superantigen‐induced cytokines suppress growth of human colon‐carcinoma cells. Int J Cancer. 1993;54:482–8.

    Article  CAS  PubMed  Google Scholar 

  12. Hedlund G, Dohlsten M, Lando P, Kalland T. Staphylococcal enterotoxins direct and trigger CTL killing of autologous HLA-DR+ mononuclear leukocytes and freshly prepared leukemia cells. Cell Immunol. 1990;129:426–34.

    Article  CAS  PubMed  Google Scholar 

  13. Terman DS, Serier A, Dauwalder O, Badiou C, Dutour A, Thomas D, Brun V, Bienvenu J, Etienne J, Vandenesch F. Staphylococcal entertotoxins of the enterotoxin gene cluster (egcses) induce nitrous oxide-and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells. Front Cell Infect Microbiol 2013;13:38.

  14. Yousefi F, Mousavi SF, Siadat SD, Aslani MM, Amani J, Rad HS, Fooladi AAI. Preparation and in vitro evaluation of antitumor activity of tgfαl3-seb as a ligand-targeted superantigen. Cancer Res treat 2015. doi:10.1177/1533034614568753.

  15. Xu M-K, Zhang C-G, Chen Y, Guo W, Cai Y-M, Liu C-X. Research advances on immunopharmacology and cancer therapy of staphylococcal enterotoxins. Asian J Pharmacodyn Pharmacokinet. 2008;8:83–108.

    Google Scholar 

  16. Hu H-M, Poehlein CH, Urba WJ, Fox BA. Development of antitumor immune responses in reconstituted lymphopenic hosts. Cancer Res. 2002;62:3914–9.

    CAS  PubMed  Google Scholar 

  17. Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer. 2002;2:750–63.

    Article  CAS  PubMed  Google Scholar 

  18. Wu H-C, Chang D-K, Huang C-T. Targeted-therapy for cancer. J Cancer Mol. 2006;2:57–66.

    CAS  Google Scholar 

  19. Hosseini HM, Fooladi AAI, Soleimanirad J, Nourani MR, Mahdavi M. Exosome/staphylococcal enterotoxin b, an anti tumor compound against pancreatic cancer. J BUON. 2014;19:440–8.

    Google Scholar 

  20. Hosseini HM, Fooladi AAI, Soleimanirad J, Nourani MR, Davaran S, Mahdavi M. Staphylococcal entorotoxin B anchored exosome induces apoptosis in negative esterogen receptor breast cancer cells. Tumor Biol. 2014;35:3699–707.

    Article  Google Scholar 

  21. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem. 1987;56:881–914.

    Article  CAS  PubMed  Google Scholar 

  22. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield M. Close similarity of epidermal growth factor receptor and v-erb-b oncogene protein sequences. Nature. 1984 ;307(5951):521–7.

  23. Real FX, Rettig WJ, Chesa PG, Melamed MR, Old LJ, Mendelsohn J. Expression of epidermal growth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation. Cancer Res. 1986;46:4726–31.

    CAS  PubMed  Google Scholar 

  24. Santos S, Baptista CS, Abreu RM, Bastos E, Amorim I, Gut IG, et al. ERBB2 in cat mammary neoplasias disclosed a positive correlation between RNA and protein low expression levels: a model for ERBB-2 negative human breast cancer. PLoS One. 2013;8:e83673.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Khiavi MM, Vosoughhosseini S, Saravani S, Halimi M. Immunohistochemical correlation of epidermal growth factor receptor and c-erbB-2 with histopathologic grading of mucoepidermoid carcinoma. J Cancer Res Ther. 2012;8:586.

    Article  PubMed  Google Scholar 

  26. Connor AE, Baumgartner RN, Baumgartner KB, Pinkston CM, John EM, Torres-Mejía G, et al. Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among hispanic and non-hispanic white women: the breast cancer health disparities study. Int J Mol Epidemiol Genet. 2013;4:235.

    PubMed  PubMed Central  Google Scholar 

  27. Faloppi L, Andrikou K, Cascinu S. Cetuximab: still an option in the treatment of pancreatic cancer? Expert Opin Biol Ther. 2013;13:791–801.

    Article  CAS  PubMed  Google Scholar 

  28. Sabbatino F, Ferrone S. Can the “right” EGFR-specific mAb dramatically improve EGFR-targeted therapy? Clin Cancer Res. 2013;19:958–60.

    Article  CAS  PubMed  Google Scholar 

  29. Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995;55:5536–9.

    CAS  PubMed  Google Scholar 

  30. Kamposioras K, Pentheroudakis G, Pavlidis N. Exploring the biology of cancer of unknown primary: breakthroughs and drawbacks. Eur J Clin Investig. 2013;43:491–500.

    Article  CAS  Google Scholar 

  31. Aziz S, Pervez S, Khan S, Kayani N, Rahbar M. Epidermal growth factor receptor (EGFR) as a prognostic marker: an immunohistochemical study on 315 consecutive breast carcinoma patients. J Pak Med Assoc. 2002;52:104–10.

    CAS  PubMed  Google Scholar 

  32. Dua R, Zhang J, Nhonthachit P, Penuel E, Petropoulos C, Parry G. EGFR over-expression and activation in high HER2, ER negative breast cancer cell line induces trastuzumab resistance. Breast Cancer Res Treat. 2010;122:685–97.

    Article  CAS  PubMed  Google Scholar 

  33. Grupka NL, Lear-Kaul KC, Kleinschmidt-DeMasters BK, Singh M. Epidermal growth factor receptor status in breast cancer metastases to the central nervous system: comparison with HER-2/neu status. Arch Pathol Lab Med. 2004;128:974–9.

    CAS  PubMed  Google Scholar 

  34. Xu Q, Zhang X, Yue J, Liu C, Cao C, Zhong H, et al. Human TGFalpha-derived peptide TGFalphal3 fused with superantigen for immunotherapy of EGFR-expressing tumours. BMC Biotechnol. 2010;10:91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Saltz LB, Meropol NJ, Loehrer PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.

    Article  CAS  PubMed  Google Scholar 

  36. Imani-Fooladi AA, Yousefi F, Mousavi SF, Amani J. In silico design and analysis of TGFαl3-seb fusion protein as “a new antitumor agent” candidate by ligand-targeted superantigens technique. Iran J Cancer Prev. 2014;7:152.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Xanthopoulos J, Romano A, Majumdar S. Response of mouse breast cancer cells to anastrozole, tamoxifen, and the combination. BioMed Res Int. 2005;2005:10–9.

    CAS  Google Scholar 

  38. Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander A, et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One. 2014;9:e85311.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Liu Q, Tan Q, Zheng Y, Chen K, Qian C, Li N, et al. Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation. J Biol Chem. 2014;289:11522–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Heimburg J, Yan J, Morey S, Glinskii OV, Huxley VH, Wild L, et al. Inhibition of spontaneous breast cancer metastasis by anti-Thomsen-Friedenreich antigen monoclonal antibody JAA-F11. Neoplasia. 2006;8:939–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fooladi AAI, Halabian R, Mahdavi M, Amin M, Hosseini HM. Staphylococcal enterotoxin b/texosomes as a candidate for breast cancer immunotherapy. Tumor Biol. 2015;1–10. doi:10.1007/s13277-015-3877-1.

  42. Pita JCLR, Xavier AL, Sousa TKG, Mangueira VM, Tavares JF, Júnior RJO, et al. In vitro and in vivo antitumor effect of trachylobane-360, a diterpene from Xylopia langsdorffiana. Molecules. 2012;17:9573–89.

    Article  CAS  PubMed  Google Scholar 

  43. Al-Ghananeem AM, Malkawi AH, Muammer YM, Balko JM, Black EP, Mourad W, et al. Intratumoral delivery of paclitaxel in solid tumor from biodegradable hyaluronan nanoparticle formulations. AAPS PharmSciTech. 2009;10:410–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Celikoglu F, Celikoglu SI, Goldberg EP. Techniques for intratumoral chemotherapy of lung cancer by bronchoscopic drug delivery. Cancer Ther. 2008;6:545–52.

    CAS  Google Scholar 

  45. Hudson KR, Tiedemann RE, Urban RG, Lowe SC, Strominger JL, Fraser JD. Staphylococcal enterotoxin a has two cooperative binding sites on major histocompatibility complex class II. J Exp Med. 1995;182:711–20.

    Article  CAS  PubMed  Google Scholar 

  46. Binek M, Newcomb J, Rogers C, Rogers T. Localisation of the mitogenic epitope of staphylococcal enterotoxin B. J Med Microbiol. 1992;36:155–63.

    Article  Google Scholar 

  47. Buelow R, O’Hehir R, Schreifels R, Kummerehl T, Riley G, Lamb J. Localization of the immunologic activity in the superantigen staphylococcal enterotoxin B using truncated recombinant fusion proteins. J Immunol. 1992;148:1–6.

    CAS  PubMed  Google Scholar 

  48. Issa A, Gill JW, Heideman MR, Sahin O, Wiemann S, Dey JH, et al. Combinatorial targeting of FGF and ERBB receptors blocks growth and metastatic spread of breast cancer models. Breast Cancer Res. 2013;15:R8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miller F, Miller B, Heppner G. Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability. Invasion Metastasis. 1982;3:22–31.

    Google Scholar 

  50. Miller F. Tumor subpopulation interactions in metastasis. Invasion Metastasis. 1982;3:234–42.

    Google Scholar 

  51. Nicolson GL, Brunson KW, Fidler IJ. Specificity of arrest, survival, and growth of selected metastatic variant cell lines. Cancer Res. 1978;38:4105–11.

    CAS  PubMed  Google Scholar 

  52. Goldberg EP, Hadba AR, Almond BA, Marotta JS. Intratumoral cancer chemotherapy and immunotherapy: opportunities for nonsystemic preoperative drug delivery. J Pharm Pharmacol. 2002;54:159–80.

    Article  CAS  PubMed  Google Scholar 

  53. Guo C, Buranych A, Sarkar D, Fisher PB, Wang X-Y. The role of tumor-associated macrophages in tumor vascularization. Vasc Cell. 2013;5:20.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tong Q, Liu K, Lu X-M, Shu X-G, Wang G-B. Construction and characterization of a novel fusion protein mg7-scfv/seb against gastric cancer. J of Biomed and Biotechnol. 2010. doi:10.1155/2010/121094.

  55. Fooladi A, Sattari M, Nourani MR. Synergistic effects between staphylococcal enterotoxin type b and Monophosphoryl lipid A against mouse fibrosarcoma. J BUON. 2010;15:340–7.

    Google Scholar 

  56. Wang D, Xu Z, Yu H, Chen X, Feng B, Cui Z, et al. Treatment of metastatic breast cancer by combination of chemotherapy and photothermal ablation using doxorubicin-loaded DNA wrapped gold nanorods. Biomaterials. 2014;35:8374–84.

    Article  CAS  PubMed  Google Scholar 

  57. Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res. 2013;3:46.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was financially supported by the Pasteur Institute of Iran (Ph.D Grant No. B-8804).

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Authors and Affiliations

  1. Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran

    Forough Yousefi, Seyed Davar Siadat, Mohammad Mehdi Aslani & Seyed Fazlollah Mousavi

  2. Department of Medical Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Alireza Azizi Saraji

  3. Department of Pathobiology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Saeed Hesaraki

  4. Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Abbas Ali Imani Fooladi

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  1. Forough Yousefi
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  2. Seyed Davar Siadat
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  3. Alireza Azizi Saraji
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  4. Saeed Hesaraki
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  5. Mohammad Mehdi Aslani
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  6. Seyed Fazlollah Mousavi
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  7. Abbas Ali Imani Fooladi
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Correspondence to Seyed Fazlollah Mousavi or Abbas Ali Imani Fooladi.

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All of the animal experiments were carried out under a project license issued by the Pasteur Institute of Iran according to the local Animal Experimentation Rules.

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Yousefi, F., Siadat, S.D., Saraji, A.A. et al. Tagging staphylococcal enterotoxin B (SEB) with TGFaL3 for breast cancer therapy. Tumor Biol. 37, 5305–5316 (2016). https://doi.org/10.1007/s13277-015-4334-x

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  • DOI: https://doi.org/10.1007/s13277-015-4334-x

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