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Endostatin gene therapy delivered by attenuated Salmonella typhimurium in murine tumor models

Cancer Gene Therapy volume 25, pages 167–183 (2018)Cite this article

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Abstract

Salmonella typhimurium (hereafter S. typhimurium), as Gram-negative facultative anaerobic bacteria, are good candidates for cancer therapy and delivering therapeutic antitumor agents. However, it is necessary to reduce the virulence of such bacteria and enhance their tumor-targeting ability, and their immunostimulatory ability to induce tumor cell apoptosis. In this study, we constructed a S. typhimurium mutant named S634 harboring aroA mutation and additional mutations involved in modifications of lipid A. Upon intraperitoneal infection in mice, the aroA-deficient strain S634 showed greatly attenuated virulence and preferential accumulation within tumor tissue. We next investigated the ability of S636, the asd mutant derivative of S634, to deliver the anti-angiogenic agent “endostatin” (S636/pES) and to inhibit tumor growth in mouse CT26 colon carcinoma and B16F10 melanoma models. S636/pES-treated tumor-bearing mice showed suppressed tumor growth and prolonged survival, compared to mice treated with either the bacteria carrying empty plasmids or PBS intraperitoneally. Immunohistochemical studies demonstrated that, when tumor-bearing mice were infected with S636/pES, Salmonella colonization and endostatin expression were accompanied by the increase of apoptosis level and suppression of tumor angiogenesis within tumor tissues. Our findings showed that endostatin gene therapy delivered by attenuated S. typhimurium displays therapeutic antitumor effects in murine tumor models.

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References

  1. Chang WW, Lee CH. Salmonella as an innovative therapeutic antitumor agent. Int J Mol Sci. 2014;15:14546–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Malmgren RA, Flanigan CC. Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer Res. 1955;15:473–8.

    PubMed  CAS  Google Scholar 

  3. Kohwi Y, Imai K, Tamura Z, Hashimoto Y. Antitumor effect of Bifidobacterium infantis in mice. Gan. 1978;69:613–8.

    PubMed  CAS  Google Scholar 

  4. Stritzker J, Weibel S, Hill PJ, Oelschlaeger TA, Goebel W, Szalay AA. Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice. Int J Med Microbiol. 2007;297:151–62.

    Article  PubMed  CAS  Google Scholar 

  5. Pawelek JM, Low KB, Bermudes D. Tumor-targeted Salmonella as a novel anticancer vector. Cancer Res. 1997;57:4537–44.

    PubMed  CAS  Google Scholar 

  6. Low KB, Ittensohn M, Le T, Platt J, Sodi S, Amoss M, et al. Lipid A mutant Salmonella with suppressed virulence and TNF alpha induction retain tumor-targeting in vivo. Nat Biotechnol. 1999;17:37–41.

    Article  PubMed  CAS  Google Scholar 

  7. Forbes NS, Munn LL, Fukumura D, Jain RK. Sparse initial entrapment of systemically injected Salmonella typhimurium leads to heterogeneous accumulation within tumors. Cancer Res. 2003;63:5188–93.

    PubMed  CAS  Google Scholar 

  8. Ganai S, Arenas RB, Sauer JP, Bentley B, Forbes NS. In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis. Cancer Gene Ther. 2011;18:457–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zhang M, Forbes NS. Trg-deficient Salmonella colonize quiescent tumor regions by exclusively penetrating or proliferating. J Control Release. 2015;199:180–9.

    Article  PubMed  CAS  Google Scholar 

  10. Forbes NS. Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer. 2010;10:785–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Avogadri F, Martinoli C, Petrovska L, Chiodoni C, Transidico P, Bronte V, et al. Cancer immunotherapy based on killing of Salmonella-infected tumor cells. Cancer Res. 2005;65:3920–7.

    Article  PubMed  CAS  Google Scholar 

  12. Kaimala S, Mohamed YA, Nader N, Issac J, Elkord E, Chouaib S, et al. Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity. Cancer Immunol Immunother. 2014;63:587–99.

    Article  PubMed  CAS  Google Scholar 

  13. Jia LJ, Xu HM, Ma DY, Hu QG, Huang XF, Jiang WH, et al. Enhanced therapeutic effect by combination of tumor-targeting Salmonella and endostatin in murine melanoma model. Cancer Biol Ther. 2005;4:840–5.

    Article  PubMed  CAS  Google Scholar 

  14. Jiang T, Zhou C, Gu J, Liu Y, Zhao L, Li W, et al. Enhanced therapeutic effect of cisplatin on the prostate cancer in tumor-bearing mice by transfecting the attenuated Salmonella carrying a plasmid co-expressing p53 gene and mdm2 siRNA. Cancer Lett. 2013;337:133–42.

    Article  PubMed  CAS  Google Scholar 

  15. Fritz SE, Henson MS, Greengard E, Winter AL, Stuebner KM, Yoon U, et al. A phase I clinical study to evaluate safety of orally administered, genetically engineered Salmonella enterica serovar typhimurium for canine osteosarcoma. Vet Med Sci. 2016;2:179–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Nemunaitis J, Cunningham C, Senzer N, Kuhn J, Cramm J, Litz C, et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. 2003;10:737–44.

    Article  PubMed  CAS  Google Scholar 

  17. Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol. 2002;20:142–52.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hayashi K, Zhao M, Yamauchi K, Yamamoto N, Tsuchiya H, Tomita K, et al. Cancer metastasis directly eradicated by targeted therapy with a modified Salmonella typhimurium. J Cell Biochem. 2009;106:992–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hoffman RM. Tumor-seeking Salmonella amino acid auxotrophs. Curr Opin Biotechnol. 2011;22:917–23.

    Article  PubMed  CAS  Google Scholar 

  20. Matsumoto Y, Miwa S, Zhang Y, Zhao M, Yano S, Uehara F, et al. Intraperitoneal administration of tumor-targeting Salmonella typhimurium A1-R inhibits disseminated human ovarian cancer and extends survival in nude mice. Oncotarget. 2015;6:11369–77.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhao M, Yang M, Ma H, Li X, Tan X, Li S, et al. Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice. Cancer Res. 2006;66:7647–52.

    Article  PubMed  CAS  Google Scholar 

  22. Hoiseth SK, Stocker BAD. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature. 1981;291:238–9.

    Article  PubMed  CAS  Google Scholar 

  23. Sebastian F, Michael F, Dino K, Manfred R, Denitsa E, Agata B, et al. aroA-deficient Salmonella enterica serovar typhimurium is more than a metabolically attenuated mutant. Mbio. 2016;7:e01220–16.

    Google Scholar 

  24. Miyake K. Innate recognition of lipopolysaccharide by Toll-like receptor 4–MD-2. Trends Microbiol. 2004;12:186.

    Article  PubMed  CAS  Google Scholar 

  25. Knirel YA, Valvano MA. Bacterial lipopolysaccharides: structure, chemical synthesis, biogenesis, and interaction with host cells. SpringerWienNewYork: Vienna, Austria and New York, USA, 2011.

  26. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71:635–700.

    Article  PubMed  CAS  Google Scholar 

  27. Ohto U, Fukase K, Miyake K, Shimizu T. Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2. Proc Natl Acad Sci USA. 2012;109:7421–6.

    Article  PubMed  Google Scholar 

  28. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science. 2013;341:1250–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashitakamura S, et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science. 2013;341:1246–9.

    Article  PubMed  CAS  Google Scholar 

  30. Nunesalves C. Host response: new LPS receptors discovered. Nat Rev Microbiol. 2014;12:658

    Article  CAS  Google Scholar 

  31. Teghanemt A, Zhang D, Levis EN, Weiss JP, Gioannini TL. Molecular basis of reduced potency of underacylated endotoxins. J Immunol. 2005;175:4669–76.

    Article  PubMed  CAS  Google Scholar 

  32. Rossignol DP, Lynn M. TLR4 antagonists for endotoxemia and beyond. Curr Opin Investig Drugs. 2005;6:496–502.

    PubMed  CAS  Google Scholar 

  33. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.

    Article  PubMed  CAS  Google Scholar 

  34. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:273–94.

    Google Scholar 

  35. Walia A, Yang JF, Huang YH, Rosenblatt MI, Chang JH, Azar DT. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta. 2015;1850:2422–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Shichiri M, Hirata Y. Antiangiogenesis signals by endostatin. FASEB J. 2001;15:1044–53.

    Article  PubMed  CAS  Google Scholar 

  37. Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, et al. Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. J Biol Chem. 2002;277:16464–9.

    Article  PubMed  CAS  Google Scholar 

  38. Kim YM, Hwang S, Kim YM, Pyun BJ, Kim TY, Lee ST, et al. Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J Biol Chem. 2002;277:27872–9.

    Article  PubMed  CAS  Google Scholar 

  39. Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci USA. 2003;100:4766–71.

    Article  PubMed  CAS  Google Scholar 

  40. Shi H, Huang Y, Zhou H, Song X, Yuan S, Fu Y, et al. Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin. Blood. 2007;110:2899–906.

    Article  PubMed  CAS  Google Scholar 

  41. Kisker O, Becker CM, Prox D, Fannon M, D’Amato R, Flynn E, et al. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 2001;61:7669–74.

    PubMed  CAS  Google Scholar 

  42. Perletti G, Concari P, Giardini R, Marras E, Piccinini F, Folkman J, et al. Antitumor activity of endostatin against carcinogen-induced rat primary mammary tumors. Cancer Res. 2000;60:1793.

    PubMed  CAS  Google Scholar 

  43. Yamaguchi N, Anand‐Apte B, Lee M, Sasaki T, Fukai N, Shapiro R, et al. Endostatin inhibits VEGF‐induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J. 1999;18:4414–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Kulke MH, Bergsland EK, Ryan DP, Enzinger PC, Lynch TJ, Zhu AX, et al. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol. 2006;24:3555–61.

    Article  PubMed  CAS  Google Scholar 

  45. Xu R, Ma N, Wang F, Ma L, Chen R, Chen R, et al. Results of a randomized and controlled clinical trial evaluating the efficacy and safety of combination therapy with Endostar and S-1 combined with oxaliplatin in advanced gastric cancer. Oncotargets Ther. 2013;6:925–9.

    CAS  Google Scholar 

  46. Yang L, Wang JW, Sun Y, Zhu YZ, Liu XQ, Li WL, et al. Randomized phase II trial on escalated doses of Rh-endostatin (YH-16) for advanced non-small cell lung cancer. Chin J Oncol. 2006;28:138–41.

    Google Scholar 

  47. Jia H, Li Y, Zhao T, Li X, Hu J, Yin D, et al. Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma. Cancer Immunol Immunother. 2012;61:1977–87.

    Article  PubMed  CAS  Google Scholar 

  48. Li X, Li Y, Wang B, Ji K, Liang Z, Guo B, et al. Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment. J Cancer Res Clin Oncol. 2013;139:971–80.

    Article  PubMed  CAS  Google Scholar 

  49. Li C, Chen X, Kou L, Hu B, Zhu LP, Fan YR, et al. Selenium-Bifidobacterium longum as a delivery system of endostatin for inhibition of pathogenic bacteria and selective regression of solid tumor. Exp Ther Med. 2010;1:129–35.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wang S, Kong Q, Curtiss R 3rd. New technologies in developing recombinant attenuated Salmonella vaccine vectors. Microb Pathog. 2013;58:17–28.

    Article  PubMed  CAS  Google Scholar 

  51. Hitchcock PJ, Brown TM. Morphological heterogeneity among Salmonella lipopolysaccharide chemotypes in silver-stained polyacrylamide gels. J Bacteriol. 1983;154:269–77.

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Kong Q, Yang J, Liu Q, Alamuri P, Roland KL, Curtiss R. Effect of deletion of genes involved in lipopolysaccharide core and O-antigen synthesis on virulence and immunogenicity of Salmonella enterica serovar typhimurium. Infect Immun. 2011;79:4227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Seung-Hwan P, Hai ZJ, Hong NV, Jiang SN, Dong-Yeon K, Michael S, et al. RGD peptide cell-surface display enhances the targeting and therapeutic efficacy of attenuated Salmonella-mediated cancer therapy. Theranostics. 2016;6:1672–82.

    Article  CAS  Google Scholar 

  54. Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.

    Article  PubMed  CAS  Google Scholar 

  55. Fina L, Molgaard H, Robertson D, Bradley N, Monaghan P, Delia D, et al. Expression of the CD34 gene in vascular endothelial cells. Blood. 1990;75:2417–26.

    PubMed  CAS  Google Scholar 

  56. Bretscher LE, Morrell MT, Funk AL, Klug CS. Purification and characterization of the L-Ara4N transferase protein ArnT from Salmonella typhimurium. Protein Expr Purif. 2006;46:33–9.

    Article  PubMed  CAS  Google Scholar 

  57. Herrera CM, Hankins JV, Trent MS. Activation of PmrA inhibits LpxT-dependent phosphorylation of lipid A promoting resistance to antimicrobial peptides. Mol Microbiol. 2010;76:1444–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Lee H, Hsu FF, Turk J, Groisman EA. The PmrA-regulated gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica. Mol Microbiol. 2004;186:4124–33.

    CAS  Google Scholar 

  59. Stead CM, Pride AC, Trent MS. Genetics and biosynthesis of lipid A. Vienna: Springer; 2011.

    Book  Google Scholar 

  60. Raetz CR, Reynolds CM, Trent MS, Bishop RE. Lipid A modification systems in Gram-negative bacteria. Annu Rev Biochem. 2007;76:295–329.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Toley BJ, Forbes NS. Motility is critical for effective distribution and accumulation of bacteria in tumor tissue. Integr Biol. 2012;4:165–76.

    Article  CAS  Google Scholar 

  62. Kasinskas RW, Forbes NS. Salmonella typhimurium lacking ribose chemoreceptors localize in tumor quiescence and induce apoptosis. Cancer Res. 2007;67:3201–9.

    Article  PubMed  CAS  Google Scholar 

  63. Crull K, Bumann D, Weiss S. Influence of infection route and virulence factors on colonization of solid tumors by Salmonella enterica serovar typhimurium. FEMS Immunol Med Microbiol. 2011;62:75–83.

    Article  PubMed  CAS  Google Scholar 

  64. Leschner S, Westphal K, Dietrich N, Viegas N, Jablonska J, Lyszkiewicz M, et al. Tumor invasion of Salmonella enterica serovar typhimurium is accompanied by strong hemorrhage promoted by TNF-α. PLoS ONE. 2009;4:e6692.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Stritzker J, Weibel S, Seubert C, Götz A, Tresch A, Van RN, et al. Enterobacterial tumor colonization in mice depends on bacterial metabolism and macrophages but is independent of chemotaxis and motility. Int J Med Microbiol. 2010;300:449–56.

    Article  PubMed  CAS  Google Scholar 

  66. Zhao M, Yang M, Li XM, Jiang P, Baranov E, Li S, et al. Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc Natl Acad Sci USA. 2005;102:755.

    Article  PubMed  CAS  Google Scholar 

  67. Zheng JH, Nguyen VH, Jiang SN, Park SH, Tan W, Hong SH, et al. Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin. Sci Transl Med. 2017;9:eaak9537.

    Article  PubMed  CAS  Google Scholar 

  68. Binder DC, Wainwright DA. The boosting potential of bacteria in cancer immunotherapy. Trends Mol Med. 2017;23:580–2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Kong Q, Six DA, Roland KL, Liu Q, Gu L, Reynolds CM, et al. Salmonella synthesizing 1-monophosphorylated LPS exhibits low endotoxic activity while retaining its immunogenicity. J Immunol. 2011;187:412–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Bravo D, Silva C, Carter JA, Hoare A, Alvarez SA, Blondel CJ, et al. Growth-phase regulation of lipopolysaccharide O-antigen chain length influences serum resistance in serovars of Salmonella. J Med Microbiol. 2008;57:938–46.

    Article  PubMed  CAS  Google Scholar 

  71. Gunn JS. The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Trends Microbiol. 2008;16:284–90.

    Article  PubMed  CAS  Google Scholar 

  72. Frahm M, Felgner S, Kocijancic D, Rohde M, Hensel M, Roy Curtiss I, et al. Efficiency of conditionally attenuated Salmonella enterica serovar typhimurium in bacterium-mediated tumor therapy. Mbio. 2015;6:e00254–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Zhang Y, Cao W, Toneri M, Zhang N, Kiyuna T, Murakami T, et al. Toxicology and efficacy of tumor-targeting Salmonella typhimurium A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice. Oncotarget. 2017;8:54616–28.

    PubMed  PubMed Central  Google Scholar 

  74. Arrach N, Cheng P, Zhao M, Santiviago CA, Hoffman RM, Mcclelland M. High-throughput screening for Salmonella avirulent mutants that retain targeting of solid tumors. Cancer Res. 2010;70:2165.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Yu B, Yang M, Shi L, Yao Y, Jiang Q, Li X, et al. Explicit hypoxia targeting with tumor suppression by creating an “obligate” anaerobic Salmonella typhimurium strain. Sci Rep. 2012;2:436.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Kocijancic D, Felgner S, Schauer T, Frahm M, Heise U, Zimmermann K, et al. Local application of bacteria improves safety of Salmonella-mediated tumor therapy and retains advantages of systemic infection. Oncotarget. 2017;8:49988–50001.

    PubMed  PubMed Central  Google Scholar 

  77. Hong EH, Chang SY, Lee BR, Pyun AR, Kim JW, Kweon MN, et al. Intratumoral injection of attenuated Salmonella vaccine can induce tumor microenvironmental shift from immune suppressive to immunogenic. Vaccine. 2013;31:1377–84.

    Article  PubMed  CAS  Google Scholar 

  78. Zheng JH, Min JJ. Targeted cancer therapy using engineered Salmonella typhimurium. Chonnam Med J. 2016;52:173–84.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Nguyen VH, Min JJ. Salmonella-mediated cancer therapy: roles and potential. Nucl Med Mol Imaging. 2017;51:118–26.

    Article  PubMed  CAS  Google Scholar 

  80. Jiang SN, Park SH, Lee HJ, Zheng JH, Kim HS, Bom HS, et al. Engineering of bacteria for the visualization of targeted delivery of a cytolytic anticancer agent. Mol Ther. 2013;21:1985–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Kim JE, Phan TX, Nguyen VH, Dinhvu HV, Zheng JH, Yun M, et al. Salmonella typhimurium suppresses tumor growth via the pro-inflammatory cytokine interleukin-1β. Theranostics. 2015;5:1328–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Phan TX, Nguyen VH, Duong MT, Hong Y, Choy HE, Min JJ. Activation of inflammasome by attenuated Salmonella typhimurium in bacteria-mediated cancer therapy. Microbiol Immunol. 2015;59:664–75.

    Article  PubMed  CAS  Google Scholar 

  83. Zhang M, Swofford CA, Forbes NS. Lipid A controls the robustness of intratumoral accumulation of attenuated Salmonella in mice. Inter J Cancer. 2014;135:647–57.

    Article  CAS  Google Scholar 

  84. Clairmont C, Lee KC, Pike J, Ittensohn M, Low KB, Pawelek J, et al. Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. J Infect Dis. 2000;181:1996–2002.

    Article  PubMed  CAS  Google Scholar 

  85. Luo X, Li Z, Lin S, Le T, Ittensohn M, Bermudes D, et al. Antitumor effect of VNP20009, an attenuated Salmonella, in murine tumor models. Oncol Res. 2001;12:501–8.

    Article  PubMed  CAS  Google Scholar 

  86. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859–68.

    Article  PubMed  CAS  Google Scholar 

  87. Kong Q, Six DA, Liu Q, Gu L, Roland KL, Raetz CRH, et al. Palmitoylation state impacts induction of innate and acquired immunity by the Salmonella enterica serovar typhimurium msbB mutant. Infect Immun. 2011;79:5027–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kong Q, Six DA, Liu Q, Gu L, Wang S, Alamuri P, et al. Phosphate groups of lipid A are essential for Salmonella enterica serovar typhimurium virulence and affect innate and adaptive immunity. Infect Immun. 2012;80:3215–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Reed SG, Bertholet S, Coler RN, Friede M. New horizons in adjuvants for vaccine development. Trends Immunol. 2009;30:23–32.

    Article  PubMed  CAS  Google Scholar 

  90. Dessel NV, Swofford CA, Forbes NS. Potent and tumor specific: arming bacteria with therapeutic proteins. Ther Deliv. 2015;6:385–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Liu F, Zhang L, Hoffman RM, Zhao M. Vessel destruction by tumor-targeting Salmonella typhimurium A1-R is enhanced by high tumor vascularity. Cell Cycle. 2010;9:4518–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Hassan JO, Rd CR. Control of colonization by virulent Salmonella typhimurium by oral immunization of chickens with avirulent delta cya delta crp S. typhimurium. Res Microbiol. 1990;141:839–50.

    Article  PubMed  CAS  Google Scholar 

  93. Roland K, Rd CR, Sizemore D. Construction and evaluation of a delta cya delta crp Salmonella typhimurium strain expressing avian pathogenic Escherichia coli O78 LPS as a vaccine to prevent airsacculitis in chickens. Avian Dis. 1999;43:429–41.

    Article  PubMed  CAS  Google Scholar 

  94. Kang HY, Srinivasan J, Curtiss R. Immune responses to recombinant pneumococcal PspA antigen delivered by live attenuated Salmonella enterica serovar typhimurium vaccine. Infect Immun. 2002;70:1739–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was funded by National Natural Science Foundation of China (grant numbers 31570928 and 31472179).

Author contributions

Q.K., K.L., and Q.L. initiated the research. K.L. and Q.L. led in vitro and in vivo experimental design, data acquisition and analysis, and manuscript preparation together. P.L., Y.H., X.B., and Y.T. aided in data acquisition. Q.K. participated in experimental design, data analysis, and manuscript preparation.

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  1. These authors contributed equally: Kang Liang and Qing Liu.

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  1. Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, 611130, Chengdu, China

    Kang Liang, Pei Li, Yue Han & Qingke Kong

  2. College of Animal Science and Technology, Southwest University, 400715, Chongqing, China

    Qing Liu, Xiaoping Bian, Yibo Tang & Qingke Kong

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The animal care protocol was approved by Sichuan Agricultural University. All efforts were made to minimize animal suffering during the experiments.

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Liang, K., Liu, Q., Li, P. et al. Endostatin gene therapy delivered by attenuated Salmonella typhimurium in murine tumor models. Cancer Gene Ther 25, 167–183 (2018). https://doi.org/10.1038/s41417-018-0021-6

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