Article

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

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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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Additional information

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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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.

Author information

Author notes

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

Affiliations

  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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The authors declare that they have no conflict of interest.

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Correspondence to Qingke Kong.

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