S100a8/a9 regulated by LPS/TLR4 axis plays an important role in Salmonella-based tumor therapy and host defense
Yanxia Guo
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Formal analysis, Methodology, Project administration, Software, Writing - original draft, Writing - review & editing
Search for more papers by this authorYujie Sun
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Data curation, Formal analysis, Investigation, Project administration, Writing - review & editing
Search for more papers by this authorZhongying Li
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorChaohui Zuo
Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital, Changsha, Hunan, China
Contribution: Supervision, Writing - review & editing
Search for more papers by this authorXiaoqing Liu
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorYu Chen
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorZhen Xun
College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorJinling Liu
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
College of Biology, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorYang Mei
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Supervision, Writing - review & editing
Search for more papers by this authorJung-Joon Min
Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Gwangju, Republic of Korea
Contribution: Conceptualization, Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Min Wen
Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou, China
Correspondence
Min Wen, Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Email: [email protected]
Jin Hai Zheng, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Wenzhi Tan, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Contribution: Funding acquisition, Methodology, Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Jin Hai Zheng
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Correspondence
Min Wen, Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Email: [email protected]
Jin Hai Zheng, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Wenzhi Tan, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Contribution: Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
Search for more papers by this authorCorresponding Author
Wenzhi Tan
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
School of Food Science and Bioengineering, Changsha University of Science & Technology, Changsha, Hunan, China
Correspondence
Min Wen, Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Email: [email protected]
Jin Hai Zheng, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Wenzhi Tan, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Contribution: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Supervision, Writing - review & editing
Search for more papers by this authorYanxia Guo
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Formal analysis, Methodology, Project administration, Software, Writing - original draft, Writing - review & editing
Search for more papers by this authorYujie Sun
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Data curation, Formal analysis, Investigation, Project administration, Writing - review & editing
Search for more papers by this authorZhongying Li
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorChaohui Zuo
Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital, Changsha, Hunan, China
Contribution: Supervision, Writing - review & editing
Search for more papers by this authorXiaoqing Liu
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorYu Chen
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorZhen Xun
College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorJinling Liu
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
College of Biology, Hunan University, Changsha, China
Contribution: Methodology, Project administration
Search for more papers by this authorYang Mei
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Contribution: Supervision, Writing - review & editing
Search for more papers by this authorJung-Joon Min
Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Gwangju, Republic of Korea
Contribution: Conceptualization, Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Min Wen
Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou, China
Correspondence
Min Wen, Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Email: [email protected]
Jin Hai Zheng, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Wenzhi Tan, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Contribution: Funding acquisition, Methodology, Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Jin Hai Zheng
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
Correspondence
Min Wen, Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Email: [email protected]
Jin Hai Zheng, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Wenzhi Tan, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Contribution: Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
Search for more papers by this authorCorresponding Author
Wenzhi Tan
The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
School of Food Science and Bioengineering, Changsha University of Science & Technology, Changsha, Hunan, China
Correspondence
Min Wen, Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Email: [email protected]
Jin Hai Zheng, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Wenzhi Tan, The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Email: [email protected]
Contribution: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Supervision, Writing - review & editing
Search for more papers by this authorYanxia Guo, Yujie Sun, and Zhongying Li contributed equally to this study.
Abstract
Bacteria are ideal anticancer agents and carriers due to their unique capabilities that are convenient in genetic manipulation, tumor-specific targeting, and deep-tissue penetration. However, the specific molecular mechanisms of bacteria-mediated cancer therapy (BMCT) have not been clarified. In this study, we found that TLR4 signaling pathway is critical for Salmonella-mediated tumor targeting, tumor suppression, and liver and spleen protection. TLR4 knockout in mice decreased the levels of cytokines and chemokines, such as S100a8, S100a9, TNF-α, and IL-1β, in tumor microenvironments (TMEs) after Salmonella treatment, which inhibited tumor cell death and nutrient release, led to reduced bacterial contents in tumors and attenuated antitumor efficacy in a negative feedback manner. Importantly, we found that S100a8 and S100a9 played a leading role in Salmonella-mediated cancer therapy (SMCT). The antitumor efficacy was abrogated and liver damage was prominent when blocked with a specific inhibitor. These findings elucidated the mechanism of Salmonella-mediated tumor targeting, suppression, and host antibacterial defense, providing insights into clinical cancer therapeutics.
Graphical Abstract
What's new?
Colonizing bacteria in tumor tissues can kill tumor cells directly or facilitate the infiltration and activation of innate immune cells and initiate antitumor responses. Here, the authors show that the TLR4 signaling pathway is critical for Salmonella-mediated tumor targeting and tumor suppression as well as for liver and spleen protection. Moreover, S100a8/a9 upregulated by the lipopolysaccharide/TLR4 pathway promotes the production of TNF-α and IL-1β, playing a pivotal role in tumor suppression and host antibacterial defense. The findings shed light on Salmonella-mediated anticancer mechanisms and identify potential therapeutic targets for clinical translation of oncolytic bacteria.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
All RNA-seq raw data and processed read counts have been submitted to Gene Expression Omnibus (GSE229231). Other data and materials as well as software application information are available in the manuscript, the supplementary information (Data S1), or are available from the corresponding authors upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ijc35128-sup-0001-Supinfo.pdfPDF document, 27.4 MB | Data S1. Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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