Inhibition of spontaneous and experimental lung metastasis of soft-tissue sarcoma by tumor-targeting Salmonella typhimurium A1-R.

Shinji Miwa,Hiroaki Kimura,Kyung-Eun Baek,Yasunori Matsumoto,Katsuhiro Hayashi,Robert M Hoffman,Fuminari Uehara,Hiroyuki Tsuchiya,Shuya Yano,Michael Bouvet,Norio Yamamoto,Yong Zhang,Yukihiko Hiroshima,Ming Zhao,Mako Yamamoto

doi:10.18632/oncotarget.2561

Shinji Miwa, Hiroaki Kimura + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.2561

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Abstract

Prognosis of patients with lung metastases of soft-tissue sarcoma is still poor. Therefore, novel systemic therapy is needed to improve the survival of soft-tissue sarcoma. In the present study, tumor-targeting therapy with a genetically-modified auxotrophic strain of Salmonella typhimurium, termed A1-R, was evaluated. Mouse models of primary soft tissue sarcoma and spontaneous lung metastasis were obtained by orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells. S. typhimurium A1-R was administered from day 14, once a week for two weeks. On day 28, lung samples were excised and observed with a fluorescence imaging system. The number of lung metastasis was 8.8 ± 3.4 in the untreated group and 0.8 ± 0.8 in the treated group (P = 0.024). A mouse model of experimental lung metastasis was obtained by tail vein injection of HT1080-RFP cells. The mice were treated with S. typhimurium A1-R (i.v.) on day 7, once a week for three weeks. S. typhimurium A1-R significantly reduced lung metastases and improved overall survival (P = 0.004). S. typhimurium A1-R bacterial therapy has future potential for treating advanced soft tissue sarcoma and improving prognosis of patients with lung metastasis.

Highlights

The 5-year survival rate of the patients with lung metastases from soft-tissue sarcoma is 15.5% [1]
The interaction between S. typhimurium A1-R expressing green fluorescent protein (GFP) and HT-1080 fibrosarcoma cells labeled with RFP was observed with the Fluoview FV1000 confocal microscope (Olympus Corp., Tokyo, Japan)
Specific targeting of S. typhimurium A1-R to soft tissue sarcoma in vivo

Summary

Introduction

The 5-year survival rate of the patients with lung metastases from soft-tissue sarcoma is 15.5% [1]. Treatment with tumor-targeting S. typhimurium A1-R completely prevented the appearance of bone metastasis of a high metastatic variant of breast cancer in nude mice [16]. S. typhimurium A1-R was administered i.v. to nude mice which had primary osteosarcoma bone tumor and lung metastasis. We determined the efficacy of S. typhimurium A1-R on primary tumors and experimental and spontaneous metastasis in mouse models of human soft-tissue sarcoma.

Results

Conclusion