Salmonella choleraesuis as an anticancer agent in a syngeneic model of orthotopic hepatocellular carcinoma

Some anaerobic and facultative anaerobic bacteria represent novel therapeutic agents that have been recently applied in cancer therapy. Previously, we found that Salmonella choleraesuis in combination with cisplatin could retard tumor growth in the murine subsutaneous hepatocellular carcinoma (HCC) model. In this regard, we investigated the antitumor activity of S. choleraesuis in the ML-1 orthotopic tumor model. Systemically administered S. choleraesuis accumulated within not only subcutaneous but also orthotopic tumors for at least 30 days, forming tumor-to-normal tissue ratios exceeding 1,000-10,000 to 1. The antitumor effects of S. choleraesuis were evaluated in mice bearing subcutaneous and orthotopic ML-1 tumors. Compared with the control treatment, 5. choleraesuis significantly prolonged the animal survival, reduced the tumor size, as well as upregulated interferon (IFN)-γ and induced IFN-inducible chemokines CXCL10 (IP-10) productions. Furthermore, immunohistochemical staining of the tumors revealed decreased intratumoral microvessel density, increased infiltration of neutrophils, CD4⁺ and CD8⁺ T cells, and induced cell death in tumor microenvironment. In conclusion, these results suggest that tumor-targeted therapy using 5. choleraesuis, which exerts tumoricidal and antiangiogenic activities, represents a potential strategy for the treatment of HCC.