Tuning Salmonella for cancer therapy

This article refers to:

Targeted deletion of the ara operon of Salmonella typhimurium enhances L-arabinose accumulation and drives PBAD-promoted expression of anti-cancer toxins and imaging agents

Some bacteria, such as Salmonella typhimurium, have unique mechanisms that can be exploited for cancer therapy.¹ Such bacteria specifically target and penetrate into tumors, eventually killing tumor cells by secreting cytotoxins. Furthermore, they can be used as vehicles for delivering therapeutic agents to cancer cells. Much effort has been made to use such bacteria for therapeutic purpose by reducing their cytotoxicity and thereby maximizing their therapeutic efficacy.^1-3

In this issue of Cell Cycle, Min and colleagues report the enhanced expression of inducible cytoxins and imaging agents in Salmonella typhimurium, thereby increasing the sensitivity in visualization of tumors and therapeutic efficacy.⁴ For tumor-specific expression of cytotoxins with reduced toxicity against normal cells, they used P_BAD promoter for the attenuated Salmonella typhimurium as an inducible system, which can be activated by L-arabinose.⁵ However, L-arabinose does not accumulate because it is metabolized by enzymes encoded by the ara operon in Salmonellae. Thus, Min and colleagues genetically engineered the attenuated Salmonella typhimurium through specific deletion of ara operon. As a result, the expression of imaging agents, Renilla luciferase 8 (RLuc8), which is inducible by P_BAD promoter, was shown to increase by 49-fold in the engineered Salmonella. Intravenous injection of the engineered Salmonella harboring RLuc8 into xenograft mice with murine colon cancer (CT26) led to ∼30-fold enhanced bioluminescence, allowing the visualization of tumors with enhanced sensitivity.

Min and colleagues further investigate the antitumor activity of the engineered Salmonella expressing enhanced level of cytotoxins, cytolysin A (ClyA). Injection of the engineered Salmonella harboring clyA into xenograft mice with murine colon cancer (CT26) showed a significant tumor suppression comparing to the parental strain, causing no severe weight loss. This result demonstrates potential of the engineered Salmonella in tumor suppression in vivo as well as its reduced non-specific toxicity.

Many studies have recently shown that tumor-targeting bacteria can suppress the tumor growth and promote survival in mice.¹ From the clinical point of view, however, safety and therapeutic potential should be more intensively assessed. Anyway, the results by Min and colleagues have provided intriguing principle in engineering and use of bacteria for therapeutic purpose.