Influence of infection route and virulence factors on colonization of solid tumors by Salmonella enterica serovar Typhimurium

Administration of facultative anaerobic bacteria like Salmonella enterica serovar Typhimurium (S. typhimurium) as anti-cancer treatment holds a great therapeutic potential. Here we tested different routes of application of S. typhimurium with regard to tumor colonization and therapeutic efficacy. No differences between iv and ip infection were observed, often leading to a complete tumor clearance. In contrast, after oral application tumor colonization was inefficient and delayed. No therapeutic effect was observed under such conditions. We also could show that tumor invasion and colonization was independent of functional SPI 1 and SPI 2. Furthermore, tumor invasion and colonization did not require bacterial motility nor chemotactic responsiveness. The distribution of the bacteria within the tumor was independent of such functions

Biofilm formation by Salmonella enterica serovar Typhimurium colonizing solid tumours.

Systemic administration of Salmonella enterica serovar Typhimurium to tumour bearing mice results in preferential colonization of the tumours and retardation of tumour growth. Although the bacteria are able to invade the tumour cells in vitro, in tumours they were never detected intracellularly. Ultrastructural analysis of Salmonella-colonized tumours revealed that the bacteria had formed biofilms. Interestingly, depletion of neutrophilic granulocytes drastically reduced biofilm formation. Obviously, bacteria form biofilms in response to the immune reactions of the host. Importantly, we tested Salmonella mutants that were no longer able to form biofilms by deleting central regulators of biofilm formation. Such bacteria could be observed intracellularly in immune cells of the host or in tumour cells. Thus, tumour colonizing S. typhimurium might form biofilms as protection against phagocytosis. Since other bacteria are behaving similarly, solid murine tumours might represent a unique model to study biofilm formation in vivo

Antibiotic control of tumor-colonizing Salmonella enterica serovar Typhimurium.

Systemic administration of Salmonella enterica serovar Typhimurium (S. typhimurium) into tumor-bearing mice results in preferential colonization of tumors and causes shrinkage and sometimes complete tumor clearance. However, in spite of these beneficial antitumor effects, the systemic administration of a bacterial pathogen raises serious safety concerns as well. Addressing those concerns, here, we demonstrate that tumor-colonizing Salmonella can be readily controlled by systemic administration of the antibiotic - ciprofloxacin. Treatment was most effective when started early postinfection. This was achieved at the expense of the efficacy of tumor therapy. In many of the mice treated in such a way, tumors re-grew again. Nevertheless, some mice were able to clear the tumor despite the start of antibiotic treatment only 24 h after the start of infection. Furthermore, we could demonstrate that such mice had elicited a specific antitumor immune response. Thus, S. typhimurium-mediated tumor therapy might be applied safely when combined with early antibiotic treatment. However, the therapeutic power of the bacteria needs to be enhanced in order to provide a more effective therapeutic tool