Vasculature Disruption Enhances Bacterial Targeting of Autochthonous Tumors.
Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has been developed as a vector to deliver therapeutic agents to tumors. The potential of S. Typhimurium in cancer therapy is largely due to its reported propensity to accumulate at greater than 1,000-fold higher concentrations in tumors relative to healthy tissues. In this study, we compared bacterial colonization of tumors in a subcutaneous transplantation model with a more clinically relevant autochthonous tumor model. Following intravenous administration of attenuated S. Typhimurium strain SL3261, we observed approximately 10,000-fold less bacteria in autochthonous tumors that sporadically develop in transgenic BALB-neuT mice compared to tumors developed from subcutaneous transplantation of 4T1 murine breast cancer cells in BALB/c mice. Treatment of BALB-neuT mice with a vasculature-disrupting agent (VDA) prior to bacterial treatment caused necrosis of tumor tissue and significantly increased the bacterial targeting of autochthonous tumors by approximately 1,000-fold. These observations emphasize the importance of appropriate model selection in developing bacteria-based cancer therapies and demonstrate the potential of combining VDA pre-treatment with bacteria to facilitate targeting of clinically relevant tumors.
1. Department of Surgery, University of Minnesota, 195 MMC, 420 Delaware St SE, Minneapolis, Minnesota 55455, USA.
Jeremy J
JJ
Drees
1. Department of Surgery, University of Minnesota, 195 MMC, 420 Delaware St SE, Minneapolis, Minnesota 55455, USA.
Michael J
MJ
Mertensotto
1. Department of Surgery, University of Minnesota, 195 MMC, 420 Delaware St SE, Minneapolis, Minnesota 55455, USA.
Lance B
LB
Augustin
2. Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, 1479 Gortner Ave., St. Paul, MN 55108, USA.
Janet L
JL
Schottel
1. Department of Surgery, University of Minnesota, 195 MMC, 420 Delaware St SE, Minneapolis, Minnesota 55455, USA.
Daniel A
DA
Saltzman
4T1; BALB-neuT; Salmonella; autochthonous; breast cancer; cancer therapy; combretastatin A-4; necrosis; spontaneous; tumor-targeting; vasculature disruption