Solid tumors provide niche-specific conditions that lead to preferential growth of Salmonella

Abstract

Therapeutic attenuated strains of Salmonella Typhimurium target and eradicate tumors in mouse models. However, the mechanism of S. Typhimurium for tumor targeting is still poorly understood. We performed a high-throughput screening of single-gene deletion mutants of S. Typhimurium in an orthotopic, syngeneic murine mammary model of breast cancer. The mutants under selection in this system were classified into functional categories to identify bacterial processes involved in Salmonella accumulation within tumors. Niche-specific genes involved in preferential tumor colonization were identified and exemplars were confirmed by competitive infection assays. Our results show that the chemotaxis gene cheY and the motility genes motAB confer an advantage for colonization of Salmonella within orthotopic syngeneic breast tumors. In addition, eutC, a gene belonging to the ethanolamine metabolic pathway, also confers an advantage for Salmonella within tumors, perhaps by exploiting either ethanolamine or an alternative nutrient in the inflamed tumor environment.

Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions

“…Although the mechanism of bacterial tumor tropism is poorly understood there is evidence indicating that irregular organization of blood vessels within the tumor tissue that often leads to the development of hypoxic and/or necrotic regions and/or an immune-suppressive microenvironment inside the tumor mass may facilitate survival and growth of attenuated auxotrophic bacteria by providing them with nutrients and immune-protection ( Forbes et al, 2003 ; Wouters et al, 2003 ; Yu et al, 2004 ). Moreover, niche-specific genes involved in the process of preferential tumor colonization after systemic bacteria delivery, were also identified ( Silva-Valenzuela et al, 2014 ).…”

Detection of tumors with fluoromarker‐releasing bacteria

“…These include entrapment in tumor vasculature; 14 increased influx of bacteria into the tumor site after systemic injection due to inflammation and tumor necrosis factor (TNF)-α response; 16,17 protection from clearance by the immune system; 18 chemotaxis into tumor sites; 19,20 and preferential growth in the nutrient-rich tumor microenvironment. 13,19,21 In our study, we utilized a nonpathogenic strain of Salmonella (VNP20009) that is 10,000-fold less toxic than its wild-type counterpart because of a partial deletion of the msbB gene. 6,22 This mutation reduces the TNF immune response to bacterial lipopolysaccharides and prevents septic shock.…”

Cancer Immunotherapy: Priming the Host Immune Response with Live Attenuated Salmonella enterica

“…Recent studies have described the ability of Salmonella Typhimurium to sense the concentrations of ethanolamine, a part of membrane lipids, and hence colonize the gastrointestinal tract [ 25 ]. Interestingly, abnormal ethanolamine and other lipid levels of the cell membrane have been detected in different types of neoplasia [ 26 ], and they may be acting as chemoattractants of Salmonella enterica to the tumor [ 27 ].…”

“…On the other hand, there is controversial data on the role played by certain Salmonella enterica proteins involved in their ability to colonize tumor tissue, particularly the two-component system CheA/CheY; some authors mentioned that the presence of this system is indispensable for effective distribution and bacterial recruitment into tumor tissue [ 23 , 24 , 28 ]; its absence leads to decreased tumor colonization due to lower bacterial motility [ 29 ]. However, other studies have reported that the lack of CheY protein, as well as other bacterial components involved in motility such as the flagellar components fliA, fliC, and flgE, does not compromise Samonella enterica colonization of tumor tissue [ 27 , 30 , 31 ].…”