Targeting Tumors with Salmonella <i>Typhimurium</i> - Potential for Therapy

Wall, Daniel M.; Srikanth, Chittur V.; McCormick, Beth A.

doi:10.18632/oncotarget.206

Cited by 47 publications

(26 citation statements)

References 57 publications

(65 reference statements)

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“…The gram-negative facultative anaerobic bacterium Salmonella enterica serovar Typhimurium has essentially prevailed as a therapeutic candidate since the millennium and remains subject to most investigations nowadays [26–30]. Intrinsically virulent, an absolute requisite for its application is attenuation.…”

Section: Introductionmentioning

confidence: 99%

Therapy of solid tumors using probiotic Symbioflor-2 - restraints and potential

et al. 2016

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To date, virulent bacteria remain the basis of most bacteria mediated cancer therapies. For clinical application attenuation is required. However, this might result in a drastically lowered therapeutic capacity. Herein we argue that the E. coli probiotic Symbioflor-2, with a history of safe application may constitute a viable tumor therapeutic candidate. We demonstrate that Symbioflor-2 displays a highly specific tumor targeting ability as determined in murine CT26 and RenCa tumor models. The excellent specificity was ascribed to reduced levels of adverse colonization. A high safety standard was demonstrated in WT and Rag1−/− mice. Thus, Symbioflor-2 may represent an ideal tumor targeting delivery system for therapeutic molecules. Moreover, Symbioflor-2 was capable of inducing CT26 tumor clearance as result of an adjuvant effect on tumor specific CD8+ T cells analogous to the Salmonella variant SL7207. However, lower therapeutic efficacy against RenCa tumors suggested a generally reduced therapeutic potency for probiotics. Interestingly, concurrent depletion of Gr-1+ or Ly6G+ cells installed therapeutic efficacy equal to SL7207, thus highlighting the role of innate effector cells in restraining the anti-tumor effects of Symbioflor-2. Collectively, our findings argue for a strategy of safe strain application and a more sustainable use of bacteria as a delivery system for therapeutic molecules.

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Section: Introductionmentioning

confidence: 99%

Therapy of solid tumors using probiotic Symbioflor-2 - restraints and potential

et al. 2016

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“…The most extensive work in this area has been conducted using Salmonella [4], due to its ability to grow in the absence and presence of oxygen, and because of the vast knowledge and genetic tools developed in this bacterial model [5]. These are features that provide a potential advantage to Salmonella when compared to Clostridium and other therapeutic bacteria [2, 6].…”

Section: Introductionmentioning

confidence: 99%

“…Some avirulent strains of S. Typhimurium retain specificity for tumor tissue colonization, and several attenuated mutants have been used for anti-cancer experiments in animal models [4] and human clinical trials [20, 21]. Attenuated S. Typhimurium strains have proved to be very successful in animal models.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…Non-surgical treatments including radiofrequency ablation, alcohol injection and transcatheter arterial chemoembolization have made great advances in recent years. However, they have substantial limitations, including toxicity, insufficient tissue penetration and poor tumor targeting, which together often result in incomplete destruction of the tumors (4–6). Therefore, the development of novel adjuvant therapies for the suppression of liver cancer growth and metastasis is essential.…”

Section: Introductionmentioning

confidence: 99%

‘Obligate’ anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice

Shi

et al. 2016

Oncology Letters

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The antitumor properties of bacteria have been demonstrated over the past decades. However, the efficacy is limited and unclear. Furthermore, systemic infection remains a serious concern in bacteria treatment. In this study, the effect of YB1, a rationally designed ‘obligate’ anaerobic Salmonella typhimurium strain, on liver tumor growth and metastasis in a nude mouse orthotopic liver tumor model was investigated. The orthotopic liver tumor model was established in nude mice using the hepatocellular carcinoma cell line MHCC-97L. Two weeks after orthotopic liver tumor implantation, YB1, SL7207 and saline were respectively administered through the tail vein of the mice. Longitudinal monitoring of tumor growth and metastasis was performed using Xenogen IVIS, and direct measurements of tumor volume were taken 3 weeks after treatment. In vitro, MHCC-97L and PLC cells were incubated with YB1 or SL7207 under anaerobic conditions. YB1 was observed to invade tumor cells and induce tumor cell apoptosis and death. The results revealed that all mice in the YB1 group were alive 3 weeks after YB1 injection while all mice in the SL7207 group died within 11 days of the SL7207 injection. The body weight decreased by ~9% on day 1 after YB1 injection and but subsequently recovered. Liver tumor growth and metastases were significantly inhibited following YB1 treatment. By contrast to the control group, a large number of Gr1-positive cells were detected on days 1 to 21 following YB1 treatment. Furthermore, YB1 also effectively invaded tumor cells and induced tumor cell apoptosis and death. In conclusion, YB1 suppressed liver tumor growth and metastasis in a nude mice liver tumor model. The potential mechanism may be through enhancing innate immune response and inducing tumor cell apoptosis and cell death.

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Targeting Tumors with Salmonella Typhimurium - Potential for Therapy

Cited by 47 publications

References 57 publications

Therapy of solid tumors using probiotic Symbioflor-2 - restraints and potential

Therapy of solid tumors using probiotic Symbioflor-2 - restraints and potential

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

‘Obligate’ anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice

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