Enterobacterial tumor colonization in mice depends on bacterial metabolism and macrophages but is independent of chemotaxis and motility

Stritzker, Jochen; Weibel, Stephanie; Seubert, Carolin; Götz, Andreas W.; Tresch, Achim; Rooijen, Nico van; Oelschlaeger, Tobias A.; Hill, Philip J.; Gentschev, Ivaylo; Szalay, Aladar A.

doi:10.1016/j.ijmm.2010.02.004

Cited by 66 publications

(47 citation statements)

References 44 publications

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“…Although the process of bacterial tumor targeting is not entirely clear, macrophage was reported not to be a transporter of bacteria to tumor, and depleting macrophages did not affect tumor colonization [36]. Our results further confirmed this finding because the mutants with reduced survival within macrophages reached the same accumulation level in tumors as VNP20009.…”

Section: Discussionsupporting

confidence: 85%

“…Our results further confirmed this finding because the mutants with reduced survival within macrophages reached the same accumulation level in tumors as VNP20009. In addition, S. enterica was found both intracellular and extracellular in the tumor, where immune surveillance fails to function [36]. Three days post infection, when the bacterial titer reached the highest level in the tumor, all the mutants reached the same accumulation level in tumor as VNP20009 because the growth and replication rates of the mutants within melanoma cells were not impaired [37].…”

Section: Discussionmentioning

confidence: 99%

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The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009

Zhang

Yang

et al. 2016

Oncotarget

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VNP20009 is a very effective anti-cancer agent and can specifically target tumors and inhibit tumor growth. It was assumed that the tumor targeting ability of VNP20009 correlated to its anticancer capacity. However, our observation contradicted to this assumption. Three VNP20009 mutant strains ( ΔslyA , ΔSTM3120 and ΔhtrA ) with reduced fitness in normal tissues and unchanged fitness in tumors partially or completely lost their anti-cancer capacities. The genes slyA , STM3120 and htrA were required for survival within macrophages and were indispensable for tumor microenvironment remodeling by VNP20009. The infiltration of immune cells occurred less in the tumors of mice infected with the mutant strains. In addition, the mRNA levels of TNF-α and IL-1β were significantly decreased in the tumors of mice treated with the mutant strains. Our results indicate that the immune responses elicited by bacteria rather than the bacterial titer in tumors play a “decisive” role in VNP20009-mediated bacterial cancer therapy, which provides a novel perspective for the underlying mechanism of bacterial cancer therapy.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009

Zhang

Yang

et al. 2016

Oncotarget

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“…Reports about the role of motility in bacterial penetration and accumulation in tumors, however, have been contradictory. It has been shown for some bacterial strains that the extent of bacterial accumulation in tumors is independent of motility 39–40 . Some non-motile bacteria have been shown to have better transport properties through porous surfaces than motile bacteria 41 , possibly because of lesser probability of collision with pore surfaces 41–42 .…”

Section: Introductionmentioning

confidence: 99%

Motility is critical for effective distribution and accumulation of bacteria in tumor tissue

Toley

Forbes

2011

Integrative Biology

123

101

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Motile bacteria can overcome the penetration limitations of cancer chemotherapeutics because they can actively migrate into solid tumors. Although several genera of bacteria have been shown to accumulate preferentially in tumors, the spatiotemporal dynamics of bacterial tumor colonization and their dependence on bacterial motility is not clear. For effective tumor regression, bacteria must penetrate and distribute uniformly throughout tumors. To measure these dynamics, we used an in vitro model of continuously perfused tumor tissue to mimic the delivery and systemic clearance of Salmonella typhimurium strains SL1344 and VNP20009, and Escherichia coli strains K12 and DH5α. Tissues were treated for 1 hour with 105 or 107 CFU/ml suspensions of each strain and the location and extent of bacterial accumulation was observed for 30 hours. Salmonella had 14.5 times greater average swimming speeds than E.coli and colonized tissues at 100 times lower doses than E.coli. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. When inoculated at 105 CFU/ml, motile Salmonella formed colonies denser than 1010 CFU/(g-tissue) and less motile E.coli showed no detectable colonization. Based on spatio-temporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. Bacterial colonization caused apoptosis in tumors and apoptosis levels correlated (R2 = 98.6%) with colonization density. These results show that motility is critical for effective distribution of bacteria in tumors and is essential for designing cancer therapies that can overcome the barrier of limited tumor penetration.

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“…Recently, a VNP20009 mutant strain lacking the chemoreceptor Trg was observed to penetrate further into tumors than the parental strain (Zhang and Forbes, 2015). Conversely, it has been reported in a mouse model system that tumor colonization by Escherichia coli Nissle is independent of both bacterial chemotaxis and motility (Stritzker et al, 2010). Furthermore, murine tumor colonization of non-motile and non-chemotactic Salmonella strains was found to be comparable to wild type 24 h after infection (Crull et al, 2011).…”

Section: Introductionmentioning

confidence: 98%

Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009

Broadway

Denson

Jensen

et al. 2015

Journal of Biotechnology

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Enterobacterial tumor colonization in mice depends on bacterial metabolism and macrophages but is independent of chemotaxis and motility

Cited by 66 publications

References 44 publications

The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009

The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009

Motility is critical for effective distribution and accumulation of bacteria in tumor tissue

Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009

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