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Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-alpha.

Leschner S, Westphal K, Dietrich N, Viegas N, Jablonska J, Lyszkiewicz M, Lienenklaus S, Falk W, Gekara N, Loessner H, Weiss S - PLoS ONE (2009)

Bottom Line: A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines.In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes.Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization.

View Article: PubMed Central - PubMed

Affiliation: Molecular Immunology, HZI-Helmholtz Centre for Infection Research, Braunschweig, Germany. sara.leschner@helmholtz-hzi.de

ABSTRACT

Background: Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy.

Methodology/principal findings: We describe the initial events of colonization of an ectopic transplantable tumor by Salmonella enterica serovar Typhimurium. Initially, after intravenous administration, bacteria were found in blood, spleen, and liver. Low numbers were also detected in tumors associated with blood vessels as could be observed by immunohistochemistry. A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines. This induced a tremendous influx of blood into the tumors by vascular disruption that could be visualized in H&E stainings and quantified by hemoglobin measurements of tumor homogenate. Most likely, together with the blood, bacteria were flushed into the tumor. In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes. Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization.

Conclusion: Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria.

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Related in: MedlinePlus

TNF-α release into the blood of S. Typhimurium-infected, CT26 tumor-bearing mice.(a) RT-PCRs were performed with RNA isolated from S. Typhimurium-infected CT26 cells (in vitro) and from CT26 tumors of S. Typhimurium-infected, tumor-bearing BALB/c mice (in vivo) at the indicated time points. The amplification product has a size of 212 bp. (b) TNF-α concentration in the blood of CT26 tumor-bearing BALB/c mice at different times p.i. determined using TNF sensitive L929 fibroblasts. Error bars show standard deviations of means. Results are representative for at least two independent experiments with 3–5 mice per group.
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pone-0006692-g003: TNF-α release into the blood of S. Typhimurium-infected, CT26 tumor-bearing mice.(a) RT-PCRs were performed with RNA isolated from S. Typhimurium-infected CT26 cells (in vitro) and from CT26 tumors of S. Typhimurium-infected, tumor-bearing BALB/c mice (in vivo) at the indicated time points. The amplification product has a size of 212 bp. (b) TNF-α concentration in the blood of CT26 tumor-bearing BALB/c mice at different times p.i. determined using TNF sensitive L929 fibroblasts. Error bars show standard deviations of means. Results are representative for at least two independent experiments with 3–5 mice per group.

Mentions: The strong hemorrhage of tumors and the subsequent infiltration of neutrophils suggested the induction of blood vessel-disrupting, neutrophil-attracting factors by the infected solid tumors. One cytokine that is known to promote such phenomena is TNF-α [31]. However, neither RT-PCRs from Salmonella-infected CT26 cells in vitro, nor RT-PCRs from Salmonella-infected CT26 tumors in vivo showed expression of TNF-α by CT26 cells or immune cells residing in CT26 tumors (Fig. 3a). Nevertheless, in blood we could detect TNF-α shortly after administration of bacteria (Fig. 3b). Here, TNF-α levels peaked between 30 min and 2 h p.i. and reached background levels again by 4 h p.i..


Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-alpha.

Leschner S, Westphal K, Dietrich N, Viegas N, Jablonska J, Lyszkiewicz M, Lienenklaus S, Falk W, Gekara N, Loessner H, Weiss S - PLoS ONE (2009)

TNF-α release into the blood of S. Typhimurium-infected, CT26 tumor-bearing mice.(a) RT-PCRs were performed with RNA isolated from S. Typhimurium-infected CT26 cells (in vitro) and from CT26 tumors of S. Typhimurium-infected, tumor-bearing BALB/c mice (in vivo) at the indicated time points. The amplification product has a size of 212 bp. (b) TNF-α concentration in the blood of CT26 tumor-bearing BALB/c mice at different times p.i. determined using TNF sensitive L929 fibroblasts. Error bars show standard deviations of means. Results are representative for at least two independent experiments with 3–5 mice per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2724709&req=5

pone-0006692-g003: TNF-α release into the blood of S. Typhimurium-infected, CT26 tumor-bearing mice.(a) RT-PCRs were performed with RNA isolated from S. Typhimurium-infected CT26 cells (in vitro) and from CT26 tumors of S. Typhimurium-infected, tumor-bearing BALB/c mice (in vivo) at the indicated time points. The amplification product has a size of 212 bp. (b) TNF-α concentration in the blood of CT26 tumor-bearing BALB/c mice at different times p.i. determined using TNF sensitive L929 fibroblasts. Error bars show standard deviations of means. Results are representative for at least two independent experiments with 3–5 mice per group.
Mentions: The strong hemorrhage of tumors and the subsequent infiltration of neutrophils suggested the induction of blood vessel-disrupting, neutrophil-attracting factors by the infected solid tumors. One cytokine that is known to promote such phenomena is TNF-α [31]. However, neither RT-PCRs from Salmonella-infected CT26 cells in vitro, nor RT-PCRs from Salmonella-infected CT26 tumors in vivo showed expression of TNF-α by CT26 cells or immune cells residing in CT26 tumors (Fig. 3a). Nevertheless, in blood we could detect TNF-α shortly after administration of bacteria (Fig. 3b). Here, TNF-α levels peaked between 30 min and 2 h p.i. and reached background levels again by 4 h p.i..

Bottom Line: A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines.In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes.Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization.

View Article: PubMed Central - PubMed

Affiliation: Molecular Immunology, HZI-Helmholtz Centre for Infection Research, Braunschweig, Germany. sara.leschner@helmholtz-hzi.de

ABSTRACT

Background: Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy.

Methodology/principal findings: We describe the initial events of colonization of an ectopic transplantable tumor by Salmonella enterica serovar Typhimurium. Initially, after intravenous administration, bacteria were found in blood, spleen, and liver. Low numbers were also detected in tumors associated with blood vessels as could be observed by immunohistochemistry. A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines. This induced a tremendous influx of blood into the tumors by vascular disruption that could be visualized in H&E stainings and quantified by hemoglobin measurements of tumor homogenate. Most likely, together with the blood, bacteria were flushed into the tumor. In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes. Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization.

Conclusion: Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria.

Show MeSH
Related in: MedlinePlus