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In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis.

Ganai S, Arenas RB, Sauer JP, Bentley B, Forbes NS - Cancer Gene Ther. (2011)

Bottom Line: From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 μm.All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma.These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA, USA.

ABSTRACT
Motile bacteria can overcome diffusion resistances that substantially reduce the efficacy of standard cancer therapies. Many reports have also recently described the ability of Salmonella to deliver therapeutic molecules to tumors. Despite this potential, little is known about the spatiotemporal dynamics of bacterial accumulation in solid tumors. Ultimately this timing will affect how these microbes are used therapeutically. To determine how bacteria localize, we intravenously injected Salmonella typhimurium into BALB/c mice with 4T1 mammary carcinoma and measured the average bacterial content as a function of time. Immunohistochemistry was used to measure the extent of apoptosis, the average distance of bacteria from tumor vasculature and the location of bacteria in four different regions: the core, transition, body and edge. Bacteria accumulation was also measured in pulmonary and hepatic metastases. The doubling time of bacterial colonies in tumors was measured to be 16.8 h, and colonization was determined to delay tumor growth by 48 h. From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 μm. After 48 h, bacteria migrated away from the tumor edge toward the central core and induced apoptosis. After 96 h, bacteria began to marginate to the tumor transition zone. All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma. These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.

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Salmonella proliferated exponentially in 4T1 mammary tumorsA, bacterial density(cfu/g) in tumors and liver samples harvested after systemic injection of S. typhimurium. Density was greater at 12 hours compared to 3 hours (*, p<0.05). Exponential growth was observed in both tissues. B, Tumor volume was significantly less in tumors treated with S. typhimurium at 48 and 144 hours compared to saline controls (*, p<0.05). Tumor volumes were normalized to initial volume.
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Figure 1: Salmonella proliferated exponentially in 4T1 mammary tumorsA, bacterial density(cfu/g) in tumors and liver samples harvested after systemic injection of S. typhimurium. Density was greater at 12 hours compared to 3 hours (*, p<0.05). Exponential growth was observed in both tissues. B, Tumor volume was significantly less in tumors treated with S. typhimurium at 48 and 144 hours compared to saline controls (*, p<0.05). Tumor volumes were normalized to initial volume.

Mentions: Following systemic inoculation, an immediate tropism of S. typhimurium was observed towards subcutaneous mammary tumors (Figure 1). Tumor bacterial density at 3 hours after inoculation was significantly greater than zero (P<0.05) and increased significantly until hour 12 (P<0.05; Figure 1A). Bacteria preferentially colonized mammary tumors compared to livers (Figure 1A). Averaging all time points, bacteria concentrations were approximately 5000 times greater in tumor than livers; the average bacterial concentrations were 2.6 × 106 cfu/g (95% CI, 8.7 × 104 – 5.2 × 106 cfu/g) in tumor compared to 477 cfu/g (95% CI, 0 – 980 cfu/g) in liver (p<0.05). All mice demonstrated colonization of tumors, whereas only 65% of liver samples had detectable bacterial colonies. The extent of bacterial colonization increased exponentially with time (t, hours), with doubling times of 16.8h (95% CI, 12.5 – 25.6 h) in tumors and 11.2h (95% CI, 9.8 – 13.3 h) in liver. Treatment with S. typhimurium delayed tumor growth by approximately 48 hours (Figure 1B). At the time of treatment (21 days of growth) most tumors were large, vascular, and highly necrotic. The mean tumor volume was 1291.3 mm3 (95% CI, 1045.9 – 1536.7 mm3) and the maximal (craniocaudal) dimension was 17.74mm (95% CI, 16.42 – 19.06mm). There was a significant difference in tumor volume between treatment groups at both 48 and 144 hours (P<0.05).


In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis.

Ganai S, Arenas RB, Sauer JP, Bentley B, Forbes NS - Cancer Gene Ther. (2011)

Salmonella proliferated exponentially in 4T1 mammary tumorsA, bacterial density(cfu/g) in tumors and liver samples harvested after systemic injection of S. typhimurium. Density was greater at 12 hours compared to 3 hours (*, p<0.05). Exponential growth was observed in both tissues. B, Tumor volume was significantly less in tumors treated with S. typhimurium at 48 and 144 hours compared to saline controls (*, p<0.05). Tumor volumes were normalized to initial volume.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3117926&req=5

Figure 1: Salmonella proliferated exponentially in 4T1 mammary tumorsA, bacterial density(cfu/g) in tumors and liver samples harvested after systemic injection of S. typhimurium. Density was greater at 12 hours compared to 3 hours (*, p<0.05). Exponential growth was observed in both tissues. B, Tumor volume was significantly less in tumors treated with S. typhimurium at 48 and 144 hours compared to saline controls (*, p<0.05). Tumor volumes were normalized to initial volume.
Mentions: Following systemic inoculation, an immediate tropism of S. typhimurium was observed towards subcutaneous mammary tumors (Figure 1). Tumor bacterial density at 3 hours after inoculation was significantly greater than zero (P<0.05) and increased significantly until hour 12 (P<0.05; Figure 1A). Bacteria preferentially colonized mammary tumors compared to livers (Figure 1A). Averaging all time points, bacteria concentrations were approximately 5000 times greater in tumor than livers; the average bacterial concentrations were 2.6 × 106 cfu/g (95% CI, 8.7 × 104 – 5.2 × 106 cfu/g) in tumor compared to 477 cfu/g (95% CI, 0 – 980 cfu/g) in liver (p<0.05). All mice demonstrated colonization of tumors, whereas only 65% of liver samples had detectable bacterial colonies. The extent of bacterial colonization increased exponentially with time (t, hours), with doubling times of 16.8h (95% CI, 12.5 – 25.6 h) in tumors and 11.2h (95% CI, 9.8 – 13.3 h) in liver. Treatment with S. typhimurium delayed tumor growth by approximately 48 hours (Figure 1B). At the time of treatment (21 days of growth) most tumors were large, vascular, and highly necrotic. The mean tumor volume was 1291.3 mm3 (95% CI, 1045.9 – 1536.7 mm3) and the maximal (craniocaudal) dimension was 17.74mm (95% CI, 16.42 – 19.06mm). There was a significant difference in tumor volume between treatment groups at both 48 and 144 hours (P<0.05).

Bottom Line: From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 μm.All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma.These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA, USA.

ABSTRACT
Motile bacteria can overcome diffusion resistances that substantially reduce the efficacy of standard cancer therapies. Many reports have also recently described the ability of Salmonella to deliver therapeutic molecules to tumors. Despite this potential, little is known about the spatiotemporal dynamics of bacterial accumulation in solid tumors. Ultimately this timing will affect how these microbes are used therapeutically. To determine how bacteria localize, we intravenously injected Salmonella typhimurium into BALB/c mice with 4T1 mammary carcinoma and measured the average bacterial content as a function of time. Immunohistochemistry was used to measure the extent of apoptosis, the average distance of bacteria from tumor vasculature and the location of bacteria in four different regions: the core, transition, body and edge. Bacteria accumulation was also measured in pulmonary and hepatic metastases. The doubling time of bacterial colonies in tumors was measured to be 16.8 h, and colonization was determined to delay tumor growth by 48 h. From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 μm. After 48 h, bacteria migrated away from the tumor edge toward the central core and induced apoptosis. After 96 h, bacteria began to marginate to the tumor transition zone. All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma. These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.

Show MeSH
Related in: MedlinePlus