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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 targets breast cancer metastasesContiguous hepatic (A, B) and pulmonary (C, D) sections were stained with hematoxylin and eosin (A, C) and Salmonella immunohistochemistry (brown in B, D). A–B, Salmonella accumulated in hepatic metastases with greater specificity than normal liver parenchyma. Bacterial colonies (boundary indicated with dark arrows in B) colocalized with metastatic tissue (boundary indicated with white arrows in A). Scale bars are 250μm. C–D, Salmonella (e.g. white arrow) accumulated in small pulmonary micro-metastases. The micro-metastasis encased a vascular channel containing an inflammatory infiltrate (black arrow). Scale bars are 50μm.
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Figure 5: Salmonella targets breast cancer metastasesContiguous hepatic (A, B) and pulmonary (C, D) sections were stained with hematoxylin and eosin (A, C) and Salmonella immunohistochemistry (brown in B, D). A–B, Salmonella accumulated in hepatic metastases with greater specificity than normal liver parenchyma. Bacterial colonies (boundary indicated with dark arrows in B) colocalized with metastatic tissue (boundary indicated with white arrows in A). Scale bars are 250μm. C–D, Salmonella (e.g. white arrow) accumulated in small pulmonary micro-metastases. The micro-metastasis encased a vascular channel containing an inflammatory infiltrate (black arrow). Scale bars are 50μm.

Mentions: Six days after inoculation, gross metastases were observed in all livers, and microscopic metastases were observed in all lungs. On examination with Salmonella immunohistochemistry, colonization was noted within every macroscopic hepatic metastasis and numerous microscopic pulmonary metastases (Figure 5). Hepatic metastases had a mean diameter of 2.6mm (95% CI, 2.1 – 3.1mm) and cross-sectional area of 5.3mm2 (95% CI, 3.9 – 6.7 mm2; Figure 5A). Liver metastases had bacterial colonization in 44% (95% CI, 24 – 64%) of their cross-sectional area, compared to 0.5% (95% CI, 0 – 1.2%; P<0.05) within normal hepatic parenchyma, demonstrating tissue specificity towards metastatic cancer tissue (Figure 5B).


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 targets breast cancer metastasesContiguous hepatic (A, B) and pulmonary (C, D) sections were stained with hematoxylin and eosin (A, C) and Salmonella immunohistochemistry (brown in B, D). A–B, Salmonella accumulated in hepatic metastases with greater specificity than normal liver parenchyma. Bacterial colonies (boundary indicated with dark arrows in B) colocalized with metastatic tissue (boundary indicated with white arrows in A). Scale bars are 250μm. C–D, Salmonella (e.g. white arrow) accumulated in small pulmonary micro-metastases. The micro-metastasis encased a vascular channel containing an inflammatory infiltrate (black arrow). Scale bars are 50μm.
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Related In: Results  -  Collection

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Figure 5: Salmonella targets breast cancer metastasesContiguous hepatic (A, B) and pulmonary (C, D) sections were stained with hematoxylin and eosin (A, C) and Salmonella immunohistochemistry (brown in B, D). A–B, Salmonella accumulated in hepatic metastases with greater specificity than normal liver parenchyma. Bacterial colonies (boundary indicated with dark arrows in B) colocalized with metastatic tissue (boundary indicated with white arrows in A). Scale bars are 250μm. C–D, Salmonella (e.g. white arrow) accumulated in small pulmonary micro-metastases. The micro-metastasis encased a vascular channel containing an inflammatory infiltrate (black arrow). Scale bars are 50μm.
Mentions: Six days after inoculation, gross metastases were observed in all livers, and microscopic metastases were observed in all lungs. On examination with Salmonella immunohistochemistry, colonization was noted within every macroscopic hepatic metastasis and numerous microscopic pulmonary metastases (Figure 5). Hepatic metastases had a mean diameter of 2.6mm (95% CI, 2.1 – 3.1mm) and cross-sectional area of 5.3mm2 (95% CI, 3.9 – 6.7 mm2; Figure 5A). Liver metastases had bacterial colonization in 44% (95% CI, 24 – 64%) of their cross-sectional area, compared to 0.5% (95% CI, 0 – 1.2%; P<0.05) within normal hepatic parenchyma, demonstrating tissue specificity towards metastatic cancer tissue (Figure 5B).

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