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The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma.

Chen JQ, Zhan YF, Wang W, Jiang SN, Li XY - Onco Targets Ther (2015)

Bottom Line: The differences between the three groups in tumor volume and survival time were analyzed.MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01).In addition, the survival time was significantly prolonged in the bacteria-treated group compared to the PBS-treated control group (P<0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.

ABSTRACT

Objective: To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA) in advanced stage of glioma.

Materials and methods: The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then randomly divided into the treatment group (SL + ClyA) (n=12), negative control group (SL) (n=12), and control group (phosphate-buffered saline [PBS]) (n=12). In the treatment group, the attenuated S. typhimurium were transformed with the plasmid-encoded antitumor gene ClyA. The expression of ClyA was controlled by the TetR-regulated promoter in response to extracellular doxycycline. The plasmid also contained an imaging gene lux to allow illumination of the tumor infected by the bacteria. The rat glioma C6 cells were implanted into the caudate nucleus of all rats. The engineered S. typhimurium and respective controls were injected intravenously into the rats 21 days after initial tumor implantation. The pathological analysis of the glioma tumor was performed at 21 days and 28 days (7 days after doxycycline treatment) postimplantation. All rats underwent MRI (magnetic resonance imaging) and bioluminescence study at 21 days and 28 days postimplantation to detect tumor volume. The differences between the three groups in tumor volume and survival time were analyzed.

Results: Advanced stage glioma was detected at 21 days postimplantation. Bioluminescence showed that the engineered S. typhimurium accumulated in glioma tumors and disappeared in the normal reticuloendothelial tissues 3 days after intravenous injection. MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01). In addition, the survival time was significantly prolonged in the bacteria-treated group compared to the PBS-treated control group (P<0.01).

Conclusion: The engineered S. typhimurium can significantly induce cancer cell apoptosis in the tumor center and inhibit cancer cell proliferation in the outer zone of advanced glioma tumor, leading to a prolonged survival time in rats. In addition, the engineered S. typhimurium that carried the antitumor and imaging genes controlled by the TetR-regulated promoter have high delivery efficiency with tolerable side effects in rats.

No MeSH data available.


Related in: MedlinePlus

Engineered Salmonella typhimurium significantly reduced glioma tumor volume by inducing necrosis.Notes: Contrast-enhanced T1 weighted image showed the implanted glioma tumors in control and SL group at: (A, C) 21 days postimplantation, (B, D) 28 days postimplantation, (E) before doxycycline treatment, and (F) after doxycycline treatment. (G) Tumor volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). (H) Necrosis volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). *P<0.05 versus the control group, #P<0.01 versus the control group.Abbreviations: PBS, phosphate-buffered saline; SL, treatment group; ClyA, cytolysin A.
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f3-ott-8-2555: Engineered Salmonella typhimurium significantly reduced glioma tumor volume by inducing necrosis.Notes: Contrast-enhanced T1 weighted image showed the implanted glioma tumors in control and SL group at: (A, C) 21 days postimplantation, (B, D) 28 days postimplantation, (E) before doxycycline treatment, and (F) after doxycycline treatment. (G) Tumor volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). (H) Necrosis volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). *P<0.05 versus the control group, #P<0.01 versus the control group.Abbreviations: PBS, phosphate-buffered saline; SL, treatment group; ClyA, cytolysin A.

Mentions: MRI study demonstrated that the glioma tumor volume was significantly increased 21 days postimplantation, suggesting successful implantation of glioma (Figure 3A and B). There were no significant difference in tumor volume and tumor necrosis volume before adding doxycycline. The average tumor volumes of the SL + ClyA group, SL group, and control group were 186.4±12.7 mm3, 187.8±15.4 mm3, 177.6±10.8 mm3, respectively at day 21 (P>0.05). The average necrosis volumes of the SL + ClyA group, SL group, and control group were 26.1±3.7 mm3, 27.7±5.2 mm3, 24.5±4.3 mm3, respectively, at day 21 (P>0.05) (Figure 3E). However, the tumor volume of the SL + ClyA group was significantly reduced compared with the other two groups 7 days post-doxycycline treatment or 28 days postimplantation (control: 278.7±28.1 mm3; SL: 253.2±27.1 mm3; SL + ClyA: 201.5±20.4 mm3, P<0.05, Figure 3C and D). In addition, the necrotic tumor volume significantly increased in the SL + ClyA group 7 days after doxycycline treatment compared to the other two groups (control: 37.8±4.9 mm3; SL: 94.7±9.2 mm3; SL + ClyA: 98.7±12.6 mm3, P<0.01, Figure 3F).


The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma.

Chen JQ, Zhan YF, Wang W, Jiang SN, Li XY - Onco Targets Ther (2015)

Engineered Salmonella typhimurium significantly reduced glioma tumor volume by inducing necrosis.Notes: Contrast-enhanced T1 weighted image showed the implanted glioma tumors in control and SL group at: (A, C) 21 days postimplantation, (B, D) 28 days postimplantation, (E) before doxycycline treatment, and (F) after doxycycline treatment. (G) Tumor volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). (H) Necrosis volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). *P<0.05 versus the control group, #P<0.01 versus the control group.Abbreviations: PBS, phosphate-buffered saline; SL, treatment group; ClyA, cytolysin A.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592054&req=5

f3-ott-8-2555: Engineered Salmonella typhimurium significantly reduced glioma tumor volume by inducing necrosis.Notes: Contrast-enhanced T1 weighted image showed the implanted glioma tumors in control and SL group at: (A, C) 21 days postimplantation, (B, D) 28 days postimplantation, (E) before doxycycline treatment, and (F) after doxycycline treatment. (G) Tumor volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). (H) Necrosis volumes were compared between the three groups at 21 days postimplantation and 7 days post-doxycycline treatment (28 days postimplantation). *P<0.05 versus the control group, #P<0.01 versus the control group.Abbreviations: PBS, phosphate-buffered saline; SL, treatment group; ClyA, cytolysin A.
Mentions: MRI study demonstrated that the glioma tumor volume was significantly increased 21 days postimplantation, suggesting successful implantation of glioma (Figure 3A and B). There were no significant difference in tumor volume and tumor necrosis volume before adding doxycycline. The average tumor volumes of the SL + ClyA group, SL group, and control group were 186.4±12.7 mm3, 187.8±15.4 mm3, 177.6±10.8 mm3, respectively at day 21 (P>0.05). The average necrosis volumes of the SL + ClyA group, SL group, and control group were 26.1±3.7 mm3, 27.7±5.2 mm3, 24.5±4.3 mm3, respectively, at day 21 (P>0.05) (Figure 3E). However, the tumor volume of the SL + ClyA group was significantly reduced compared with the other two groups 7 days post-doxycycline treatment or 28 days postimplantation (control: 278.7±28.1 mm3; SL: 253.2±27.1 mm3; SL + ClyA: 201.5±20.4 mm3, P<0.05, Figure 3C and D). In addition, the necrotic tumor volume significantly increased in the SL + ClyA group 7 days after doxycycline treatment compared to the other two groups (control: 37.8±4.9 mm3; SL: 94.7±9.2 mm3; SL + ClyA: 98.7±12.6 mm3, P<0.01, Figure 3F).

Bottom Line: The differences between the three groups in tumor volume and survival time were analyzed.MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01).In addition, the survival time was significantly prolonged in the bacteria-treated group compared to the PBS-treated control group (P<0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.

ABSTRACT

Objective: To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA) in advanced stage of glioma.

Materials and methods: The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then randomly divided into the treatment group (SL + ClyA) (n=12), negative control group (SL) (n=12), and control group (phosphate-buffered saline [PBS]) (n=12). In the treatment group, the attenuated S. typhimurium were transformed with the plasmid-encoded antitumor gene ClyA. The expression of ClyA was controlled by the TetR-regulated promoter in response to extracellular doxycycline. The plasmid also contained an imaging gene lux to allow illumination of the tumor infected by the bacteria. The rat glioma C6 cells were implanted into the caudate nucleus of all rats. The engineered S. typhimurium and respective controls were injected intravenously into the rats 21 days after initial tumor implantation. The pathological analysis of the glioma tumor was performed at 21 days and 28 days (7 days after doxycycline treatment) postimplantation. All rats underwent MRI (magnetic resonance imaging) and bioluminescence study at 21 days and 28 days postimplantation to detect tumor volume. The differences between the three groups in tumor volume and survival time were analyzed.

Results: Advanced stage glioma was detected at 21 days postimplantation. Bioluminescence showed that the engineered S. typhimurium accumulated in glioma tumors and disappeared in the normal reticuloendothelial tissues 3 days after intravenous injection. MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01). In addition, the survival time was significantly prolonged in the bacteria-treated group compared to the PBS-treated control group (P<0.01).

Conclusion: The engineered S. typhimurium can significantly induce cancer cell apoptosis in the tumor center and inhibit cancer cell proliferation in the outer zone of advanced glioma tumor, leading to a prolonged survival time in rats. In addition, the engineered S. typhimurium that carried the antitumor and imaging genes controlled by the TetR-regulated promoter have high delivery efficiency with tolerable side effects in rats.

No MeSH data available.


Related in: MedlinePlus