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Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse.

Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN - ASN Neuro (2010)

Bottom Line: GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer.Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion.In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

View Article: PubMed Central - PubMed

Affiliation: Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, U.S.A.

ABSTRACT
GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer. We recently developed a novel brain cancer model in the inbred VM mouse strain that shares several characteristics with human GBM. Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion. CR targets glycolysis and rapid tumour cell growth in part by lowering circulating glucose levels. The VM-M3 tumour cells were implanted intracerebrally in the syngeneic VM mouse host. Approx. 12-15 days post-implantation, brains were removed and both ipsilateral and contralateral hemispheres were imaged to measure bioluminescence of invading tumour cells. CR significantly reduced the invasion of tumour cells from the implanted ipsilateral hemisphere into the contralateral hemisphere. The total percentage of Ki-67-stained cells within the primary tumour and the total number of blood vessels was also significantly lower in the CR-treated mice than in the mice fed ad libitum, suggesting that CR is anti-proliferative and anti-angiogenic. Our findings indicate that the VM-M3 GBM model is a valuable tool for studying brain tumour cell invasion and for evaluating potential therapeutic approaches for managing invasive brain cancer. In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

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Related in: MedlinePlus

Influence of CR on VM-M3/Fluc tumour cell invasion to the contralateral hemisphereVM-M3/Fluc tumour fragments were implanted as described in Figure 1. Histological analysis (H&E) was used to validate the presence of tumour cells under AL (top panels) and CR (bottom panels) in cerebral cortex (200×), hippocampus (100×), cerebellum (100×) and brain stem (200×). Arrows indicate the presence of tumour cells. At least three samples were examined per group.
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Figure 4: Influence of CR on VM-M3/Fluc tumour cell invasion to the contralateral hemisphereVM-M3/Fluc tumour fragments were implanted as described in Figure 1. Histological analysis (H&E) was used to validate the presence of tumour cells under AL (top panels) and CR (bottom panels) in cerebral cortex (200×), hippocampus (100×), cerebellum (100×) and brain stem (200×). Arrows indicate the presence of tumour cells. At least three samples were examined per group.

Mentions: As seen in Figure 2, CR reduced the growth and invasion of the VM-M3 primary tumour. Compared with the diffuse, ill-defined border of the VM-M3 tumour observed in the AL-fed control mice, the tumour grown in the CR mice appeared denser with a more defined border. We evaluated the level of invasion into the contralateral hemisphere using bioluminescent imaging as described in the Materials and methods section. The total amount of bioluminescence in the contralateral hemisphere was significantly less in the CR-fed mice than in the AL-fed mice (Figure 3). Histology was used to confirm the extent of tumour-cell invasion into the contralateral hemisphere between the AL and CR groups. As shown in Figure 4, invading tumour cells were identified in all regions of the contralateral hemisphere of the AL-fed mice (arrows). In contrast, we identified sub-pial spread only to the cortex in the contralateral hemisphere of the CR group. The number of migrating cells was also noticeably less in the CR-fed mice than in the AL-fed mice (Figure 4). In addition, the percentage of Ki-67-positive tumour cells was significantly lower in the CR mice than in the AL mice (Figure 5). Factor VIII staining was used to measure blood vessel density in the tumours (Figure 6). Blood vessel density was significantly lower in the primary tumours of CR mice than in the AL mice. Blood vessel size was also smaller in the tumours of the CR mice than the AL mice (Figure 6).


Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse.

Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN - ASN Neuro (2010)

Influence of CR on VM-M3/Fluc tumour cell invasion to the contralateral hemisphereVM-M3/Fluc tumour fragments were implanted as described in Figure 1. Histological analysis (H&E) was used to validate the presence of tumour cells under AL (top panels) and CR (bottom panels) in cerebral cortex (200×), hippocampus (100×), cerebellum (100×) and brain stem (200×). Arrows indicate the presence of tumour cells. At least three samples were examined per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908744&req=5

Figure 4: Influence of CR on VM-M3/Fluc tumour cell invasion to the contralateral hemisphereVM-M3/Fluc tumour fragments were implanted as described in Figure 1. Histological analysis (H&E) was used to validate the presence of tumour cells under AL (top panels) and CR (bottom panels) in cerebral cortex (200×), hippocampus (100×), cerebellum (100×) and brain stem (200×). Arrows indicate the presence of tumour cells. At least three samples were examined per group.
Mentions: As seen in Figure 2, CR reduced the growth and invasion of the VM-M3 primary tumour. Compared with the diffuse, ill-defined border of the VM-M3 tumour observed in the AL-fed control mice, the tumour grown in the CR mice appeared denser with a more defined border. We evaluated the level of invasion into the contralateral hemisphere using bioluminescent imaging as described in the Materials and methods section. The total amount of bioluminescence in the contralateral hemisphere was significantly less in the CR-fed mice than in the AL-fed mice (Figure 3). Histology was used to confirm the extent of tumour-cell invasion into the contralateral hemisphere between the AL and CR groups. As shown in Figure 4, invading tumour cells were identified in all regions of the contralateral hemisphere of the AL-fed mice (arrows). In contrast, we identified sub-pial spread only to the cortex in the contralateral hemisphere of the CR group. The number of migrating cells was also noticeably less in the CR-fed mice than in the AL-fed mice (Figure 4). In addition, the percentage of Ki-67-positive tumour cells was significantly lower in the CR mice than in the AL mice (Figure 5). Factor VIII staining was used to measure blood vessel density in the tumours (Figure 6). Blood vessel density was significantly lower in the primary tumours of CR mice than in the AL mice. Blood vessel size was also smaller in the tumours of the CR mice than the AL mice (Figure 6).

Bottom Line: GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer.Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion.In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

View Article: PubMed Central - PubMed

Affiliation: Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, U.S.A.

ABSTRACT
GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer. We recently developed a novel brain cancer model in the inbred VM mouse strain that shares several characteristics with human GBM. Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion. CR targets glycolysis and rapid tumour cell growth in part by lowering circulating glucose levels. The VM-M3 tumour cells were implanted intracerebrally in the syngeneic VM mouse host. Approx. 12-15 days post-implantation, brains were removed and both ipsilateral and contralateral hemispheres were imaged to measure bioluminescence of invading tumour cells. CR significantly reduced the invasion of tumour cells from the implanted ipsilateral hemisphere into the contralateral hemisphere. The total percentage of Ki-67-stained cells within the primary tumour and the total number of blood vessels was also significantly lower in the CR-treated mice than in the mice fed ad libitum, suggesting that CR is anti-proliferative and anti-angiogenic. Our findings indicate that the VM-M3 GBM model is a valuable tool for studying brain tumour cell invasion and for evaluating potential therapeutic approaches for managing invasive brain cancer. In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

Show MeSH
Related in: MedlinePlus