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The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model.

Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC - PLoS ONE (2015)

Bottom Line: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B.Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin.Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

View Article: PubMed Central - PubMed

Affiliation: Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America; School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America.

ABSTRACT

Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.

Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.

Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

No MeSH data available.


Related in: MedlinePlus

Analysis of tumor microvasculature components and gene expression.(A) CD31 immunostaining of tissue harvested at 21 days post-implantation. Representative images are shown. (B) Quantification of CD31 staining was performed on 2 independent tumors from each group. Data calculated as the average pixel density in 5 random, 200x fields within the same tumor and represented as a fold change from SD (**p < 0.01).
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pone.0130357.g004: Analysis of tumor microvasculature components and gene expression.(A) CD31 immunostaining of tissue harvested at 21 days post-implantation. Representative images are shown. (B) Quantification of CD31 staining was performed on 2 independent tumors from each group. Data calculated as the average pixel density in 5 random, 200x fields within the same tumor and represented as a fold change from SD (**p < 0.01).

Mentions: To assess the effect of KC on tumor microvasculature and the expression of the angiogenic marker CD31, we performed immunohistochemical staining of paraffin-embedded tissue sections (Fig 4A). Quantitation of staining demonstrated a statistically significant decrease in the percentage of CD31 positive areas within the tumors of animals fed KC (Fig 4B). These results were confirmed with western blot analysis of CD31 from whole lysate of GL261-luc2 tumors (Fig 5A) which demonstrated a statistically significant 2-fold decrease in expression of CD31 in animals fed KC when compared to SD fed animals (Fig 5B).


The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model.

Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC - PLoS ONE (2015)

Analysis of tumor microvasculature components and gene expression.(A) CD31 immunostaining of tissue harvested at 21 days post-implantation. Representative images are shown. (B) Quantification of CD31 staining was performed on 2 independent tumors from each group. Data calculated as the average pixel density in 5 random, 200x fields within the same tumor and represented as a fold change from SD (**p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470583&req=5

pone.0130357.g004: Analysis of tumor microvasculature components and gene expression.(A) CD31 immunostaining of tissue harvested at 21 days post-implantation. Representative images are shown. (B) Quantification of CD31 staining was performed on 2 independent tumors from each group. Data calculated as the average pixel density in 5 random, 200x fields within the same tumor and represented as a fold change from SD (**p < 0.01).
Mentions: To assess the effect of KC on tumor microvasculature and the expression of the angiogenic marker CD31, we performed immunohistochemical staining of paraffin-embedded tissue sections (Fig 4A). Quantitation of staining demonstrated a statistically significant decrease in the percentage of CD31 positive areas within the tumors of animals fed KC (Fig 4B). These results were confirmed with western blot analysis of CD31 from whole lysate of GL261-luc2 tumors (Fig 5A) which demonstrated a statistically significant 2-fold decrease in expression of CD31 in animals fed KC when compared to SD fed animals (Fig 5B).

Bottom Line: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B.Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin.Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

View Article: PubMed Central - PubMed

Affiliation: Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America; School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America.

ABSTRACT

Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.

Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.

Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

No MeSH data available.


Related in: MedlinePlus