Limits...
The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

Dang MT, Wehrli S, Dang CV, Curran T - PLoS ONE (2015)

Bottom Line: The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention.Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed.These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

No MeSH data available.


Related in: MedlinePlus

Medulloblastoma have increased HK2, and the ketogenic diet does not slow growth of Ptch1+/-Trp53-/- medulloblastoma.(A) Immunohistochemistry with HK2 antibody show tumors have increased HK2 level in comparison to normal cerebellum and comparable to a heightened level seen in the external granule layer of P7 mice containing rapidly dividing cerebellar granule neuron precursor cells. Western analysis quantification show tumor tissues have increased HK2 level over normal cerebellar tissue (p = 0.000012) and to whole P7 cerebellar tissue (p = 0.000012). EGL = external granule layer, IGL = internal granule layer. (B) Six-week old Ptch1+/-Trp53-/- mice were imaged with MRI and tumor volumes were calculated. Four consecutive MRI images of one spontaneous medulloblastoma, traced for volume calculation. Representative images of a single tumor over two weeks. (C) No changes were seen in individual tumor sizes before and after one week of ketogenic diet initiation compared to mice on a standard diet. The average percentage of tumor volume change from initial volumes in the standard and ketogenic diet groups were 182 ± 66% and 240 ± 123% respectively (p = 0.437). (D) The ketogenic diet did not affect survival (p = 0.778). (E) Mice on the standard diet lost an average of 10% of their body weight while mice on the ketogenic diet maintained their body weight (p = 0.030 on day 10). S = standard diet, K = ketogenic diet.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4507880&req=5

pone.0133633.g001: Medulloblastoma have increased HK2, and the ketogenic diet does not slow growth of Ptch1+/-Trp53-/- medulloblastoma.(A) Immunohistochemistry with HK2 antibody show tumors have increased HK2 level in comparison to normal cerebellum and comparable to a heightened level seen in the external granule layer of P7 mice containing rapidly dividing cerebellar granule neuron precursor cells. Western analysis quantification show tumor tissues have increased HK2 level over normal cerebellar tissue (p = 0.000012) and to whole P7 cerebellar tissue (p = 0.000012). EGL = external granule layer, IGL = internal granule layer. (B) Six-week old Ptch1+/-Trp53-/- mice were imaged with MRI and tumor volumes were calculated. Four consecutive MRI images of one spontaneous medulloblastoma, traced for volume calculation. Representative images of a single tumor over two weeks. (C) No changes were seen in individual tumor sizes before and after one week of ketogenic diet initiation compared to mice on a standard diet. The average percentage of tumor volume change from initial volumes in the standard and ketogenic diet groups were 182 ± 66% and 240 ± 123% respectively (p = 0.437). (D) The ketogenic diet did not affect survival (p = 0.778). (E) Mice on the standard diet lost an average of 10% of their body weight while mice on the ketogenic diet maintained their body weight (p = 0.030 on day 10). S = standard diet, K = ketogenic diet.

Mentions: To confirm that Ptch1+/-Trp53-/- medulloblastoma have increased glycolysis, three P7 cerebella, three adult Ptch1+/+Trp53-/- cerebella and three adult Ptch1+/-Trp53-/- cerebella with tumors were analyzed for levels of hexokinase 2, the first rate-limiting enzyme in glycolysis by both immunohistochemistry and Western blot analysis. Similar to previously published reports in another HH-MB model [21], tumors have increased hexokinase 2 staining in comparison to normal cerebellum. A heightened level of HK2 staining was seen in the external granule layer of P7 mice containing rapidly dividing cerebellar granule neuron precursor cells (Fig 1A). Western blot analysis shows that HK2 level is significantly higher in cerebella with tumor in comparison to P7 whole cerebellum (p = 0.000012) and adult whole cerebellum (p = 0.000012).


The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

Dang MT, Wehrli S, Dang CV, Curran T - PLoS ONE (2015)

Medulloblastoma have increased HK2, and the ketogenic diet does not slow growth of Ptch1+/-Trp53-/- medulloblastoma.(A) Immunohistochemistry with HK2 antibody show tumors have increased HK2 level in comparison to normal cerebellum and comparable to a heightened level seen in the external granule layer of P7 mice containing rapidly dividing cerebellar granule neuron precursor cells. Western analysis quantification show tumor tissues have increased HK2 level over normal cerebellar tissue (p = 0.000012) and to whole P7 cerebellar tissue (p = 0.000012). EGL = external granule layer, IGL = internal granule layer. (B) Six-week old Ptch1+/-Trp53-/- mice were imaged with MRI and tumor volumes were calculated. Four consecutive MRI images of one spontaneous medulloblastoma, traced for volume calculation. Representative images of a single tumor over two weeks. (C) No changes were seen in individual tumor sizes before and after one week of ketogenic diet initiation compared to mice on a standard diet. The average percentage of tumor volume change from initial volumes in the standard and ketogenic diet groups were 182 ± 66% and 240 ± 123% respectively (p = 0.437). (D) The ketogenic diet did not affect survival (p = 0.778). (E) Mice on the standard diet lost an average of 10% of their body weight while mice on the ketogenic diet maintained their body weight (p = 0.030 on day 10). S = standard diet, K = ketogenic diet.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507880&req=5

pone.0133633.g001: Medulloblastoma have increased HK2, and the ketogenic diet does not slow growth of Ptch1+/-Trp53-/- medulloblastoma.(A) Immunohistochemistry with HK2 antibody show tumors have increased HK2 level in comparison to normal cerebellum and comparable to a heightened level seen in the external granule layer of P7 mice containing rapidly dividing cerebellar granule neuron precursor cells. Western analysis quantification show tumor tissues have increased HK2 level over normal cerebellar tissue (p = 0.000012) and to whole P7 cerebellar tissue (p = 0.000012). EGL = external granule layer, IGL = internal granule layer. (B) Six-week old Ptch1+/-Trp53-/- mice were imaged with MRI and tumor volumes were calculated. Four consecutive MRI images of one spontaneous medulloblastoma, traced for volume calculation. Representative images of a single tumor over two weeks. (C) No changes were seen in individual tumor sizes before and after one week of ketogenic diet initiation compared to mice on a standard diet. The average percentage of tumor volume change from initial volumes in the standard and ketogenic diet groups were 182 ± 66% and 240 ± 123% respectively (p = 0.437). (D) The ketogenic diet did not affect survival (p = 0.778). (E) Mice on the standard diet lost an average of 10% of their body weight while mice on the ketogenic diet maintained their body weight (p = 0.030 on day 10). S = standard diet, K = ketogenic diet.
Mentions: To confirm that Ptch1+/-Trp53-/- medulloblastoma have increased glycolysis, three P7 cerebella, three adult Ptch1+/+Trp53-/- cerebella and three adult Ptch1+/-Trp53-/- cerebella with tumors were analyzed for levels of hexokinase 2, the first rate-limiting enzyme in glycolysis by both immunohistochemistry and Western blot analysis. Similar to previously published reports in another HH-MB model [21], tumors have increased hexokinase 2 staining in comparison to normal cerebellum. A heightened level of HK2 staining was seen in the external granule layer of P7 mice containing rapidly dividing cerebellar granule neuron precursor cells (Fig 1A). Western blot analysis shows that HK2 level is significantly higher in cerebella with tumor in comparison to P7 whole cerebellum (p = 0.000012) and adult whole cerebellum (p = 0.000012).

Bottom Line: The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention.Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed.These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

No MeSH data available.


Related in: MedlinePlus