title: 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.
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.
authors.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.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Woolf
authors.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.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Curley
authors.affiliation: BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Liu
authors.affiliation: BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Turner
authors.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.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Charlton
authors.affiliation: Neurosurgery Research, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Preul
authors.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; Neurosurgery Research, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America.
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Scheck
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000098:blood supply / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D002463:Cell Membrane Permeability; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000178:diet therapy* / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; C569043:Tjp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D020778:Matrix Metalloproteinase 2; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C492796:Car9 protein, mouse