Journal of Neuro-Oncology

, Volume 114, Issue 1, pp 25–32 | Cite as

Caloric restriction reduces edema and prolongs survival in a mouse glioma model

Laboratory Investigation


Regardless of their cell type of origin, all aggressive brain tumors, such as malignant gliomas and metastatic tumors produce brain edema, which is an important cause of patient morbidity and mortality. Caloric restriction (CR) has long been recognized as a natural therapy that improves health, promotes longevity, and significantly reduces both the incidence and growth of many tumor types. The aim of present work was to investigate the effect of CR on edema and survival in the mice implanted with U87 gliomas. We found that CR significantly inhibited the intracerebral tumor growth, attenuated brain edema, and ultimately prolonged survival of mice with U87 gliomas. Plasma corticosterone level was found higher and serum VEGF and IGF-1 levels were found lower in CR, when compared to AL group. CR upregulated tight junction proteins including claudin-1, claudin-5 and ZO-1, downregulated VEGF and VEGFR2, enhanced α-SMA expression, and reduced AQP1 expression in U87 gliomas. In addition, CR suppressed inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) formation in U87 gliomas. In conclusion, CR attenuated edema in U87 orthotopic mouse glioma model associated with elevation of corticosterone, suppression of VEGF/VEGFR2, improvement of tight junctions, and suppression of iNOS expression and NO formation. Our results suggested that CR might be an effective therapy for recurrent malignant brain cancers through alleviating associated edema.


Caloric restriction Edema Glioma Permeability 


Ethical standards

The experiments comply with the current laws of China.

Conflict of interest

The authors declare that we have no conflict of interest.

Supplementary material

11060_2013_1154_MOESM1_ESM.doc (144 kb)
Supplementary material 1 (DOC 144 kb)


  1. 1.
    Stupp R, Hegi ME, Mason WP, Van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466PubMedCrossRefGoogle Scholar
  2. 2.
    Papadopoulos MC, Saadoun S, Davies DC, Bell BA (2001) Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 15:101–108PubMedCrossRefGoogle Scholar
  3. 3.
    Marshall LF, King J, Langfitt TW (1977) The complications of high-dose corticosteroid therapy in neurosurgical patients: a prospective study. Ann Neurol 1:201–203PubMedCrossRefGoogle Scholar
  4. 4.
    Weissman DE, Dufer D, Vogel V, Abeloff MD (1987) Corticosteroid toxicity in neuro-oncology patients. J Neurooncol 5:125–128PubMedCrossRefGoogle Scholar
  5. 5.
    Tannenbaum A (1942) The genesis and growth of tumors. II. Effects of caloric restriction per se. Cancer Res 2:460–467Google Scholar
  6. 6.
    Weindruch R, Walford RL, Fligiel S, Guthrie D (1986) The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 116:641–654PubMedGoogle Scholar
  7. 7.
    Kritchevsky D (2002) Caloric restriction and experimental carcinogenesis. Hybrid Hybridom 21:147–151CrossRefGoogle Scholar
  8. 8.
    Seyfried TN, Kiebish MA, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P (2011) Metabolic management of brain cancer. Biochim Biophys Acta 1807:577–594PubMedCrossRefGoogle Scholar
  9. 9.
    Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P (2003) Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 89:1375–1382PubMedCrossRefGoogle Scholar
  10. 10.
    Urits I, Mukherjee P, Meidenbauer J, Seyfried TN (2012) Dietary restriction promotes vessel maturation in a mouse astrocytoma. J Oncol 2012:264039PubMedCrossRefGoogle Scholar
  11. 11.
    Mukherjee P, Abate LE, Seyfried TN (2004) Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res 10:5622–5629PubMedCrossRefGoogle Scholar
  12. 12.
    Marsh J, Mukherjee P, Seyfried TN (2008) Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma. Clin Cancer Res 14:7751–7762PubMedCrossRefGoogle Scholar
  13. 13.
    Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN (2010) Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro 2:e00038PubMedCrossRefGoogle Scholar
  14. 14.
    Ranes MK, El-Abbadi M, Manfredi MG, Mukherjee P, Platt FM, Seyfried TN (2001) N-butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours. Br J Cancer 84:1107–1114PubMedCrossRefGoogle Scholar
  15. 15.
    Groothuis DR, Fischer JM, Pasternak JF, Blasberg RG, Vick NA, Bigner DD (1983) Regional measurements of blood-to-tissue transport in experimental RG-2 rat gliomas. Cancer Res 43:3368–3373PubMedGoogle Scholar
  16. 16.
    Nomura T, Inamura T, Black KL (1994) Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors. Brain Res 659:62–66PubMedCrossRefGoogle Scholar
  17. 17.
    Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN (2007) The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab 4:5CrossRefGoogle Scholar
  18. 18.
    Nebeling LC, Miraldi F, Shurin SB, Lerner E (1995) Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr 14:202–208PubMedGoogle Scholar
  19. 19.
    Ruggeri BA, Klurfeld DM, Kritchevsky D (1987) Biochemical alterations in 7,12-dimethylbenz[a]anthraceneinduced mammary tumors from rats subjected to caloric restriction. Biochim Biophys Acta 929:239–246PubMedCrossRefGoogle Scholar
  20. 20.
    Roslin M, Henriksson R, Bergstrom P, Ungerstedt U, Bergenheim AT (2003) Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J Neuro-oncol 61:151–160CrossRefGoogle Scholar
  21. 21.
    Oudard S, Boitier E, Miccoli L, Rousset S, Dutrillaux B, Poupon MF (1997) Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure. Anticancer Res 17:1903–1911PubMedGoogle Scholar
  22. 22.
    Galicich JH, French LA, Melby JC (1961) Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet 81:46–53PubMedGoogle Scholar
  23. 23.
    Pashko LL, Schwartz AG (1992) Reversal of food restriction-induced inhibition of mouse skin tumor promotion by adrenalectomy. Carcinogenesis 13:1925–1928PubMedCrossRefGoogle Scholar
  24. 24.
    Groothuis DR, Lapin GD, Vriesendorp FJ, Mikhael MA, Patlak CS (1991) A method to quantitatively measure transcapillary transport of iodinated compounds in canine brain tumors with computed tomography. J Cereb Blood Flow Metab 11:939–948PubMedCrossRefGoogle Scholar
  25. 25.
    Seitz RJ, Wechsler W (1987) Immunohistochemical demonstration of serum proteins in human cerebral gliomas. Acta Neuropathol (Berl) 73:145–152CrossRefGoogle Scholar
  26. 26.
    Gerstner ER, Duda DG, di Tomaso E, Ryg PA, Loeffler JS, Sorensen AG, Ivy P, Jain RK, Batchelor TT (2009) VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol 6:229–236PubMedCrossRefGoogle Scholar
  27. 27.
    Kamoun WS, Ley CD, Farrar CT, Duyverman AM, Lahdenranta J, Lacorre DA, Batchelor TT, di Tomaso E, Duda DG, Munn LL, Fukumura D, Sorensen AG, Jain RK (2009) Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 27:2542–2552PubMedCrossRefGoogle Scholar
  28. 28.
    Lee J, Baird A, Eliceiri BP (2011) In vivo measurement of glioma-induced vascular permeability. Methods Mol Biol 763:417–422PubMedCrossRefGoogle Scholar
  29. 29.
    Rascher G, Fischmann A, Kroger S, Duffner F, Grote EH, Wolburg H (2002) Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol (Berl) 104:85–91CrossRefGoogle Scholar
  30. 30.
    Ramalingam A, Wang X, Gabello M, Valenzano MC, Soler AP, Ko A, Morin PJ, Mullin JM (2010) Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern. Am J Physiol Cell Physiol 299:C1028–C1035PubMedCrossRefGoogle Scholar
  31. 31.
    Mullin JM, Skrovanek SM, Valenzano MC (2009) Modification of tight junction structure and permeability by nutritional means. Ann N Y Acad Sci 1165:99–112PubMedCrossRefGoogle Scholar
  32. 32.
    Verbeek MM, Otte-Höller I, Wesseling P, Ruiter DJ, de Waal RM (1994) Induction of alpha-smooth muscle actin expression in cultured human brain pericytes by transforming growth factor-beta 1. Am J Pathol 144:372–382PubMedGoogle Scholar
  33. 33.
    De Bock K, Cauwenberghs S, Carmeliet P (2011) Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications. Curr Opin Genet Dev 21:73–79PubMedCrossRefGoogle Scholar
  34. 34.
    Yin D, Wang X, Konda BM, Ong JM, Hu J, Sacapano MR, Ko MK, Espinoza AJ, Irvin DK, Shu Y, Black KL (2008) Increase in brain tumor permeability in glioma-bearing rats with nitric oxide donors. Clin Cancer Res 14:4002–4009PubMedCrossRefGoogle Scholar
  35. 35.
    Kostourou V, Cartwright JE, Johnstone AP, Boult JK, Cullis ER, Whitley G, Robinson SP (2011) The role of tumour-derived iNOS in tumour progression and angiogenesis. Br J Cancer 104:83–90PubMedCrossRefGoogle Scholar
  36. 36.
    Yamaguchi S, Bell HS, Shinoda J, Holmes MC, Wharton SB, Whittle IR (2002) Glioma tumourgenicity is decreased by iNOS knockout: experimental studies using the C6 striatal implantation glioma model. Br J Neurosurg 16:567–572PubMedGoogle Scholar
  37. 37.
    Zanetti M, Gortan Cappellari G, Burekovic I, Barazzoni R, Stebel M, Guarnieri G (2010) Caloric restriction improves endothelial dysfunction during vascular aging: effects on nitric oxide synthase isoforms and oxidative stress in rat aorta. Exp Gerontol 45:848–855PubMedCrossRefGoogle Scholar
  38. 38.
    Venero JL, Vizuete ML, Machado A, Cano J (2001) Aquaporins in the central nervous system. Prog Neurobiol 63:321–336PubMedCrossRefGoogle Scholar
  39. 39.
    Agre P, Kozono D (2003) Aquaporin water channels: molecular mechanisms for human diseases. FEBS Lett 555:72–78PubMedCrossRefGoogle Scholar
  40. 40.
    Papadopoulos MC, Krishna S, Verkman AS (2002) Aquaporin water channels and brain edema. Mt Sinai J Med 69:242–248PubMedGoogle Scholar
  41. 41.
    Saadoun S, Papadopoulos MC, Davies DC, Bell BA, Krishna S (2002) Increased aquaporin 1 water channel expression in human brain tumours. Br J Cancer 87:621–623PubMedCrossRefGoogle Scholar
  42. 42.
    Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA (2002) Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatry 72:262–265PubMedCrossRefGoogle Scholar
  43. 43.
    Hayashi Y, Edwards NA, Proescholdt MA, Oldfield EH, Merrill MJ (2007) Regulation and function of aquaporin-1 in glioma cells. Neoplasia 9:777–787PubMedCrossRefGoogle Scholar
  44. 44.
    Kalaany NY, Sabatini DM (2009) Tumours with PI3K activation are resistant to dietary restriction. Nature 458:725–731PubMedCrossRefGoogle Scholar
  45. 45.
    Chaparro RJ, Konigshofer Y, Beilhack GF, Shizuru JA, McDevitt HO, Chien YH (2006) Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes. Proc Natl Acad Sci USA 103:12475–12480PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center of Tumor, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  2. 2.Department of Neurology, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China

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