Abstract
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.
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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 10:459–466
Papadopoulos MC, Saadoun S, Davies DC, Bell BA (2001) Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 15:101–108
Marshall LF, King J, Langfitt TW (1977) The complications of high-dose corticosteroid therapy in neurosurgical patients: a prospective study. Ann Neurol 1:201–203
Weissman DE, Dufer D, Vogel V, Abeloff MD (1987) Corticosteroid toxicity in neuro-oncology patients. J Neurooncol 5:125–128
Tannenbaum A (1942) The genesis and growth of tumors. II. Effects of caloric restriction per se. Cancer Res 2:460–467
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 116:641–654
Kritchevsky D (2002) Caloric restriction and experimental carcinogenesis. Hybrid Hybridom 21:147–151
Seyfried TN, Kiebish MA, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P (2011) Metabolic management of brain cancer. Biochim Biophys Acta 1807:577–594
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 89:1375–1382
Urits I, Mukherjee P, Meidenbauer J, Seyfried TN (2012) Dietary restriction promotes vessel maturation in a mouse astrocytoma. J Oncol 2012:264039
Mukherjee P, Abate LE, Seyfried TN (2004) Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res 10:5622–5629
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 14:7751–7762
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:e00038
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 84:1107–1114
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 43:3368–3373
Nomura T, Inamura T, Black KL (1994) Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors. Brain Res 659:62–66
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 4:5
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 14:202–208
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 929:239–246
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 61:151–160
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 17:1903–1911
Galicich JH, French LA, Melby JC (1961) Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet 81:46–53
Pashko LL, Schwartz AG (1992) Reversal of food restriction-induced inhibition of mouse skin tumor promotion by adrenalectomy. Carcinogenesis 13:1925–1928
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 11:939–948
Seitz RJ, Wechsler W (1987) Immunohistochemical demonstration of serum proteins in human cerebral gliomas. Acta Neuropathol (Berl) 73:145–152
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 6:229–236
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 27:2542–2552
Lee J, Baird A, Eliceiri BP (2011) In vivo measurement of glioma-induced vascular permeability. Methods Mol Biol 763:417–422
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) 104:85–91
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–C1035
Mullin JM, Skrovanek SM, Valenzano MC (2009) Modification of tight junction structure and permeability by nutritional means. Ann N Y Acad Sci 1165:99–112
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 144:372–382
De Bock K, Cauwenberghs S, Carmeliet P (2011) Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications. Curr Opin Genet Dev 21:73–79
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 14:4002–4009
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 104:83–90
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 16:567–572
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 45:848–855
Venero JL, Vizuete ML, Machado A, Cano J (2001) Aquaporins in the central nervous system. Prog Neurobiol 63:321–336
Agre P, Kozono D (2003) Aquaporin water channels: molecular mechanisms for human diseases. FEBS Lett 555:72–78
Papadopoulos MC, Krishna S, Verkman AS (2002) Aquaporin water channels and brain edema. Mt Sinai J Med 69:242–248
Saadoun S, Papadopoulos MC, Davies DC, Bell BA, Krishna S (2002) Increased aquaporin 1 water channel expression in human brain tumours. Br J Cancer 87:621–623
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 72:262–265
Hayashi Y, Edwards NA, Proescholdt MA, Oldfield EH, Merrill MJ (2007) Regulation and function of aquaporin-1 in glioma cells. Neoplasia 9:777–787
Kalaany NY, Sabatini DM (2009) Tumours with PI3K activation are resistant to dietary restriction. Nature 458:725–731
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 103:12475–12480
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Jiang, YS., Wang, FR. Caloric restriction reduces edema and prolongs survival in a mouse glioma model. J Neurooncol 114, 25–32 (2013). https://doi.org/10.1007/s11060-013-1154-y
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DOI: https://doi.org/10.1007/s11060-013-1154-y