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Dietary Sphingolipids in Colon Cancer Prevention

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Bioactive Sphingolipids in Cancer Biology and Therapy

Abstract

Complex sphingolipids (sphingomyelin, cerebrosides, gangliosides) are natural components of our diet, amounting to an approximate intake of 0.3-0.4g per day. In the intestinal tract, they are digested to the bioactive metabolites ceramide and free sphingoid bases. These metabolites regulate proliferation, survival and cell death, alter gene expression levels and modulate functions such as angiogenesis, migration and invasion. They also impact local and systemic inflammation, affecting both epithelial and immune cells. Thus, they are involved in the regulation of functions that contribute to cancer cell promotion, progression and metastasis. Here we review evidence that dietary or orally administered sphingolipids are beneficial in the prevention of colon and other cancers in rodent models, and discuss the molecular mechanisms and cellular targets in the complex tumor microenvironment of the colon. We also investigate factors that contribute to a permissive tumor microenvironment such as inflammation, obesity and the intestinal microbiota as potential novel targets of dietary sphingolipids in the prevention of colon cancer.

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References

  1. SEER Program N. SEER Stat fact sheets: Colon and rectum cancer (2014) http://seer.cancer.gov/statfacts/html/colorect.html

  2. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Article  CAS  PubMed  Google Scholar 

  3. Femia AP, Dolara P, Giannini A, Salvadori M, Biggeri A, Caderni G (2007) Frequent mutation of Apc gene in rat colon tumors and mucin-depleted foci, preneoplastic lesions in experimental colon carcinogenesis. Cancer Res 67:445–449

    Article  CAS  PubMed  Google Scholar 

  4. Paulsen JE, Knutsen H, Olstorn HB, Loberg EM, Alexander J (2006) Identification of flat dysplastic aberrant crypt foci in the colon of azoxymethane-treated A/J mice. Int J Cancer 118:540–546

    Article  CAS  PubMed  Google Scholar 

  5. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600

    Article  CAS  PubMed  Google Scholar 

  6. Bienz M, Clevers H (2000) Linking colorectal cancer to Wnt signaling. Cell 103:311–320

    Article  CAS  PubMed  Google Scholar 

  7. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–611

    Article  CAS  PubMed  Google Scholar 

  9. Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, Clevers H (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337:730–735

    Article  CAS  PubMed  Google Scholar 

  10. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Goktuna SI, Ziegler PK, Canli O, Heijmans J, Huels DJ, Moreaux G et al (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152:25–38

    Article  CAS  PubMed  Google Scholar 

  11. Hammoud SS, Cairns BR, Jones DA (2013) Epigenetic regulation of colon cancer and intestinal stem cells. Curr Opin Cell Biol 25:177–183

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Beggs AD, Jones A, El-Bahrawy M, Abulafi M, Hodgson SV, Tomlinson IP (2013) Whole-genome methylation analysis of benign and malignant colorectal tumours. J Pathol 229:697–704

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Vesper H, Schmelz EM, Nikolova-Karakashian MN, Dillehay DL, Lynch DV, Merrill AH Jr (1999) Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J Nutr 129:1239–1250

    CAS  PubMed  Google Scholar 

  14. Yunoki K, Ogawa T, Ono J, Miyashita R, Aida K, Oda Y, Ohnishi M (2008) Analysis of sphingolipid classes and their contents in meals. Biosci Biotechnol Biochem 72:222–225

    Article  CAS  PubMed  Google Scholar 

  15. Pata MO, Hannun YA, Ng CK (2010) Plant sphingolipids: decoding the enigma of the Sphinx. New Phytol 185:611–630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Pruett ST, Bushnev A, Hagedorn K, Adiga M, Haynes CA, Sullards MC, Liotta DC, Merrill AH Jr (2008) Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols. J Lipid Res 49:1621–1639

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Blaas N, Humpf HU (2013) Structural profiling and quantitation of glycosyl inositol phosphoceramides in plants with Fourier transform mass spectrometry. J Agric Food Chem 61:4257–4269

    Article  CAS  PubMed  Google Scholar 

  18. Cacas JL, Bure C, Furt F, Maalouf JP, Badoc A, Cluzet S, Schmitter JM, Antajan E, Mongrand S (2013) Biochemical survey of the polar head of plant glycosylinositolphosphoceramides unravels broad diversity. Phytochemistry 96:191–200

    Article  CAS  PubMed  Google Scholar 

  19. Nilsson A (1968) Metabolism of sphingomyelin in the intestinal tract of the rat. Biochim Biophys Acta 164:575–584

    Article  CAS  PubMed  Google Scholar 

  20. Nilsson A (1969) The presence of spingomyelin- and ceramide-cleaving enzymes in the small intestinal tract. Biochim Biophys Acta 176:339–347

    Article  CAS  PubMed  Google Scholar 

  21. Schmelz EM, Crall KJ, Larocque R, Dillehay DL, Merrill AH Jr (1994) Uptake and metabolism of sphingolipids in isolated intestinal loops of mice. J Nutr 124:702–712

    CAS  PubMed  Google Scholar 

  22. Zhang Y, Cheng Y, Hansen GH, Niels-Christiansen LL, Koentgen F, Ohlsson L, Nilsson A, Duan RD (2011) Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice. J Lipid Res 52:771–781

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Duan RD (2011) Physiological functions and clinical implications of sphingolipids in the gut. J Dig Dis 12:60–70

    Article  CAS  PubMed  Google Scholar 

  24. Duan RD, Nilsson A (2009) Metabolism of sphingolipids in the gut and its relation to inflammation and cancer development. Prog Lipid Res 48:62–72

    Article  CAS  PubMed  Google Scholar 

  25. Schmelz EM, Sullards MC, Dillehay DL, Merrill AH Jr (2000) Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1, 2-dimethylhydrazine-treated CF1 mice. J Nutr 130:522–527

    CAS  PubMed  Google Scholar 

  26. Thomas RL Jr, Matsko CM, Lotze MT, Amoscato AA (1999) Mass spectrometric identification of increased C16 ceramide levels during apoptosis. J Biol Chem 274:30580–30588

    Article  CAS  PubMed  Google Scholar 

  27. Oskouian B, Sooriyakumaran P, Borowsky AD, Crans A, Dillard-Telm L, Tam YY, Bandhuvula P, Saba JD (2006) Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc Natl Acad Sci U S A 103:17384–17389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Fukuda Y, Kihara A, Igarashi Y (2003) Distribution of sphingosine kinase activity in mouse tissues: contribution of SPHK1. Biochem Biophys Res Commun 309:155–160

    Article  CAS  PubMed  Google Scholar 

  29. Sugawara T, Kinoshita M, Ohnishi M, Nagata J, Saito M (2003) Digestion of maize sphingolipids in rats and uptake of sphingadienine by Caco-2 cells. J Nutr 133:2777–2782

    CAS  PubMed  Google Scholar 

  30. Sugawara T, Tsuduki T, Yano S, Hirose M, Duan J, Aida K, Ikeda I, Hirata T (2010) Intestinal absorption of dietary maize glucosylceramide in lymphatic duct cannulated rats. J Lipid Res 51:1761–1769

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Ohlsson L, Hertervig E, Jonsson BA, Duan RD, Nyberg L, Svernlov R, Nilsson A (2010) Sphingolipids in human ileostomy content after meals containing milk sphingomyelin. Am J Clin Nutr 91:672–678

    Article  CAS  PubMed  Google Scholar 

  32. Nyberg L, Nilsson A, Lundgren P, Duan RD (1997) Localization and capacity of sphingomyelin digestion in the rat intestinal tract. J Nutr Biochem 8:112–118

    Article  CAS  Google Scholar 

  33. Garmy N, Taieb N, Yahi N, Fantini J (2005) Apical uptake and transepithelial transport of sphingosine monomers through intact human intestinal epithelial cells: physicochemical and molecular modeling studies. Arch Biochem Biophys 440:91–100

    Article  CAS  PubMed  Google Scholar 

  34. Kobayashi T, Shimizugawa T, Osakabe T, Watanabe S, Okuyama H (1997) A long-term feeding of sphingolipids affected the levels of plasma cholesterol and hepatic triacylglycerol but not tissue phospholipids and sphingolipids. Nutr Res 17

    Google Scholar 

  35. Larsson SC, Bergkvist L, Wolk A (2005) High-fat dairy food and conjugated linoleic acid intakes in relation to colorectal cancer incidence in the Swedish Mammography Cohort. Am J Clin Nutr 82:894–900

    CAS  PubMed  Google Scholar 

  36. Huncharek M, Muscat J, Kupelnick B (2009) Colorectal cancer risk and dietary intake of calcium, vitamin D, and dairy products: a meta-analysis of 26,335 cases from 60 observational studies. Nutr Cancer 61:47–69

    Article  CAS  PubMed  Google Scholar 

  37. Aune D, Lau R, Chan DS, Vieira R, Greenwood DC, Kampman E, Norat T (2012) Dairy products and colorectal cancer risk: a systematic review and meta-analysis of cohort studies. Ann Oncol 23:37–45

    Article  CAS  PubMed  Google Scholar 

  38. Dillehay DL, Webb SK, Schmelz EM, Merrill AH Jr (1994) Dietary sphingomyelin inhibits 1,2-dimethylhydrazine-induced colon cancer in CF1 mice. J Nutr 124:615–620

    CAS  PubMed  Google Scholar 

  39. Schmelz EM, Dillehay DL, Webb SK, Reiter A, Adams J, Merrill AH Jr (1996) Sphingomyelin consumption suppresses aberrant colonic crypt foci and increases the proportion of adenomas versus adenocarcinomas in CF1 mice treated with 1,2-dimethylhydrazine: implications for dietary sphingolipids and colon carcinogenesis. Cancer Res 56:4936–4941

    CAS  PubMed  Google Scholar 

  40. Exon JH, South EH (2003) Effects of sphingomyelin on aberrant colonic crypt foci development, colon crypt cell proliferation and immune function in an aging rat tumor model. Food Chem Toxicol 41:471–476

    Article  CAS  PubMed  Google Scholar 

  41. Schmelz EM, Bushnev AS, Dillehay DL, Liotta DC, Merrill AH Jr (1997) Suppression of aberrant colonic crypt foci by synthetic sphingomyelins with saturated or unsaturated sphingoid base backbones. Nutr Cancer 28:81–85

    Article  CAS  PubMed  Google Scholar 

  42. Schmelz EM, Roberts PC, Kustin EM, Lemonnier LA, Sullards MC, Dillehay DL, Merrill AH Jr (2001) Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids. Cancer Res 61:6723–6729

    CAS  PubMed  Google Scholar 

  43. Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E, Kelly S, Allegood JC, Liu Y, Peng Q et al (1758) Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta 2006:1864–1884

    Google Scholar 

  44. Snow DR, Ward RE, Olsen A, Jimenez-Flores R, Hintze KJ (2011) Membrane-rich milk fat diet provides protection against gastrointestinal leakiness in mice treated with lipopolysaccharide. J Dairy Sci 94:2201–2212

    Article  CAS  PubMed  Google Scholar 

  45. Zhang P, Li B, Gao S, Duan RD (2008) Dietary sphingomyelin inhibits colonic tumorigenesis with an up-regulation of alkaline sphingomyelinase expression in ICR mice. Anticancer Res 28:3631–3635

    CAS  PubMed  Google Scholar 

  46. Lemonnier LA, Dillehay DL, Vespremi MJ, Abrams J, Brody E, Schmelz EM (2003) Sphingomyelin in the suppression of colon tumors: prevention versus intervention. Arch Biochem Biophys 419:129–138

    Article  CAS  PubMed  Google Scholar 

  47. Hu Y, Le Leu RK, Belobrajdic D, Young GP (2008) The potential of sphingomyelin as a chemopreventive agent in AOM-induced colon cancer model: wild-type and p53+/- mice. Mol Nutr Food Res 52:558–566

    Article  CAS  PubMed  Google Scholar 

  48. Inamine M, Suzui M, Morioka T, Kinjo T, Kaneshiro T, Sugishita T, Okada T, Yoshimi N (2005) Inhibitory effect of dietary monoglucosylceramide 1-O-beta-glucosyl-N-2′-hydroxyarachidoyl-4,8-sphingadienine on two different categories of colon preneoplastic lesions induced by 1,2-dimethylhydrazine in F344 rats. Cancer Sci 96:876–881

    Article  CAS  PubMed  Google Scholar 

  49. Symolon H, Schmelz EM, Dillehay DL, Merrill AH Jr (2004) Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice. J Nutr 134:1157–1161

    CAS  PubMed  Google Scholar 

  50. Wargovich MJ, Harris C, Chen CD, Palmer C, Steele VE, Kelloff GJ (1992) Growth kinetics and chemoprevention of aberrant crypts in the rat colon. J Cell Biochem Suppl 16G:51–54

    Article  CAS  PubMed  Google Scholar 

  51. Nagase H, Nakamura Y (1993) Mutations of the APC (adenomatous polyposis coli) gene. Hum Mutat 2:425–434

    Article  CAS  PubMed  Google Scholar 

  52. Fyrst H, Oskouian B, Bandhuvula P, Gong Y, Byun HS, Bittman R, Lee AR, Saba JD (2009) Natural sphingadienes inhibit Akt-dependent signaling and prevent intestinal tumorigenesis. Cancer Res 69:9457–9464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Kumar A, Pandurangan AK, Lu F, Fyrst H, Zhang M, Byun HS, Bittman R, Saba JD (2012) Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3beta pathway in colon cancer. Carcinogenesis 33:1726–1735

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Kawamori T, Kaneshiro T, Okumura M, Maalouf S, Uflacker A, Bielawski J, Hannun YA, Obeid LM (2009) Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J 23:405–414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Liotta DC, Bushnev AS, Baillie MT, Holt JJ, Menaldino DS, Merrill AH (2010) An efficient asymmetric synthesis of Enigmols (1-deoxy-5-hydroxysphingoid bases), an important class of bioactive lipid modulators. Arkivoc 8:263–277

    Google Scholar 

  56. Symolon H, Bushnev A, Peng Q, Ramaraju H, Mays SG, Allegood JC, Pruett ST, Sullards MC, Dillehay DL, Liotta DC, Merrill AH Jr (2011) Enigmol: a novel sphingolipid analogue with anticancer activity against cancer cell lines and in vivo models for intestinal and prostate cancer. Mol Cancer Ther 10:648–657

    Article  CAS  PubMed  Google Scholar 

  57. Morales PR, Dillehay DL, Moody SJ, Pallas DC, Pruett S, Allgood JC, Symolon H, Merrill AH Jr (2007) Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation. Drug Chem Toxicol 30:197–216

    Article  CAS  PubMed  Google Scholar 

  58. Dickson MA, Carvajal RD, Merrill AH Jr, Gonen M, Cane LM, Schwartz GK (2011) A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. Clin Cancer Res 17:2484–2492

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Park EJ, Suh M, Ramanujam K, Steiner K, Begg D, Clandinin MT (2005) Diet-induced changes in membrane gangliosides in rat intestinal mucosa, plasma and brain. J Pediatr Gastroenterol Nutr 40:487–495

    Article  CAS  PubMed  Google Scholar 

  60. Hasegawa T, Shimada H, Uchiyama T, Ueda O, Nakashima M, Matsuoka Y (2011) Dietary glucosylceramide enhances cornified envelope formation via transglutaminase expression and involucrin production. Lipids 46:529–535

    Article  CAS  PubMed  Google Scholar 

  61. Ueda O, Hasegawa M, Kitamura S (2009) Distribution in skin of ceramide after oral administration to rats. Drug Metab Pharmacokinet 24:180–184

    Article  CAS  PubMed  Google Scholar 

  62. Oshida K, Shimizu T, Takase M, Tamura Y, Yamashiro Y (2003) Effects of dietary sphingomyelin on central nervous system myelination in developing rats. Pediatr Res 53:589–593

    Article  CAS  PubMed  Google Scholar 

  63. Duan J, Sugawara T, Sakai S, Aida K, Hirata T (2011) Oral glucosylceramide reduces 2,4-dinitrofluorobenzene induced inflammatory response in mice by reducing TNF-alpha levels and leukocyte infiltration. Lipids 46:505–512

    Article  CAS  PubMed  Google Scholar 

  64. Yunoki K, Renaguli M, Kinoshita M, Matsuyama H, Mawatari S, Fujino T, Kodama Y, Sugiyama M, Ohnishi M (2010) Dietary sphingolipids ameliorate disorders of lipid metabolism in Zucker fatty rats. J Agric Food Chem 58:7030–7035

    Article  CAS  PubMed  Google Scholar 

  65. Silins I, Nordstrand M, Hogberg J, Stenius U (2003) Sphingolipids suppress preneoplastic rat hepatocytes in vitro and in vivo. Carcinogenesis 24:1077–1083

    Article  CAS  PubMed  Google Scholar 

  66. Simon KW, Tait L, Miller F, Cao C, Davy KP, LeRoith T, Schmelz EM (2010) Suppression of breast xenograft growth and progression in nude mice: implications for the use of orally administered sphingolipids as chemopreventive agents against breast cancer. Food Funct 1:90–98

    Article  CAS  PubMed  Google Scholar 

  67. Fujiwara K, Kitatani K, Fukushima K, Yazama H, Umehara H, Kikuchi M, Igarashi Y, Kitano H, Okazaki T (2011) Inhibitory effects of dietary glucosylceramides on squamous cell carcinoma of the head and neck in NOD/SCID mice. Int J Clin Oncol 16:133–140

    Article  CAS  PubMed  Google Scholar 

  68. Lui C, Mills K, Brocardo MG, Sharma M, Henderson BR (2012) APC as a mobile scaffold: regulation and function at the nucleus, centrosomes, and mitochondria. IUBMB Life 64:209–214

    Article  CAS  PubMed  Google Scholar 

  69. Fagotto F, Funayama N, Gluck U, Gumbiner BM (1996) Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus. J Cell Biol 132:1105–1114

    Article  CAS  PubMed  Google Scholar 

  70. Orsulic S, Peifer M (1996) An in vivo structure-function study of armadillo, the beta-catenin homologue, reveals both separate and overlapping regions of the protein required for cell adhesion and for wingless signaling. J Cell Biol 134:1283–1300

    Article  CAS  PubMed  Google Scholar 

  71. Hoschuetzky H, Aberle H, Kemler R (1994) Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol 127:1375–1380

    Article  CAS  PubMed  Google Scholar 

  72. Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Oku N, Miyazawa K, Kitamura N, Takeichi M, Ito F (1994) Tyrosine phosphorylation of beta-catenin and plakoglobin enhanced by hepatocyte growth factor and epidermal growth factor in human carcinoma cells. Cell Adhes Commun 1:295–305

    Article  CAS  PubMed  Google Scholar 

  73. Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P (1995) Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A 92:3046–3050

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P (1996) Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 272:1023–1026

    Article  CAS  PubMed  Google Scholar 

  75. de Sousa EM, Vermeulen L, Richel D, Medema JP (2011) Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res 17:647–653

    Article  PubMed  CAS  Google Scholar 

  76. Giles RH, van Es JH, Clevers H (2003) Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653:1–24

    CAS  PubMed  Google Scholar 

  77. Hadjihannas MV, Bruckner M, Jerchow B, Birchmeier W, Dietmaier W, Behrens J (2006) Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer. Proc Natl Acad Sci U S A 103:10747–10752

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Song JH, Huels DJ, Ridgway RA, Sansom OJ, Kholodenko BN, Kolch W, Cho KH (2014) The APC network regulates the removal of mutated cells from colonic crypts. Cell Rep 7:94–103

    Article  CAS  PubMed  Google Scholar 

  79. Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, Knuechel R, Kirchner T (2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A 98:10356–10361

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Simon KW, Roberts PC, Vespremi MJ, Manchen S, Schmelz EM (2009) Regulation of beta-catenin and connexin-43 expression: targets for sphingolipids in colon cancer prevention. Mol Nutr Food Res 53:332–340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Kim JS, Crooks H, Foxworth A, Waldman T (2002) Proof-of-principle: oncogenic beta-catenin is a valid molecular target for the development of pharmacological inhibitors. Mol Cancer Ther 1:1355–1359

    CAS  PubMed  Google Scholar 

  82. Creekmore AL, Silkworth WT, Cimini D, Jensen RV, Roberts PC, Schmelz EM (2011) Changes in gene expression and cellular architecture in an ovarian cancer progression model. PLoS One 6:e17676

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Creekmore AL, Heffron CL, Brayfield BP, Roberts PC, Schmelz EM (2013) Regulation of cytoskeleton organization by sphingosine in a mouse cell model of progressive ovarian cancer. Biomolecules 3:386–407

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  84. Ketene AN, Roberts PC, Shea AA, Schmelz EM, Agah M (2012) Actin filaments play a primary role for structural integrity and viscoelastic response in cells. Integr Biol (Camb) 4:540–549

    Article  CAS  Google Scholar 

  85. Babahosseini H, Ketene AN, Schmelz EM, Roberts PC, Agah M (2014) Biomechanical profile of cancer stem-like/tumor-initiating cells derived from a progressive ovarian cancer model. Nanomedicine 10(5):1013–9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Babahosseini H, Roberts PC, Schmelz EM, Agah M (2013) Bioactive sphingolipid metabolites modulate ovarian cancer cell structural mechanics. Integr Biol (Camb) 5:1385–1392

    Article  CAS  Google Scholar 

  87. Salmanzadeh A, Elvington ES, Roberts PC, Schmelz EM, Davalos RV (2013) Sphingolipid metabolites modulate dielectric characteristics of cells in a mouse ovarian cancer progression model. Integr Biol (Camb) 5:843–852

    Article  CAS  Google Scholar 

  88. Anderson AS, Roberts PC, Frisard MI, McMillan RP, Brown TJ, Lawless MH, Hulver MW, Schmelz EM (2013) Metabolic changes during ovarian cancer progression as targets for sphingosine treatment. Exp Cell Res 319:1431–1442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Lin CI, Chen CN, Lin PW, Lee H (2007) Sphingosine 1-phosphate regulates inflammation-related genes in human endothelial cells through S1P1 and S1P3. Biochem Biophys Res Commun 355:895–901

    Article  CAS  PubMed  Google Scholar 

  90. Wu D, Ren Z, Pae M, Guo W, Cui X, Merrill AH, Meydani SN (2007) Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J Immunol 179:4829–4839

    Article  CAS  PubMed  Google Scholar 

  91. Teichgraber V, Ulrich M, Endlich N, Riethmuller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kurthy G, Schmid KW et al (2008) Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 14:382–391

    Article  PubMed  CAS  Google Scholar 

  92. Claycombe KJ, Wu D, Nikolova-Karakashian M, Palmer H, Beharka A, Paulson KE, Meydani SN (2002) Ceramide mediates age-associated increase in macrophage cyclooxygenase-2 expression. J Biol Chem 277:30784–30791

    Article  CAS  PubMed  Google Scholar 

  93. Nagahashi M, Hait NC, Maceyka M, Avni D, Takabe K, Milstien S, Spiegel S (2014) Sphingosine-1-phosphate in chronic intestinal inflammation and cancer. Adv Biol Regul 54:112–120

    Article  CAS  PubMed  Google Scholar 

  94. Park EJ, Suh M, Thomson B, Thomson AB, Ramanujam KS, Clandinin MT (2005) Dietary ganglioside decreases cholesterol content, caveolin expression and inflammatory mediators in rat intestinal microdomains. Glycobiology 15:935–942

    Article  CAS  PubMed  Google Scholar 

  95. Xu J, Anderson V, Schwarz SM (2013) Dietary GD3 ganglioside reduces the incidence and severity of necrotizing enterocolitis by sustaining regulatory immune responses. J Pediatr Gastroenterol Nutr 57:550–556

    Article  CAS  PubMed  Google Scholar 

  96. Sjoqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, Lofberg R (2002) Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity. Inflamm Bowel Dis 8:258–263

    Article  PubMed  Google Scholar 

  97. Cooper HS, Everley L, Chang WC, Pfeiffer G, Lee B, Murthy S, Clapper ML (2001) The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis. Gastroenterology 121:1407–1416

    Article  CAS  PubMed  Google Scholar 

  98. Bleyer AOLM, Barr R, Ries LAG (eds) (2006) Cancer epidemiology in older adolescents and young adults 15 to 29 Years of age, including SEER incidence and survival: 1975-2000. National Cancer Institute, Bethesda, MD, NIH Pub. No. 06-5767

    Google Scholar 

  99. Peneau A, Savoye G, Turck D, Dauchet L, Fumery M, Salleron J, Lerebours E, Ligier K, Vasseur F, Dupas JL et al (2013) Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study. Am J Gastroenterol 108:1647–1653

    Article  PubMed  Google Scholar 

  100. Lakatos PL, Lakatos L (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 14:3937–3947

    Article  PubMed Central  PubMed  Google Scholar 

  101. Scheinin T, Butler DM, Salway F, Scallon B, Feldmann M (2003) Validation of the interleukin-10 knockout mouse model of colitis: antitumour necrosis factor-antibodies suppress the progression of colitis. Clin Exp Immunol 133:38–43

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Mazzei JC, Zhou H, Brayfield BP, Hontecillas R, Bassaganya-Riera J, Schmelz EM (2011) Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: importance of peroxisome proliferator-activated receptor gamma expression. J Nutr Biochem 22:1160–1171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Furuya H, Ohkawara S, Nagashima K, Asanuma N, Hino T (2008) Dietary sphingomyelin alleviates experimental inflammatory bowel disease in mice. Int J Vitam Nutr Res 78:41–49

    Article  CAS  PubMed  Google Scholar 

  104. Wu XF, Wu XX, Guo WJ, Luo Q, Gu YH, Shen Y, Tan RX, Sun Y, Xu Q (2012) Cerebroside D, a glycoceramide compound, improves experimental colitis in mice with multiple targets against activated T lymphocytes. Toxicol Appl Pharmacol 263:296–302

    Article  CAS  PubMed  Google Scholar 

  105. Bassaganya-Riera J, Reynolds K, Martino-Catt S, Cui Y, Hennighausen L, Gonzalez F, Rohrer J, Benninghoff AU, Hontecillas R (2004) Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease. Gastroenterology 127:777–791

    Article  CAS  PubMed  Google Scholar 

  106. Fischbeck A, Leucht K, Frey-Wagner I, Bentz S, Pesch T, Kellermeier S, Krebs M, Fried M, Rogler G, Hausmann M, Humpf HU (2011) Sphingomyelin induces cathepsin D-mediated apoptosis in intestinal epithelial cells and increases inflammation in DSS colitis. Gut 60:55–65

    Article  CAS  PubMed  Google Scholar 

  107. Noh SK, Koo SI (2004) Milk sphingomyelin is more effective than egg sphingomyelin in inhibiting intestinal absorption of cholesterol and fat in rats. J Nutr 134:2611–2616

    CAS  PubMed  Google Scholar 

  108. Andersson D, Kotarsky K, Wu J, Agace W, Duan RD (2009) Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model. Dig Dis Sci 54:1440–1448

    Article  CAS  PubMed  Google Scholar 

  109. Bauer J, Liebisch G, Hofmann C, Huy C, Schmitz G, Obermeier F, Bock J (2009) Lipid alterations in experimental murine colitis: role of ceramide and imipramine for matrix metalloproteinase-1 expression. PLoS One 4, e7197

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  110. Chumanevich AA, Poudyal D, Cui X, Davis T, Wood PA, Smith CD, Hofseth LJ (2010) Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis 31:1787–1793

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Sakata A, Ochiai T, Shimeno H, Hikishima S, Yokomatsu T, Shibuya S, Toda A, Eyanagi R, Soeda S (2007) Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice. Immunology 122:54–64

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Mizushima T, Ito T, Kishi D, Kai Y, Tamagawa H, Nezu R, Kiyono H, Matsuda H (2004) Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis. Inflamm Bowel Dis 10:182–192

    Article  PubMed  Google Scholar 

  113. Deguchi Y, Andoh A, Yagi Y, Bamba S, Inatomi O, Tsujikawa T, Fujiyama Y (2006) The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. Oncol Rep 16:699–703

    CAS  PubMed  Google Scholar 

  114. Maines LW, Fitzpatrick LR, French KJ, Zhuang Y, Xia Z, Keller SN, Upson JJ, Smith CD (2008) Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 53:997–1012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC, Pulendran B (2010) Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329:849–853

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Keerthivasan S, Aghajani K, Dose M, Molinero L, Khan MW, Venkateswaran V, Weber C, Emmanuel AO, Sun T, Bentrem DJ et al (2014) β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci Transl Med 6:225

    Article  CAS  Google Scholar 

  117. Salim T, Sand-Dejmek J, Sjolander A (2014) The inflammatory mediator leukotriene D(4) induces subcellular beta-catenin translocation and migration of colon cancer cells. Exp Cell Res 321:255–266

    Article  CAS  PubMed  Google Scholar 

  118. Bäckhed F, Ley R, Sonnenburg J, Peterson D, Gordon J (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920

    Article  PubMed  CAS  Google Scholar 

  119. Savage D (1977) Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 31:107–133

    Article  CAS  PubMed  Google Scholar 

  120. Xu J, Gordon JI (2003) Inaugural Article: Honor thy symbionts. Proc Natl Acad Sci 100:10452–10459

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI (2007) The human microbiome project. Nature 449:804–810

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Larsen N, Vogensen F, van den Berg F, Nielsen D, Andreasen A, Pedersen B, Abu Al-Soud W, Sorensen S, Hansen L, Jakobsen M (2010) Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults. PLoS One 5, e9085

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Bergman EN (1990) Energy contributions of volatile fatty-acids from the gastrointestinal-tract in various species. Physiol Rev 70:567–590

    CAS  PubMed  Google Scholar 

  124. Duncan S, Hold G, Barcenilla A, Stewart C, Flint H (2002) Roseburia intestinalis sp nov., a novel saccharolytic, butyrate-producing bacterium from human faeces. Int J Syst Evol Microbiol 52:1615–1620

    CAS  PubMed  Google Scholar 

  125. Gibson G, Roberfroid M (1995) Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 125:1401–1412

    CAS  PubMed  Google Scholar 

  126. Hylemon P, Harder J (1999) Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems. FEMS Microbiol Rev 475–488

    Google Scholar 

  127. Chen T, Isomaki P, Rimpilainen M, Toivanen P (1999) Human cytokine responses induced by gram-positive cell walls of normal intestinal microbiota. Clin Exp Immunol 118:261–267

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Louis P, Young P, Holtrop G, Flint HJ (2010) Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA: acetate CoA-transferase gene. Environ Microbiol 12:304–314

    Article  CAS  PubMed  Google Scholar 

  129. Munoz-Tamayo R, Laroche B, Walter E, Dore J, Duncan SH, Flint HJ, Leclerc M (2011) Kinetic modelling of lactate utilization and butyrate production by key human colonic bacterial species. FEMS Microbiol Ecol 76:615–624

    Article  CAS  PubMed  Google Scholar 

  130. Ghosh S, Dai C, Brown K, Rajendiran E, Makarenko S, Baker J, Ma C, Halder S, Montero M, Ionescu VA et al (2011) Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression. Am J Physiol Gastrointest Liver Physiol 301:G39–G49

    Article  CAS  PubMed  Google Scholar 

  131. Lam YY, Ha CWY, Campbell CR, Mitchell AJ, Dinudom A, Oscarsson J, Cook DI, Hun NH, Caterson ID, Holmes AJ, Storlien LH (2012) Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice. PLoS One 7

    Google Scholar 

  132. Gambero A, Marostica M, Abdalla Saad MJ, Pedrazzoli J (2007) Mesenteric adipose tissue alterations resulting from experimental reactivated colitis. Inflamm Bowel Dis 13:1357–1364

    Article  PubMed  Google Scholar 

  133. Holmes E, Li JV, Athanasiou T, Ashrafian H, Nicholson JK (2011) Understanding the role of gut microbiome–host metabolic signal disruption in health and disease. Trends Microbiol 19:349–359

    Article  CAS  PubMed  Google Scholar 

  134. Brown K, DeCoffe D, Molcan E, Gibson DL (2012) Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 4:1095–1119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Dicksved J, Halfvarson J, Rosenquist M, Jarnerot G, Tysk C, Apajalahti J, Engstrand L, Jansson JK (2008) Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. ISME J 2:716–727

    Article  CAS  PubMed  Google Scholar 

  136. Spor A, Koren O, Ley R (2011) Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol 9:279–290

    Article  CAS  PubMed  Google Scholar 

  137. Arthur JC, Perez-Chanona E, Muhlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB et al (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X, Yen H-R, Huso DL, Brancati FL, Wick E, McAllister F et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Yamamoto ML, Maier I, Dang AT, Berry D, Liu J, Ruegger PM, Yang J, Soto PA, Presley LL, Reliene R et al (2013) Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity. Cancer Res 73:4222–4232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M et al (2013) Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101

    Article  CAS  PubMed  Google Scholar 

  141. Dennis KL, Wang Y, Blatner NR, Wang S, Saadalla A, Trudeau E, Roers A, Weaver CT, Lee JJ, Gilbert JA et al (2013) Adenomatous polyps are driven by microbe-instigated focal inflammation and are controlled by IL-10-producing T cells. Cancer Res 73:5905–5913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. An D, Oh SF, Olszak T, Neves JF, Avci FY, Erturk-Hasdemir D, Lu X, Zeissig S, Blumberg RS, Kasper DL (2014) Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156:123–133

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Rueda R, Sabatel JL, Maldonado J, Molina-Font JA, Gil A (1998) Addition of gangliosides to an adapted milk formula modifies levels of fecal Escherichia coli in preterm newborn infants. J Pediatr 133:90–94

    Article  CAS  PubMed  Google Scholar 

  144. de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE (2010) Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 299:G440–G448

    Article  CAS  Google Scholar 

  145. Kim KA, Gu W, Lee IA, Joh EH, Kim DH (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 7, e47713

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  146. Bardou M, Barkun AN, Martel M (2013) Obesity and colorectal cancer. Gut 62:933–947

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Human Nutrition, Foods and Exercise, Virginia Tech, 1981 Kraft Drive, ILSB 1011, Blacksburg, VA, 24061, USA

    Eva M. Schmelz

  2. Virginia Tech, Blacksburg, Virginia, USA

    Hui Zhou

  3. Department of Biomedical Science and Pathobiology, Virginia Tech, Blacksburg, VA, USA

    Paul C. Roberts

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  1. Eva M. Schmelz
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  2. Hui Zhou
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  3. Paul C. Roberts
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Correspondence to Eva M. Schmelz .

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Editors and Affiliations

  1. Stony Brook University, Stony Brook Cancer Center, Stony Brook, New York, USA

    Yusuf A. Hannun

  2. Dept. of Physiology & Biophysics, Stony Brook University, Stony Brook, New York, USA

    Chiara Luberto

  3. Dept. of Medicine, Stony Brook University, Stony Brook, New York, USA

    Cungui Mao

  4. Dept. of Medicine, Stony Brook University, Stony Brook, New York, USA

    Lina Marie Obeid

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Schmelz, E.M., Zhou, H., Roberts, P.C. (2015). Dietary Sphingolipids in Colon Cancer Prevention. In: Hannun, Y., Luberto, C., Mao, C., Obeid, L. (eds) Bioactive Sphingolipids in Cancer Biology and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-20750-6_8

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