title: Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide.
abstract: BACKGROUND
  We previously reported that dietary glucosylceramides show cancer-prevention activity in a mouse xenograft model of human head and neck cancer cells (SCCKN). However, the mechanism was unclear. Ceramides, metabolites of glucosylceramides, induce apoptotic cell death in various malignancies. Here, we investigated the inhibitory effects of dietary glucosylceramides on tumor growth in vivo and in vitro.
  
  
  METHODS
  SCCKN were subcutaneously inoculated into the right flanks of NOD/SCID mice. Mice were treated with or without dietary glucosylceramides (300 mg/kg) daily for 14 consecutive days after confirmation of tumor progression. Microvessel areas around the tumor were assessed by hematoxylin-eosin staining and immunohistochemistry of CD31, and, as markers for angiogenesis, protein levels of VEGF, VEGF receptor-2, and HIF-1α were assessed by Western blotting. Mass spectrometry was performed to measure the levels of sphingolipids in mouse serum after treatment with dietary glucosylceramides.
  
  
  RESULTS
  Oral administration of glucosylceramides significantly decreased SCCKN growth in the xenograft model with inhibition of angioinvasion. In tumor-invasive areas, VEGF and HIF-1α in the tumor cells, and VEGF receptor-2 in endothelial cells decreased after treatment with dietary glucosylceramides. Dietary glucosylceramides increased serum levels of sphingosine-based ceramides as compared to the control. In SCCKN and UV♀2 cells, C6-ceramide suppressed the expressions of VEGF, VEGF receptor-2, and HIF-1α in vitro.
  
  
  CONCLUSIONS
  These results suggest that dietary glucosylceramides trigger the de novo pathway of ceramide synthesis, indicating that sphingosine-based ceramide suppresses the growth of head and neck tumors through the inhibition of pro-angiogenic signals such as VEGF, VEGF receptor-2, and HIF-1α.
authors: Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, 683-8503, Japan.
authors: Hiroaki
authors: H
authors: Yazama
authors: Kazuyuki
authors: K
authors: Kitatani
authors: Kazunori
authors: K
authors: Fujiwara
authors: Misaki
authors: M
authors: Kato
authors: Mayumi
authors: M
authors: Hashimoto-Nishimura
authors: Katsuyuki
authors: K
authors: Kawamoto
authors: Kensaku
authors: K
authors: Hasegawa
authors: Hiroya
authors: H
authors: Kitano
authors: Alicja
authors: A
authors: Bielawska
authors: Jacek
authors: J
authors: Bielawski
authors: Toshiro
authors: T
authors: Okazaki
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000178:diet therapy* / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis; D005963:Glucosylceramides / Q000008:administration & dosage*; D006258:Head and Neck Neoplasms / Q000178:diet therapy* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000178:diet therapy* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D002518:Ceramides; D005963:Glucosylceramides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2