title: Continuous taurocholic acid exposure promotes esophageal squamous cell carcinoma progression due to reduced cell loss resulting from enhanced vascular development.
abstract: BACKGROUND
  Refluxogenic effects of smoking and alcohol abuse may be related to the risk of esophageal squamous cell carcinoma (ESCC). The present study attempts to clarify the effects of continuous taurocholic acid (TCA) exposure, which is neither mutagenic nor genotoxic, on ESCC progression.
  
  
  METHODS
  A squamous carcinoma cell line (ESCC-DR) was established from a tumor induced in a rat model of gastroduodenal reflux. ESCC-DR cells were incubated with 2 mM TCA for ≥2 months. The effects of continuous TCA exposure were evaluated in vitro on cell morphology, growth, and invasion and in vivo on xenograft tumor growth in nude mice. Moreover, the mean level of secreted transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) proteins in cell culture supernatants and mRNA synthesis of TGF-β1 and VEGF-A of ESCC cells were measured. The angiogenic potential was further examined by a migration assay using human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  Continuous TCA exposure induced marked formation of filopodia in vitro. Expression levels of angiogenic factors were significantly higher in the cells treated with TCA than in control cells. Tumor xenografts derived from cells pre-exposed to TCA were larger and more vascularized than those derived from control cells. In addition, TCA exposure increased HUVEC migration.
  
  
  CONCLUSIONS
  Continuous TCA exposure enhanced ESCC progression due to reduced cell loss in vivo. Cell loss was inhibited by TCA-induced vascular endothelial cell migration, which was mediated by TGF-β1 and VEGF-A released from ESCC cells.
authors.affiliation: Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan ; Department of Oral and Maxillofacial Surgery, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Mukaisho
authors.affiliation: Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan ; Department of Oral and Maxillofacial Surgery, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Oral and Maxillofacial Surgery, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugihara
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D000077277:Esophageal Squamous Cell Carcinoma; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013656:Taurocholic Acid / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D013656:Taurocholic Acid