title: The essential role of fibroblasts in esophageal squamous cell carcinoma-induced angiogenesis.
abstract: OBJECTIVE
  Esophageal squamous cell carcinoma (ESCC) is known to be a highly angiogenic tumor. Here, we investigated the role of the stromal fibroblasts in the ESCC-induced angiogenic response using a novel 3-dimensional model.
  
  
  METHODS
  A novel assay was developed where cocultures of ESCC and esophageal fibroblasts induced human microvascular endothelial cell (HMVEC) vascular network formation in a 3-dimensional collagen gel. Biochemical studies showed that the ESCC-induced activation of the fibroblasts was required to induce vascular network formation via a transforming growth factor (TGF)-beta and vascular endothelial growth factor (VEGF)-dependent pathway.
  
  
  RESULTS
  Conditioned media from a panel of 4 ESCC lines transdifferentiated normal esophageal fibroblasts into myofibroblasts via TGF-beta signaling. The presence of fibroblasts was essential for efficient HMVEC network formation, and the addition of ESCC cells to these cultures greatly enhanced the angiogenic process. The role of TGF-beta in this process was shown by the complete inhibition of network formation following TGF-beta inhibitor treatment. Finally, we showed that ESCC-derived TGF-beta regulates angiogenesis through the release of VEGF from the fibroblasts and that the VEGF release was blocked following TGF-beta inhibition.
  
  
  CONCLUSIONS
  This study shows the essential role of fibroblasts in the ESCC angiogenic-induced response and suggests that the pharmacologic targeting of the TGF-beta signaling axis could be of therapeutic benefit in this deadly disease.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Noma
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lioni
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Wafik
authors.initials: W
authors.lastname: El-Deiry
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: King
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism*; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000378:metabolism*; D004947:Esophagus / Q000196:embryology / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005782:Gels; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008833:Microcirculation / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C519132:2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride; C509927:4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; D001549:Benzamides; D052117:Benzodioxoles; D017077:Culture Media, Conditioned; D005782:Gels; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen