title: Colorectal carcinoma cell production of transforming growth factor beta decreases expression of endothelial cell vascular endothelial growth factor receptor 2.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) signaling is a target for antiangiogenic cancer therapy. The authors have previously observed that up to 40% of vessels in colorectal carcinoma (CRC) tumors are negative for VEGF receptor 2 (VEGFR2) expression. Differential activity of transforming growth factor beta (TGF-β) is a potential contributor to this receptor heterogeneity because TGF-β contributes to both angiogenesis and CRC tumor progression.
  
  
  METHODS
  The authors analyzed VEGFR2 expression by Western blotting, and TGF-β expression in endothelial and CRC cell lines, respectively. In addition, they immunostained endothelial cells in CRC xenografts to find an association between VEGFR2 and TGF-β levels or activity.
  
  
  RESULTS
  In bovine aortic endothelial cells (BAECs), TGF-β1 significantly repressed VEGFR2 protein in a time-dependent and dose-dependent fashion (P < .05). Serum-free conditioned media from various malignant human CRC cell lines (HCT116, 379.2, Dks8, and DLD1) induced down-regulation of VEGFR2 in BAECs. This effect was proportional to the total levels of TGF-β1 and TGF-β2 and was blocked by SB-431542 and SD-208, TGF-β receptor I inhibitors. Immunofluorescence staining of subcutaneous mouse xenografts of HCT116, 379.2, Dks8, and SW480 cells revealed vessels with an inverse relationship between TGF-β activity and VEGFR2 expression. Oxygen and bone morphogenetic protein 9 levels were shown to modulate TGF-β-induced VEGFR2 down-regulation.
  
  
  CONCLUSIONS
  In combination with other factors, TGF-β may contribute to the vascular heterogeneity in human colorectal tumors.
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kuczynski
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Viloria-Petit
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Coomber
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002417:Cattle; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000096:biosynthesis; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D040301:Vascular Endothelial Growth Factor Receptor-2