title: Stromal interaction essential for vascular endothelial growth factor A-induced tumour growth via transforming growth factor-β signalling.
abstract: BACKGROUND
  High vascular endothelial growth factor (VEGFA) levels at the time of diagnosis confer a worse prognosis to multiple malignancies. Our aim was to investigate the role of VEGFA in promoting tumour growth through interaction with its environment.
  
  
  METHODS
  HL-60 cells were transduced with VEGFA165 or control vector using retroviral constructs. Control cells (n=7) or VEGFA165 cells (n=7) were subcutaneously injected into NOD/SCID mice. Immunohistochemistry of markers for angiogenesis (CD31) and cell proliferation (Ki67) and gene expression profiling of tumours were performed. Paracrine effects were investigated by mouse-specific cytokine arrays.
  
  
  RESULTS
  In vivo we observed a twofold increase in tumour weight when VEGFA165 was overexpressed (P=0.001), combined with increased angiogenesis (P=0.002) and enhanced tumour cell proliferation (P=0.001). Gene expression profiling revealed human genes involved in TGF-β signalling differentially expressed between both tumour groups, that is, TGFBR2 and SMAD5 were lower expressed whereas the inhibitory SMAD7 was higher expressed with VEGFA165. An increased expression of mouse-derived cytokines IFNG and interleukin 7 was found in VEGFA165 tumours, both described to induce SMAD7 expression.
  
  
  CONCLUSIONS
  These results suggest a role for VEGFA-driven tumour growth by TGF-β signalling inhibition via paracrine mechanisms in vivo, and underscore the importance of stromal interaction in the VEGFA-induced phenotype.
authors: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: A C
authors: AC
authors: Weidenaar
authors: A
authors: A
authors: ter Elst
authors: K R
authors: KR
authors: Kampen
authors: T G J
authors: TG
authors: Meeuwsen-de Boer
authors: H J M
authors: HJ
authors: de Jonge
authors: F J G
authors: FJ
authors: Scherpen
authors: W F A
authors: WF
authors: den Dunnen
authors: W A
authors: WA
authors: Kamps
authors: E S J M
authors: ES
authors: de Bont
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A