title: VEGF is an important mediator of tumor angiogenesis in malignant lesions in a genetically engineered mouse model of lung adenocarcinoma.
abstract: BACKGROUND
  VEGF is one of the key drivers of physiological or pathological angiogenesis hence several VEGF inhibitors are in different stages of clinical development. To further dissect the role of VEGF in different stages of tumor progression in lung tumors, we utilized KrasG12D-LSL GEMMs (genetically engineered mouse models).
  
  
  METHODS
  Intranasal delivery of adenoviruses expressing cre recombinase in KrasG12D-LSL mice results in the expression of mutant Kras that leads to development of tumor lesions ranging from adenomatous hyperplasia to large adenoma and adenocarcinoma over time in lung. In the current study, we treated KrasG12D-LSL mice at 14 weeks post inhalation with three different angiogenic inhibitors including axitinib and PF-00337210 both of which are selective inhibitors of VEGFR and sunitinib which targets VEGFR, C-SF1-R, PDGFR and KIT.
  
  
  RESULTS
  Pathology findings showed no significant difference in percentage of adenomatous hyperplastic lesions between the vehicle vs. any of the treatments suggesting that angiogenesis may not play a major role at early stages of tumorigenesis. However, each inhibitor suppressed percentage of benign adenoma lesions and almost fully inhibited growth of adenocarcinoma lesions in the recipients which was consistent with a reduction in tumor vasculature. Treatment with sunitinib which is a multi-targeted RTKI did not provide any advantage compared to selective VEGFR inhibitor further emphasizing role of VEGF in tumor angiogenesis in this model.
  
  
  CONCLUSIONS
  Overall, our studies indicate significance of VEGF and angiogenesis in a spontaneous model of lung tumorigenesis and provide a proof of mechanism for anti-cancer activity of VEGF inhibitors in this model.
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Majeti
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Brett H
authors.initials: BH
authors.lastname: Simmons
authors.forename: Farbod
authors.initials: F
authors.lastname: Shojaei
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)