title: Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas.
abstract: BACKGROUND
  In invasive malignancies, Dll4/Notch signaling inhibition enhances non-functional vessel proliferation and limits tumor growth by reducing its blood perfusion.
  
  
  METHODS
  To assess the effects of targeted Dll4 allelic deletion in the incipient stages of tumor pathogenesis, we chemically induced skin papillomas in wild-type and Dll4 (+/-) littermates, and compared tumor growth, their histological features, vascularization and the expression of angiogenesis-related molecules.
  
  
  RESULTS
  We observed that Dll4 down-regulation promotes productive angiogenesis, although with less mature vessels, in chemically-induced pre-cancerous skin papillomas stimulating their growth. The increase in endothelial activation was associated with an increase in the VEGFR2 to VEGFR1 ratio, which neutralized the tumor-suppressive effect of VEGFR-targeting sorafenib. Thus, in early papillomas, lower levels of Dll4 increase vascularization through raised VEGFR2 levels, enhancing sensitivity to endogenous levels of VEGF, promoting functional angiogenesis and tumor growth.
  
  
  CONCLUSIONS
  Tumor promoting effect of low-dosage inhibition needs to be considered when implementing Dll4 targeting therapies.
authors: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal. dusan.d.djokovic@gmail.com.
authors: Dusan
authors: D
authors: Djokovic
authors: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal. alex.jn.trindade@gmail.com.
authors: Alexandre
authors: A
authors: Trindade
authors: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal. joana.gi@gmail.com.
authors: Joana
authors: J
authors: Gigante
authors: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal. mpinho@fmv.ulisboa.pt.
authors: Mario
authors: M
authors: Pinho
authors: Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. adrian.harris@oncology.oxford.ac.uk.
authors: Adrian L
authors: AL
authors: Harris
authors: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal. aduarte@fmv.ulisboa.pt.
authors: Antonio
authors: A
authors: Duarte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002135:Calcium-Binding Proteins; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010212:Papilloma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D010671:Phenylurea Compounds / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D009536:Niacinamide; D000077157:Sorafenib; C000592875:Kdr protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2