title: Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo.
abstract: The inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models.
  
  
  
  We used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas.
  
  
  
  We found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy.
  
  
  
  By reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control.
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, University of Lisbon, Lisbon, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, University of Lisbon, Lisbon, Portugal.|Faculdade de Ciências Médicas, Nova Medical School, Nova University of Lisbon, Lisbon, Portugal.|Serviço de Obstetrícia e Ginecologia, Centro Hospitalar de Lisboa Ocidental, Hospital de São Francisco Xavier, Lisbon, Portugal.
authors.forename: Dusan
authors.initials: D
authors.lastname: Djokovic
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, University of Lisbon, Lisbon, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Gigante
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, University of Lisbon, Lisbon, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Mendonça
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, University of Lisbon, Lisbon, Portugal. aduarte@fmv.ulisboa.pt.
authors.forename: António
authors.identifier: 0000-0002-9255-3635
authors.initials: A
authors.lastname: Duarte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007340:Insulinoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins
keywords: Angiogenesis; Dll4; Drug-delivery; Metastasis; Notch; Overexpression; Tumor