title: DNA vaccination against membrane-bound Kit ligand: a new approach to inhibiting tumour growth and angiogenesis.
abstract: A functional c-Kit/Kit ligand (KitL) signalling network is required for tumour angiogenesis and growth, and therefore the c-Kit/KitL system might well be a suitable target for the cancer immunotherapy approach. We herein describe a strategy that targets membrane-bound KitL (mbKitL) via DNA vaccination. The vaccination procedure generated antibodies which are able to detect mbKitL on human tumour endothelial cells (TECs) and on the breast cancer cell line: TSA. DNA vaccination, interferes with tumour vessel formation and transplanted tumour growth in vivo. Histological analysis demonstrates that, while tumour cell proliferation and vessel stabilisation are impaired, vessel permeability is increased in mice that produce mbKitL-targeting antibodies. We also demonstrate that vessel stabilisation and tumour growth require Akt activation in endothelial cells but not in pericytes. Moreover, we found that regulatory T cells (Treg) and tumour infiltrating inflammatory cells, involved in tumour growth and angiogenesis, were reduced in number in the tumour microenvironment of mice that generate anti-mbKitL antibodies. These data provide evidence that mbKitL targeted vaccination is an effective means of inhibiting tumour angiogenesis and growth.
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Olgasi
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Iavello
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Togliatto
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Toto
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Liberatore
authors.affiliation: Molecular Biotechnology Center, University of Torino, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barutello
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Musiani
authors.affiliation: Molecular Biotechnology Center, University of Torino, Italy. Electronic address: federica.cavallo@unito.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.affiliation: Department of Medical Sciences, University of Torino, Italy. Electronic address: mariafelice.brizzi@unito.it.
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
mesh_terms: D000818:Animals; D016466:CHO Cells; D048708:Cell Growth Processes / Q000276:immunology; D003412:Cricetulus; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*; D015398:Signal Transduction; D013160:Splenic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019444:Vaccines, DNA; D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; DNA vaccination; Tumour angiogenesis; mbKitL