title: Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models.
abstract: OBJECTIVE
  The role of semaphorins in tumor progression is still poorly understood. In this study, we aimed at elucidating the regulatory role of semaphorin 3A (SEMA3A) in primary tumor growth and metastatic dissemination.
  
  
  RESULTS
  We used 3 different experimental approaches in mouse tumor models: (1) overexpression of SEMA3A in tumor cells, (2) systemic expression of SEMA3A following liver gene transfer in mice, and (3) tumor-targeted release of SEMA3A using gene modified Tie2-expressing monocytes as delivery vehicles. In each of these experimental settings, SEMA3A efficiently inhibited tumor growth by inhibiting vessel function and increasing tumor hypoxia and necrosis, without promoting metastasis. We further show that the expression of the receptor neuropilin-1 in tumor cells is required for SEMA3A-dependent inhibition of tumor cell migration in vitro and metastatic spreading in vivo.
  
  
  CONCLUSIONS
  In sum, both systemic and tumor-targeted delivery of SEMA3A inhibits tumor angiogenesis and tumor growth in multiple mouse models; moreover, SEMA3A inhibits the metastatic spreading from primary tumors. These data support the rationale for further investigation of SEMA3A as an anticancer molecule.
authors.affiliation: Institute for Cancer Research and Treatment, University of Turin School of Medicine, Candiolo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.forename: Xi
authors.initials: X
authors.lastname: Fu
authors.forename: Irja
authors.initials: I
authors.lastname: Johansson
authors.forename: Lorena
authors.initials: L
authors.lastname: Capparuccia
authors.forename: Fredrik
authors.initials: F
authors.lastname: Andersson
authors.forename: Alice
authors.initials: A
authors.lastname: Giustacchini
authors.forename: Mario Leonardo
authors.initials: ML
authors.lastname: Squadrito
authors.forename: Mary Anna
authors.initials: MA
authors.lastname: Venneri
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D039942:Neuropilin-1 / Q000378:metabolism; D019899:Paracrine Communication; D034622:RNA Interference; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D011993:Recombinant Fusion Proteins; C108639:SEMA3A protein, human; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D039942:Neuropilin-1; D042787:Receptor, TIE-2