title: Growth factor therapy and lymph node graft for lymphedema.
abstract: BACKGROUND
  Lymphedema still remains an unsolved problem. Secondary lymphedema often develops after cancer operations or radiation therapy, especially in breast cancer patients. Using a mouse model, we show here that the lymphatic network can be regenerated using lymphatic vascular growth factor therapy in combination with lymph node transfer.
  
  
  METHODS
  We have compared the therapeutic effects of different vascular endothelial growth factors (VEGF-C, VEGF-D, VEGF-C156S, and VEGF-A), in combination with lymph node transfer in mouse axilla. The lymphangiogenic effects of the growth factor therapy were examined at 3 mo postoperatively.
  
  
  RESULTS
  VEGF therapy with VEGF-C and VEGF-D induced growth of new lymphatic vessels in the defect area, and VEGF-C also improved lymphatic vessel function compared with that of controls. VEGF-C156S induced moderate lymphangiogenesis, but the effect remained statistically nonsignificant. Prolymphangiogenic growth factors (VEGF-C, -D, and -C156S) also improved lymph node survival as compared with those of the VEGF-A and control group. VEGF-C, which activates both vascular endothelial growth factor receptor 2 and vascular endothelial growth factor receptor 3, gave the best therapeutic effect in this experimental lymphedema model.
  
  
  CONCLUSIONS
  These results support our goal to treat secondary lymphedema by combining lymph node transfer with the growth factor therapy. VEGF-C provides the preferred alternative for growth factor therapy of lymphedema when compared with other VEGF-family growth factors, due to the superior lymphangiogenic response and minor blood vascular effects.
authors.affiliation: Department of Plastic Surgery, Kuopio University Hospital, Kuopio, Finland. Electronic address: tomi.tervala@kuh.fi.
authors.forename: Tomi V
authors.initials: TV
authors.lastname: Tervala
authors.affiliation: Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Hartiala
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.affiliation: Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland.
authors.forename: Mikko T
authors.initials: MT
authors.lastname: Visuri
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland; Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Saarikko
mesh_terms: D000818:Animals; D008198:Lymph Nodes / Q000637:transplantation*; D042583:Lymphangiogenesis; D008209:Lymphedema / Q000503:physiopathology / Q000628:therapy*; D008220:Lymphography; D051379:Mice; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Lymph node transfer; Lymphedema; Vascular endothelial growth factor