title: Establishment of a novel experimental model of human angiosarcoma and a VEGF-targeting therapeutic experiment.
abstract: BACKGROUND
  Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required. One factor in delaying the therapy development is the limitation of experimental models.
  
  
  OBJECTIVE
  We established a novel experimental angiosarcoma model.
  
  
  METHODS
  From surgically resected tissue, human AS cell line was established. Using xenograft of AS cell line, we performed therapeutic experiments with the anti-human VEGF Ab or the receptor tyrosine kinase inhibitor.
  
  
  RESULTS
  First we generated an angiosarcoma cell line, HAMON (human angiosarcoma, monoclonal), which expresses CD31 and produces tumors in immunodeficient mice. HAMON expresses VEGFR2 and that exogenous VEGF leads to HAMON proliferation in vitro. Anti-human VEGF Ab bevacizumab treatment failed to suppress HAMON proliferation in vitro and in vivo. Furthermore, the receptor tyrosine kinase inhibitor sunitinib did not suppress HAMON proliferation in vitro. Similarly, in in vivo therapeutic experiments, even high doses of sunitinib failed to inhibit tumor growth. Finally, we checked whether compensatory activation of VEGF signaling occurred after sunitinib addition. VEGF protein secretion, VEGF mRNA synthesis and VEGFR2 phosphorylation all were unaffected in HAMON after sunitinib treatment.
  
  
  CONCLUSIONS
  A novel in vitro and in vivo experimental model of human angiosarcoma has been successfully established. With this model, we were able to perform therapeutic experiments. In addition, our angiosarcoma cell line, HAMON, is quite useful for identifying key molecules in angiosarcoma.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Hoshina
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshioka
authors.forename: Nao
authors.initials: N
authors.lastname: Saito
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
authors.forename: Satoru
authors.initials: S
authors.lastname: Aoyagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib