title: The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells.
abstract: OBJECTIVE
  Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%) which preferentially occurs in the liver. Conventional chemotherapy being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents.
  
  
  METHODS
  We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR.
  
  
  RESULTS
  We showed that PPP efficiently block growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanism involved in metastasis, including tumor cells adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layer. Furthermore, PPP significantly delayed established of uveal melanoma tumor and drastically reduced the incidence of liver metastasis in mice.
  
  
  CONCLUSIONS
  Our data suggest that IGR-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.
authors.affiliation: Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Cancer Centre Karolinska R8:04, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Ada
authors.initials: A
authors.lastname: Girnita
authors.forename: Charlotta
authors.initials: C
authors.lastname: All-Ericsson
authors.forename: Mario A
authors.initials: MA
authors.lastname: Economou
authors.forename: Kristina
authors.initials: K
authors.lastname: Aström
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.forename: Stefan
authors.initials: S
authors.lastname: Seregard
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Leonard
authors.initials: L
authors.lastname: Girnita
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014604:Uveal Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D016326:Extracellular Matrix Proteins; D061965:Matrix Metalloproteinase Inhibitors; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin