title: Anti-tumoural effects of PlgK1-5 are directly linked to reduced ICAM expression, resulting in hepatoma cell apoptosis.
abstract: OBJECTIVE
  Angiostatin and angiostatin-like molecules are known as anti-angiogenic factors, which inhibit endothelial cell functions resulting in reduced tumour growth. Recent data indicate that these molecules, especially PlgK1-5, directly affect tumour cells, which could explain the strong anti-tumoural effects of PlgK1-5. Therefore, we have analysed whether PlgK1-5 alters tumour cell functions and expression levels of cell adhesion molecules in murine and human hepatoma cells in vitro and in vivo.
  
  
  METHODS
  First, effects on tumour growth, proliferation and apoptosis were investigated in vivo in a subcutaneous tumour model. In vitro, effects of PlgK1-5 on tumour cell apoptosis, clonal expansion, migration, corresponding ICAM expression and intracellular signal transduction in murine Hepa129 and human HuH7 hepatoma cells have been analysed.
  
  
  RESULTS
  In vivo, subcutaneous tumour growth was reduced by 75% in PlgK1-5-treated animals compared to the controls. This was accompanied by increased tumour cell apoptosis (up to 33%) and decreased tumour cell proliferation (by up to 21%). In vitro, PlgK1-5 induced apoptosis in hepatoma cells, corresponding to increased caspase-8 cleavage and reduced AKT phosphorylation. Migration and clonal expansion was also diminished in PlgK1-5-treated Hepa129, corresponding to decreased ICAM expression levels.
  
  
  CONCLUSIONS
  Here, we show that PlgK1-5 directly affects tumour cells by decreasing cell adhesion resulting-at least partly-in apoptosis. This is mediated by altered intracellular signal transduction and by activation of the caspase cascade. These findings further underscore the potential therapeutic role of PlgK1-5 in the treatment of HCC.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Esther
authors.initials: E
authors.lastname: Raskopf
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D053181:Caspase 8 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D010958:Plasminogen / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018799:Intercellular Adhesion Molecule-1; D010958:Plasminogen; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8