title: Is interferon gamma one key of metastatic potential increase in human bladder carcinoma?
abstract: OBJECTIVE
  IFN-gamma is detected in the urine of bladder cancer patients after intravesical bacillus Calmette Guerin instillation. Because it acts in the anticancer process, we studied its cellular and molecular mechanisms of action on human bladder cancer cell lines.
  
  
  RESULTS
  IFN-gamma (>5 ng.ml(-1))(>400 IU.ml(-1)) inhibited the growth of bladder cancer cell lines and modified the expression of the tumor-associated markers tissue-type plasminogen activators, Plasminogen activator inhibitor-2, urokinase plasminogen activator receptor, colony-stimulating factor 1, intercellular adhesion molecule 1, and class II MHC. Interestingly, IFN-gamma-induced apoptosis of the low-grade bladder cancer cell lines (RT4/G1 and RT112/G2) related to a cleavage of caspases 1, 8, and 9. This process was inhibited by the phosphatidylinositol 3'-kinase inhibitor (LY294002) and the protein synthesis inhibitor (cycloheximide). Moreover, low doses of IFN-gamma (<5 ng.ml(-1))(<400 IU.ml(-1)) increased the resistance to the cytotoxic effect of tumor necrosis factor alpha in the RT112 cells but not in the RT4 cells. This acquired resistance was associated with morphological changes and with an increase of the cell migration and scattering.
  
  
  CONCLUSIONS
  We demonstrated that in the low-grade bladder cancer cell lines, the effect of IFN-gamma was dose dependent: high doses (>5 ng.ml(-1)) induced apoptosis of RT4 and RT112 cells, whereas low doses (<5 ng.ml(-1)) induced a resistance to the cytotoxic effect of tumor necrosis factor alpha and increase the metastatic potential of the RT112 cells. Therefore, we propose that a similar phenomenon could participate to the immunotherapy failure observed during tumor progression of bladder cancer.
authors.affiliation: Laboratoire de Cytologie, Centre Hospitalier Universitaire de Grenoble, 38043 Grenoble Cedex, France. PChampelovier@chu-grenoble.fr
authors.forename: Pierre
authors.initials: P
authors.lastname: Champelovier
authors.forename: Annick
authors.initials: A
authors.lastname: Simon
authors.forename: Catherine
authors.initials: C
authors.lastname: Garrel
authors.forename: Geraldine
authors.initials: G
authors.lastname: Levacher
authors.forename: Vincent
authors.initials: V
authors.lastname: Praloran
authors.forename: Daniel
authors.initials: D
authors.lastname: Seigneurin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma; D020169:Caspases