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Is Interferon One Key of Metastatic Potential Increase in Human Bladder Carcinoma?

Laboratoire de Cytologie [P. C., D. S.], Laboratoire d’Hématologie [A. S.], both from Département de Biologie et de Pathologie de la Cellule, and Laboratoire de Biologie du Stress Oxydatif, Département de Biologie Intégrée [C. G.], Centre Hospitalier Universitaire de Grenoble, 38043 Grenoble Cedex; Laboratoire Migration Cellulaire et Infiltration Tumorale, Institut Albert Bonniot, La Tronche [G. L.]; and FRE 2617 du Centre National de la Recherché Scientifique, Université de Bordeaux 2, 33076 Bordeaux Cedex [V. P.], France

Purpose: IFN- 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- (>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--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- (<5 ng·ml^-1)(<400 IU·ml^-1) increased the resistance to the cytotoxic effect of tumor necrosis factor 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- 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 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.