Objectives: The Fas-Fas ligand system is an important regulator of apoptosis and is involved in tumor development. Invasive cancers downregulate Fas expression to evade antitumor immune responses. Fas is a transcriptional target of p53, which is often mutated in bladder cancers. Therefore, Fas expression and its relation to p53 mutation was investigated.
Methods: Expression of Fas protein and p53 status was studied by immunohistochemistry in 83 bladder cancer specimens. In addition, mRNA levels for soluble (decoy) and membrane-bound forms of Fas were compared between 10 bladder cancer cell lines and primary uroepithelial cells by quantitative TaqMan polymerase chain reaction. Mutational analysis of the death domain of the Fas gene was performed in all cell lines.
Results: Organ-confined tumors maintained specific Fas staining at the cell membrane and often also in the cytoplasm. In higher stage carcinomas, Fas expression became restricted to a smaller fraction of cells or was lacking entirely. The correlation of Fas staining with tumor stage was highly significant but no correlation to tumor grade or survival was found. Furthermore, no statistically significant relationship was observed with either the presence or lack of mutated p53 accumulation. Membrane-bound Fas mRNA was decreased in most, and soluble Fas was increased in all transitional cell carcinoma lines compared with primary uroepithelial cells. No mutations in the death domain were detected.
Conclusions: Fas downregulation occurring in advanced bladder cancer is unrelated to p53 mutations. The results of immunohistochemistry and mRNA studies of soluble and membrane-bound Fas in transitional cell carcinoma lines support the hypothesis of immune evasion in advanced bladder cancer.