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(American Journal of Pathology. 2003;162:1139-1149.)
© 2003 American Society for Investigative Pathology

Human Urinary Bladder Transitional Cell Carcinomas Acquire the Functional Fas Ligand during Tumor Progression

Dominique Chopin*, Reza Barei-Moniri*, Pascale Maillé*, Marie-Aude Le Frère-Belda{dagger}, Béatrice Muscatelli-Groux*, Nicolò Merendino{ddagger}, Laure Lecerf*, Antonella Stoppacciaro§ and Francesca Velotti*{ddagger}

From the Service d’Urologie et Groupe d’Etude des Tumeurs Urologiques Equipe Mixte INSERM 03-37* and the Service d’Anatomie et de Cytologie Pathologiques,{dagger} Centre Hôspitalier Universitaire Henri Mondor, Créteil, France; the Department of Experimental Medicine and Pathology,§ "La Sapienza" University, Rome, Italy; and the Department of Environmental Sciences,{ddagger} Tuscia University, Viterbo, Italy

The interaction between FasL on tumor cells and Fas on lymphocytes may represent a tumor immune escape mechanism. We explored FasL expression and function in human urinary bladder transitional cell carcinomas (TCCs). FasL expression was observed in situ in 45% of TCCs (n = 45) and was absent in normal urothelium (n = 20). A correlation existed between FasL expression and high tumor grade (0% in G1, 14% in G2, and 75% in G3; P < 0.0001) and stage (13% in superficial Ta-T1 versus 81% in invasive T2-T4; P < 0.0001). FasL function was shown by the ability of two FasL-positive primary culture TCC cell lines (established from two FasL-positive invasive TCCs) to induce Fas-mediated killing not only of conventional Fas-sensitive targets (such as Jurkat cells or phytohemagglutinin-lymphoblasts), but also of autologous T lymphocytes generated in a mixed lymphocyte tumor-cell culture. In addition, an association between FasL expression by TCC cells and activated caspase-8, -9, and -3 expression by interferon-{gamma}-producing CD8-positive tumor-infiltrating lymphocytes was observed in situ. Our results show a functional expression of TCC-expressed FasL that correlates with tumor progression. These results suggest that TCC-expressed FasL may induce apoptosis of anti-tumor T lymphocytes in vivo, providing new insights on the mechanisms involved in bladder TCC progression.




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