Control of apoptosis in Epstein Barr virus-positive nasopharyngeal carcinoma cells: opposite effects of CD95 and CD40 stimulation.
The expression and function of CD95 and CD40 were investigated in malignant cells from EBV-positive undifferentiated nasopharyngeal carcinomas (NPCs). Large amounts of CD95 and CD40 expression were detected in 15 of 16 EBV-positive NPC specimens. In contrast, CD95 was not detected in two biopsies from patients with EBV-negative differentiated NPCs. We tested whether the CD95 apoptotic pathway was functional in NPC cells by treating two EBV-positive NPC tumor lines in vitro with a CD95 agonist. In both cases, NPC cells were extremely susceptible to CD95-mediated apoptosis, despite strong constitutive expression of Bcl-x. Combined CD40 and CD95 stimulation was used to investigate the possible anti-apoptotic activity mediated by CD40. The CD40 receptor was activated by incubating NPC cells with murine L cells producing CD154, the CD40 ligand. This treatment resulted in a strong inhibition of CD95-related cytotoxicity. Such an anti-apoptotic effect of CD40 is well known for B lymphocytes, but has not previously been reported for epithelial cells. These data suggest that NPC tumor-infiltrating lymphocytes, which often produce the CD40 ligand in situ, may increase the survival of malignant cells, thereby enhancing tumor growth in patients.
Laboratoire de Biologie des Tumeurs Humaines, UMR 1598 Centre National de la Recherche Scientifique, Institut Gustave Roussy, Villejuif, France.
F
F
Sbih-Lammali
B
B
Clausse
H
H
Ardila-Osorio
R
R
Guerry
M
M
Talbot
S
S
Havouis
L
L
Ferradini
J
J
Bosq
T
T
Tursz
P
P
Busson
D000293:Adolescent; D017209:Apoptosis; D019013:CD40 Antigens / Q000032:analysis / Q000502:physiology*; D002470:Cell Survival; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000473:pathology* / Q000821:virology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D019014:fas Receptor / Q000032:analysis / Q000502:physiology*
C494811:BCL2L1 protein, human; D019013:CD40 Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor