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Resistance
to CD95 (APO-1/Fas)-Mediated Apoptosis in Human Renal Cell Carcinomas: An
Important Factor for Evasion from Negative Growth Control |
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Claus D. Gerharz,
Uwe Ramp, Marion Dáejosez, Csaba Mahotka, Beate Czarnotta, Ute Bretschneider,
Ingrid Lorenz, Martina Müller, Peter H. Krammer, and Helmut E. Gabbert |
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Institute
of Pathology (CDG, UR, MD, CM, BC, UB, HEG) and Institute of Transfusion
Medicine (IL), Heinrich Heine University, Duesseldorf; Department of Internal
Medicine iv (MM), University Hospital, and German Cancer Research Center
(DKFZ) (PHK), Heidelberg, Germany |
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SUMMARY: Disorders in negative
growth control by CD95 (APO-1/Fas)-mediated apoptosis have been suggested
to facilitate immune evasion of neoplastic cells and resistance to anticancer
drugs. The present report describes the expression and function of CD95
receptor and ligand in human renal cell carcinomas (RCC) of all major histological
types, presenting in vitro data on RCC cell lines (n = 30) and ex
vivo observations in RCC tissue samples (n = 30). Using RT-PCR, flow
cytometry and immunostaining, expression of CD95 receptor and ligand was
found in human RCC of all major histological types. The expression levels
of CD95 ligand, however, were rather low. Despite constitutive CD95 receptor
expression, resistance to CD95-mediated apoptosis became evident from the
weak response to agonistic anti-CD95 antibodies, which induced a low increase
of apoptosis in only 9 of 30 RCC cell lines. After IFN-[gamma] pretreatment,
however, apoptosis triggered by agonistic anti-CD95 antibodies was observed
in 22 of 30 RCC cell lines. These data indicated that the machinery required
for CD95-induced cell death was present, albeit inactive in most RCC. Inhibition
of protein synthesis by cycloheximide resulted in increased sensitivity
to agonistic anti-CD95 antibodies, suggesting a role for short-lived apoptosis-protective
proteins in the resistance of RCC to CD95-mediated apoptosis. Moreover,
we demonstrated the secretion of soluble CD95 receptor which might contribute
to this resistance as well. In conclusion, resistance rather than responsiveness
to CD95-mediated apoptosis is a key feature of human RCC. This resistance
might facilitate evasion from negative growth control and contribute to
the failure of cytotoxic drugs in the treatment of human RCC. |
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