The extrinsic apoptosis pathway and its prognostic impact in ovarian cancer.
OBJECTIVE
Death ligand FasL, its agonistic receptor Fas, tumor necrosis factor related apoptosis inducing ligand (TRAIL) and its agonistic death receptors DR4 and DR5 are implied in carcinogenesis, tumor immune surveillance and response to chemotherapy. TRAIL receptor agonists are evaluated as anti-cancer agents. This study aimed to relate expression of death ligands/receptors and downstream initiator caspase 8 and its anti-apoptotic homologue FLICE like inhibitory protein (c-FLIP) in ovarian cancers to chemotherapy response and survival.


METHODS
Fas, FasL, TRAIL, DR4, DR5, caspase 8 and c-FLIP were determined immunohistochemically on a tissue microarray containing 382 ovarian cancers. Protein expression profiles were correlated with clinicopathologic variables, chemotherapy response and survival.


RESULTS
Most tumors expressed DR4, DR5, caspase 8 and c-FLIP. High c-FLIP expression was associated with expression of caspase 8 and both TRAIL receptors. TRAIL and Fas were associated with low tumor grade and better progression-free survival (HR 0.63, p=.018 and HR 0.54, p=.012), respectively, and Fas with disease-specific survival (HR 0.49, p=0.009) in univariate analysis.


CONCLUSIONS
Fas and TRAIL loss is associated with dedifferentiation and worse prognosis. Expression of DR4, DR5, caspase 8 and c-FLIP by most ovarian cancers does not correlate with survival. High c-FLIP expression should be taken into account for death receptor targeted therapies.
Duiker
Evelien W
EW
Department of Medical Oncology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
van der Zee
Ate G J
AG
de Graeff
Pauline
P
Boersma-van Ek
Wytske
W
Hollema
Harry
H
de Bock
Geertruida H
GH
de Jong
Steven
S
de Vries
Elisabeth G E
EG
D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D019014:fas Receptor / Q000096:biosynthesis
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D019014:fas Receptor; D053181:Caspase 8