Perturbation of the tumor necrosis factor--related apoptosis-inducing ligand cascade in ovarian cancer: overexpression of FLIPL and deregulation of the functional receptors DR4 and DR5.
OBJECTIVE
Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancies. Due to advanced stage at diagnosis, most patients need systemic treatment in addition to surgery. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with a promising toxicity profile and synergistic activity with chemotherapeutic agents.


METHODS
We used an arrayed panel of epithelial ovarian cancer tissue to assess the protein expression of TRAIL and the clinically most relevant members of its pathway death receptors 4 and 5 (DR4 and DR5) and the long form of FLICE inhibitory protein (FLIPL).


RESULTS
We could show that a majority (66.2%) of the tumor tissues displayed either reduced DR4/DR5 expression (20.6%), increased FLIPL expression (39.7%), or both (5.9%) as determined by immunohistochemistry. Furthermore, higher TRAIL expression in the surrounding connective tissue but not in the tumor cells is significantly (P<0.05) linked with favorable overall survival in advanced-stage patients.


CONCLUSIONS
Mechanisms to escape the immune surveillance mediated by TRAIL are developed by ovarian cancer cells in a high percentage. TRAIL expression in the ovarian cancer microenvironment has an effect on overall survival. These findings enhance our understanding of ovarian cancer pathology and might be helpful in guiding TRAIL-based therapy in future.
Horak
Peter
P
Clinical Division of Oncology, Department of Medicine I, University of Vienna, Austria.
Pils
Dietmar
D
Kaider
Alexandra
A
Pinter
Alexander
A
Elandt
Katarzyna
K
Sax
Cornelia
C
Zielinski
Christoph C
CC
Horvat
Reinhard
R
Zeillinger
Robert
R
Reinthaller
Alexander
A
Krainer
Michael
M
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002277:Carcinoma / Q000737:chemistry / Q000378:metabolism* / Q000401:mortality; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007120:Immunochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000401:mortality; D040081:Protein Array Analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000378:metabolism*; D017154:Stromal Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha