Independent induction of caspase-8 and cFLIP expression during colorectal carcinogenesis in sporadic and HNPCC adenomas and carcinomas.
BACKGROUND
TNF-Related Apoptosis Inducing Ligand (TRAIL) is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase-8 and its anti-apoptotic competitor cellular Flice-Like Inhibitory Protein (cFLIP).


METHODS
The aim of this study was to investigate basic expression of caspase-8 and cFLIP in normal colorectal epithelium (n=20), colorectal adenomas (n=66) and colorectal carcinomas (n=44) using immunohistochemistry performed on both sporadic and Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome)-associated adenomas and carcinomas.


RESULTS
Expression of both caspase-8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase-8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P=0.02). Nuclear, paranuclear as well as cytoplasmic localizations of caspase-8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P<0.001). A large variation in the caspase-8/cFLIP ratio was observed between the individual adenomas and carcinomas.


CONCLUSIONS
Caspase-8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase-8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.
Heijink
D M
DM
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
Kleibeuker
J H
JH
Jalving
M
M
Boersma-van Ek
W
W
Koornstra
J J
JJ
Wesseling
J
J
de Jong
S
S
D000236:Adenoma / Q000201:enzymology* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000096:biosynthesis*; D049109:Cell Proliferation; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053181:Caspase 8