Long-term expression of fibrogenic cytokines in radiation-induced damage to the internal anal sphincter.
BACKGROUND
There is accumulating evidence, both quantitative and qualitative, that pelvic irradiation affects anorectal function. However, the molecular mechanisms responsible for radiation-induced damage to the anal sphincter remain unclear.


OBJECTIVE
To determine the expression of transforming growth factor-beta 1 (TGF-beta 1) and its downstream effector connective tissue growth factor (CTGF) in the anal sphincter of a patient irradiated for prostate cancer.


METHODS
A 82 year-old patient developed a rectal adenocarcinoma and underwent an abdomino-perineal resection (APR), four years after receiving pelvic irradiation for prostate carcinoma.


METHODS
Tissue sections of the anal sphincter were processed for histology. Immunostaining for TGF-beta 1 and CTGF were performed.


RESULTS
CTGF and TGF-beta 1 immunoreactivity was detected in the irradiated anal sphincter, and was absent in controls. Immunoreactivity for both cytokines predominated in the internal sphincter. CTGF and TGF-beta 1 were preferentially detected in endothelial cells, myofibroblasts and fibroblasts; in addition, there was strong immunoreactivity for TGF-beta 1, but not for CTGF in smooth muscle cells of the anal canal.


CONCLUSIONS
Four years after pelvic irradiation, radiation-induced damage appeared to affect predominantly the smooth muscle layer of the anal canal. The molecular mechanisms responsible for radiation-induced fibrosis to these tissues involve prolonged activation of TGF-beta 1 and its downstream effector CTGF.
Gervaz
P
P
Department of Visceral Surgery and Transplantation, University Hospital Geneva, Switzerland. pascal.gervaz@hcuge.ch
Hennig
R
R
Buechler
M
M
Soravia
C
C
Brigstock
D R
DR
Morel
Ph
P
Egger
J F
JF
Friess
H
H
D000230:Adenocarcinoma / Q000532:radiotherapy* / Q000601:surgery*; D000368:Aged; D000369:Aged, 80 and over; D001003:Anal Canal / Q000473:pathology / Q000528:radiation effects*; D055513:Connective Tissue Growth Factor; D018450:Disease Progression; D005355:Fibrosis / Q000473:pathology / Q000601:surgery; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis*; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis*; D008297:Male; D009130:Muscle, Smooth / Q000473:pathology / Q000528:radiation effects*; D009381:Neoplasms, Radiation-Induced / Q000601:surgery*; D016609:Neoplasms, Second Primary / Q000601:surgery*; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000473:pathology*; D012004:Rectal Neoplasms / Q000601:surgery*; D012007:Rectum / Q000473:pathology / Q000528:radiation effects / Q000601:surgery; D012086:Reoperation; D016212:Transforming Growth Factor beta / Q000032:analysis*; D053773:Transforming Growth Factor beta1
C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor