Wnt-signaling and apoptosis after neoadjuvant short-term radiotherapy for rectal cancer.
Recent surgical concepts for primary rectal cancer include the combination of surgery and short-term neoadjuvant radiotherapy (STNR). This is usually given in a dose of 25 Gy over five days in order to reduce local recurrence rates. Clinical studies have shown that local recurrence is found in some patients despite STNR. We identified molecular patterns of the Wnt- and apoptosis pathways as well as expression of junction-associated molecules in rectal cancer specimens of patients who received STNR and in those who did not. Expression patterns were examined by immunohistochemistry and molecular techniques such as LightCycler RT-PCR and Western blot analysis in 25 sporadic rectal adenocarcinoma specimens derived from STNR-patients or non-pretreated donors, respectively. The molecular pattern in response to STNR was heterogeneous and was reflected by responders who show activation of apoptosis and cellular remodeling, whereas the group of non-responders from STNR did not show such reaction and was very similar to untreated controls. Enhanced expression of beta-catenin was generally mediated by STNR, but exclusively in the responder group impaired expression of c-Myc and junction-associated molecules as well as cleavage of poly-ADP-ribose polymerase and of the caspase substrate cytokeratin 19 were found. The molecular profile suggests that STNR interferes with Wnt-signaling and c-Myc expression. STNR in its present form is not suitable to fully complete the sequence of apoptosis in all rectal adenocarcinomas.
Gassler
Nikolaus
N
Department of Pathology, University of Heidelberg, Heidelberg, Germany. nikolaus_gassler@med.uni-heidelberg.de
Herr
Ingrid
I
Keith
Martina
M
Autschbach
Frank
F
Schmitz-Winnenthal
Hubertus
H
Ulrich
Alexis
A
Otto
Herwart F
HF
Kartenbeck
Jürgen
J
Z'graggen
Kaspar
K
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D000328:Adult; D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D019583:Dose Fractionation, Radiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007633:Keratins / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D007633:Keratins