Assessment of biomarkers in paired primary and recurrent colorectal adenocarcinomas.
OBJECTIVE
Recurrent colorectal cancers respond poorly to anticancer treatment including radiotherapy. To better understand the biological characteristics of the recurrent colorectal tumor, we investigated various biomarkers regulating cell proliferation and cell loss in paired primary and recurrent colorectal tumor specimens within each individual.


METHODS
From a total of 11 colorectal adenocarcinoma patients, 22 specimens of paired primary and recurrent tumors were obtained for analysis. Apoptosis was evaluated by TUNEL labeling of apoptotic DNA fragmentation. Other biomarkers including proliferating cell nuclear antigen (PCNA), p53, WAF1, p34cdc2, and cyclins B1 and D1 were analyzed by immunohistochemical stains.


RESULTS
PCNA index (PCNAI) showed an increase in 6 and a decrease in 5 recurrent tumors compared to primary tumors. Median PCNAI in primary and recurrent tumors were 33.5 and 48.3, respectively (p = 0.16). In contrast, the apoptotic index (AI) decreased in 9 of 11 recurrent tumors compared to primary tumors. Median AI decreased from 4.3 in primary tumors to 1.4 in recurrent tumors (p = 0.04). The p53 expression increased in more than half of recurrent tumors compared to primary tumors. Mean staining score increased from 0.7 in primary tumors to 1.2 in recurrent tumors (p = 0.059). WAF1 and cyclin B1 did not show significant change. In contrast, both cyclin D1 and p34cdc2 increased significantly in recurrent tumors. These two biomarkers showed increased expression in 8 (cyclin D1) and 7 (p34cdc2) recurrent tumors, respectively, compared to their primary counterparts. Mean staining scores of both biomarkers in recurrent tumors increased by more than twofold compared to those in primary tumors and these differences were statistically significant (cyclin D1, p = 0.007; p34cdc2, p = 0.008).


CONCLUSIONS
This study showed significantly decreased apoptosis in recurrent colorectal tumors compared to their primary counterparts. The underlying regulatory mechanisms included increased expression of p53 and altered cell cycle regulators such as increased cyclin D1 and p34cdc2. With further study, it may be used for developing a new therapeutic strategy for the treatment of recurrent colorectal cancer.
Seong
J
J
Department of Radiation Oncology, Yonsei University Medical College, Seoul, Korea. jsseong@yumc.yonsei.ac.kr
Chung
E J
EJ
Kim
H
H
Kim
G E
GE
Kim
N K
NK
Sohn
S K
SK
Min
J S
JS
Suh
C O
CO
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis*; D016203:CDC2 Protein Kinase / Q000032:analysis; D002455:Cell Division; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D019938:Cyclin D1 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D053938:DNA Fragmentation; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012004:Rectal Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D012811:Sigmoid Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D014408:Biomarkers, Tumor; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D016203:CDC2 Protein Kinase