TY - JOUR
T1 - Early alteration of cell-cycle-regulated gene expression in colorectal neoplasia
AU - Polyak, Kornelia
AU - Hamilton, Stanley R.
AU - Vogelstein, Bert
AU - Kinzler, Kenneth W.
PY - 1996/8
Y1 - 1996/8
N2 - Aberrant crypt foci with dysplasia are thought to be the first detectable lesions of colorectal neoplasia. Because cell cycle disruption appears crucial for tumorigenesis, we analyzed the immunohistochemical expression patterns of the prototype cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and the proliferation marker Ki67 in the early stages of colorectal tumorigenesis. In colorectal epithelium, p21(WAF1/CIP1) expression was undetectable in the lower third of the crypts, where Ki67 was expressed, but then sharply increased as cells passed out of the proliferating zone and migrated toward the lumen. Hyperplastic polyps retained this normal compartmentalized pattern. In contrast, markedly decreased p21(WAF1/CIP1) immunostaining was observed in dysplastic aberrant crypt foci as well as in small adenomas. Moreover, the compartmentalization of Ki67 and p21(WAF1/CIP1) was lost, as Ki67 expression extended into the small p21-expressing zone at the top of the crypts. These data suggest that the dysregulated expression of cell-cycle-controlling genes and the consequent release from normal cell cycle controls may represent an essential early step in colorectal neoplasia.
AB - Aberrant crypt foci with dysplasia are thought to be the first detectable lesions of colorectal neoplasia. Because cell cycle disruption appears crucial for tumorigenesis, we analyzed the immunohistochemical expression patterns of the prototype cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and the proliferation marker Ki67 in the early stages of colorectal tumorigenesis. In colorectal epithelium, p21(WAF1/CIP1) expression was undetectable in the lower third of the crypts, where Ki67 was expressed, but then sharply increased as cells passed out of the proliferating zone and migrated toward the lumen. Hyperplastic polyps retained this normal compartmentalized pattern. In contrast, markedly decreased p21(WAF1/CIP1) immunostaining was observed in dysplastic aberrant crypt foci as well as in small adenomas. Moreover, the compartmentalization of Ki67 and p21(WAF1/CIP1) was lost, as Ki67 expression extended into the small p21-expressing zone at the top of the crypts. These data suggest that the dysregulated expression of cell-cycle-controlling genes and the consequent release from normal cell cycle controls may represent an essential early step in colorectal neoplasia.
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M3 - Article
C2 - 8701978
AN - SCOPUS:0030057835
SN - 0002-9440
VL - 149
SP - 381
EP - 387
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -