EARLY ALTERATION OF CELL-CYCLE-REGULATED GENE-EXPRESSION IN COLORECTAL NEOPLASIA

Aberrant crypt foci with dysplasia are thought to be the first detecta ble lesions of colorectal neoplasia. Because cell cycle disruption app ears crucial for tumorigenesis, we analyzed the immunohistochemical ex pression patterns of the prototype cyclin-dependent kinase inhibitor p 21(WAF1/CIP1) and the proliferation marker Ki67 in the early stages of colorectal tumorigenesis. In colorectal epithelium, p21(WAF1/CIP1) ex pression 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. lit contrast, markedly decreased p21(WAF1/CIP1) immunostaining was observed in dysplastic ab errant crypt foci as well as in small adenomas. Moreover, the compartm entalization of Ki67 and p21(WAF1/CIP1) was lost, as Ki67 expression e xtended into the small p21-expressing zone at the top of the crypts. T hese data suggest that the dysregulated expression of cell-cycle-contr olling genes and the consequent release from normal cell cycle control s may represent att essential early step in colorectal neoplasia.