Early alteration of cell-cycle-regulated gene expression in colorectal neoplasia.
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 humen. 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.
Polyak
K
K
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Hamilton
S R
SR
Vogelstein
B
B
Kinzler
K W
KW
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000032:analysis; D002453:Cell Cycle / Q000235:genetics*; D003111:Colonic Polyps / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007413:Intestinal Mucosa / Q000737:chemistry / Q000473:pathology; D019394:Ki-67 Antigen; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis
D000951:Antigens, Neoplasm; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins