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.

[1]  K. Kinzler,et al.  Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues. , 1996, Cancer research.

[2]  T. Muto,et al.  [Familial polyposis coli]. , 1995, Nihon rinsho. Japanese journal of clinical medicine.

[3]  R. Kolodner.  Mismatch repair: mechanisms and relationship to cancer susceptibility. , 1995, Trends in biochemical sciences.

[4]  S. Elledge,et al.  p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells , 1995, Science.

[5]  P. Nurse,et al.  Checkpoints in the cell cycle of fission yeast. , 1995, Current opinion in genetics & development.

[6]  S. Elledge,et al.  Cdk inhibitors: on the threshold of checkpoints and development. , 1994, Current opinion in cell biology.

[7]  C. Sherr.  G1 phase progression: Cycling on cue , 1994, Cell.

[8]  T. Hunter,et al.  Cyclins and cancer II: Cyclin D and CDK inhibitors come of age , 1994, Cell.

[9]  S. Gallinger,et al.  Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. , 1994, Cancer research.

[10]  K. Kinzler,et al.  Molecular determinants of dysplasia in colorectal lesions. , 1994, Cancer research.

[11]  J. R. Smith,et al.  Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. , 1994, Experimental cell research.

[12]  Robin J. Leach,et al.  Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer , 1993, Cell.

[13]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[14]  E. Kaplan,et al.  K-ras mutations in putative preneoplastic lesions in human colon. , 1993, Journal of the National Cancer Institute.

[15]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[16]  S. Elledge,et al.  The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases , 1993, Cell.

[17]  G. Capellá,et al.  Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas. , 1993, Journal of the National Cancer Institute.

[18]  P. Hall,et al.  Ki67—Structure, function, and new antibodies , 1992, The Journal of pathology.

[19]  Bert Vogelstein,et al.  APC mutations occur early during colorectal tumorigenesis , 1992, Nature.

[20]  S Ichii,et al.  Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. , 1992, Human molecular genetics.

[21]  V. Steele,et al.  Growth kinetics and chemoprevention of aberrant crypts in the rat colon , 1992, Journal of cellular biochemistry. Supplement.

[22]  S. Hamilton,et al.  The adenoma‐adenocarcinoma sequence in the large bowel: Variations on a theme , 1992, Journal of cellular biochemistry. Supplement.

[23]  T. Hunter,et al.  Cyclins and cancer , 1991, Cell.

[24]  Margaret Robertson,et al.  Identification and characterization of the familial adenomatous polyposis coli gene , 1991, Cell.

[25]  K. Kinzler,et al.  Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. , 1991, Science.

[26]  J. McPherson,et al.  Identification of deletion mutations and three new genes at the familial polyposis locus , 1991, Cell.

[27]  S. Altschul,et al.  Identification of FAP locus genes from chromosome 5q21. , 1991, Science.

[28]  L. Roncucci,et al.  Identification and quantification of aberrant crypt foci and microadenomas in the human colon. , 1991, Human pathology.

[29]  T. P. Pretlow,et al.  Aberrant crypts: putative preneoplastic foci in human colonic mucosa. , 1991, Cancer research.

[30]  B. Vogelstein,et al.  p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. , 1990, Cancer research.

[31]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[32]  T. P. Pretlow,et al.  Enzyme-altered foci in colons of carcinogen-treated rats. , 1990, Cancer research.

[33]  R. Bird,et al.  Aberrant crypts: potential preneoplastic lesions in the murine colon. , 1988, Cancer research.

[34]  R P Bird,et al.  Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. , 1987, Cancer letters.

[35]  William E. Grizzle,et al.  Detection of high incidence of K-ras oncogenes during human colon tumorigenesis , 1987, Nature.

[36]  B. Vogelstein,et al.  Prevalence of ras gene mutations in human colorectal cancers , 1987, Nature.

[37]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[38]  S. Hamilton.  Pathogenesis of polyps (adenomas) , 1983, Diseases of the colon and rectum.