Aberrant crypt foci: detection, gene abnormalities, and clinical usefulness.
Human aberrant crypt foci (ACF) were first identified as lesions consisting of large thick crypts in colonic mucosa of surgical specimens after staining with methylene blue. Previously we succeeded in identifying ACF by using magnifying endoscopy and analyzed the number, size, and dysplastic features of ACF in normal controls and patients with adenoma or cancer patients. On the basis of these analyses, we strongly suggested that ACF, particularly dysplastic ACF, are precursor lesions of the adenoma-carcinoma sequence in humans. In most sporadic ACF, K-ras mutations were positive, but APC mutations were negative irrespective of nondysplastic or dysplastic features. Conversely, in most ACF from familial adenomatous polyposis patients, APC mutations were positive but K-ras mutations were negative. These results may suggest that the molecular mechanism of sporadic colon carcinogenesis is not necessarily the same as that of familial adenomatous polyposis. It was shown that ACF acquired resistance to apoptosis induced by bile salts, whereas normal colonic epithelial cells are turning over consistently by apoptosis. This apoptosis resistance was closely associated with glutathione S-transferase P1-1 expression. One of the most important clinical applications of ACF observation with magnifying endoscopy is its use as a target lesion for chemoprevention. Because ACF are tiny lesions, they should be eradicated during a short time by administration of chemopreventive agents. In fact, we performed an open chemopreventive trial of sulindac and found that the number of ACF was reduced markedly in 2 months. We currently are proceeding with a randomized double-blind trial targeting ACF.
Takayama
Tetsuji
T
Sapporo Medical University School of Medicine, 4th Department of Internal Medicine, Hokkaido, Japan. ttakayam@sapmed.ac.jp
Miyanishi
Koji
K
Hayashi
Tsuyoshi
T
Kukitsu
Takehiro
T
Takanashi
Kunihiro
K
Ishiwatari
Hirotoshi
H
Kogawa
Takahiro
T
Abe
Tomoyuki
T
Niitsu
Yoshiro
Y
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D003113:Colonoscopy / Q000379:methods*; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging / Q000379:methods*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology