Spontaneous development of aberrant crypt foci in F344 rats

Aberrant crypt foci (ACF) have been proposed as intermediate biomarkers for colon carcinogenesis on the basis of many rodent studies. Although molecular analyses have indicated that these lesions in experimental animals are related to early events in colon carcinogenesis, their preneoplastic nature has yet to be fully elucidated. In the present study, one hundred and thirty 19-week-old male Fischer 344 rats were examined. The biological characteristics of spontaneous ACF were analyzed histopathologically, immunohistochemically and with molecular biological techniques, and compared with colon tumors found in control groups used for carcinogenicity tests. The incidences of spontaneous ACF consisting of 1, 2, 3 and 4 or more crypts were respectively 27.7%, 32.5%, 16.8% and 22.8%. Most ACF were distributed in the lower middle and upper distal colon, and proximal colon ACF was rare. Likewise, ACF frequently (42.5%) developed in untreated animals, whereas the incidence of spontaneous colorectal tumors was extremely low (0.68%) in control male rats. In addition, spontaneous ACF did not show apparent proliferative activity or c-K-ras point mutations. Our results thus suggest that spontaneous ACF rarely progress to colon tumors although long-term sequential observation might be necessary to conclude the significance of ACF.