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Apoptosis, Cell Replication, and Western-style Diet-induced Tumorigenesis in Mouse Colon¹

Centro Ricerche Neoplasie Apparato Digerente "L. Novello Miglino," Ospedale S. Giovanni Vecchio, 10123 Torino, Italy [M. R., F. P. R.]; Memorial Sloan-Kettering Cancer Center and Strang Cancer Prevention Center, New York, New York 10021 [H. N., K. Y., M. L.]; Chemoprevention Branch, Cancer Research Program, Division of Cancer Prevention and Control, National Cancer Institute, NIH, Bethesda, Maryland 20852 [V. E. S., C. W. B., G. J. K.]

In this study, feeding Western-style diets (WDs) to mice for a duration of two years without any chemical carcinogen led to the development of gross colonic lesions that were histologically classified as dysplastic crypts and focal hyperplasias with or without atypical nuclei. To better understand early biological events contributing to the development of colonic neoplasia, grossly normal colonic mucosa was investigated; mitotic and apoptotic colonic epithelial cells, atypical mitosis, and atypical nuclei were studied. A significant and transient increase of mitotic activity in the basal and intermediate portions of the colonic crypts was seen in young mice after feeding them the WDs. This was accompanied by diffuse activation of apoptosis of the colonic epithelial cells.

In the middle of the rodents' life span, after administration of both the WDs and control diet, the rodents developed a marked depletion of apoptotic epithelial cells in the mid-region of the colonic crypts; this was followed by the expansion of an epithelial cell population containing atypical nuclei, and the emergence of the gross lesions noted above. With this sequence of events, prolonged feeding of WDs to mice produced single-crypt dysplastic lesions and focal hyperplasias indicative of tumorigenesis.

¹ Supported in part by the Associazione Italiana per la Ricerca sul Cancro, the American-Italian Foundation for Cancer Research, National Cancer Institute Award NO1-CN-15363, and a grant from the National Dairy Research and Promotion Board.

² To whom requests for reprints should be addressed, at Strang Cancer Research Laboratory, The Rockefeller University, 1230 York Avenue, New York, NY 10021. Phone: (212) 734-0567.

Received 4/24/96. Accepted 9/ 3/96.

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