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Ability of Aberrant Crypt Foci Characteristics to Predict Colonic Tumor Incidence in Rats Fed Cholic Acid¹

Departments of Foods and Nutrition [B. A. M., R. P. B.], and Pathology [I. C.], University of Manitoba, Winnipeg, Manitoba, R3T 2N2 Canada

² To whom requests for reprints should be addressed.

Aberrant crypt foci (ACF) are putative preneoplastic lesions of colon cancer which are being utilized currently as a biological end point to evaluate the induction and modulation of colon carcinogenesis. In several previous short-term studies, the unexpected reduction of ACF by the reported colonic tumor promoter cholic acid (CHA) emphasized the need for a systematic evaluation of the growth of ACF in response to a tumor promoter.

The present study was conducted to determine if any characteristic(s) of ACF at various early stages of carcinogenesis would predict resulting tumor incidence in rats fed CHA. Male Sprague-Dawley rats received two injections of azoxymethane (20 mg/kg) and were fed either the AIN-76 diet or AIN-76 plus 0.2% CHA. The number, crypt multiplicity (number of crypts/focus), and size (area) of ACF were measured after 2, 8,14, and 18 weeks in 5 rats/group. The number of ACF was lower (P < 0.033) in animals fed CHA at all time points. Average crypt multiplicity of ACF was greater (P = 0.045) from CHA-fed animals after 8 weeks compared to animals fed the AIN-76 diet. The average size of ACF was smaller in CHA-fed animals after 2 weeks and then tended to be larger than the sizes of the ACF from animals fed the AIN-76 diet. All remaining animals were killed after 18 weeks. Tumor incidence was higher (P < 0.001) in the CHA-fed group (63.2%) compared to the control diet group (29.4%). CHA-fed rats also had a higher number of tumors/tumor-bearing rat compared to control diet rats (1.96 versus 1.13). The main finding of this study is that the number of ACF at early time points did not predict tumor incidence. Crypt multiplicity was a consistent predictor of tumor outcome and should be measured in future studies using ACF as a biological end point. The CHA diet appears to provide a unique tumor-modulating environment that selectively enhances the growth of a smaller number of ACF leading to an increased number of tumors compared to a control diet. The mechanism(s) by which CHA mediates this effect warrants further investigation.

¹ Funded by the National Cancer Institute of Canada and The Natural Sciences and Engineering Research Council to R. R B. B. A. M. is the recipient of a Manitoba Health Research Council Studentship. R. R B. is a recipient of a Women in Science Career Award of the Natural Sciences and Engineering Research Council. Presented in part at the Canadian Federation of Biological Societies 35th Annual Meeting, Victoria, British Columbia, Canada, June 18, 1992.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/20/92. Accepted 7/26/93.

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