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Reduced Bile Acid-induced Apoptosis in "Normal" Colorectal Mucosa: A Potential Biological Marker for Cancer Risk¹

Department of Internal Medicine, Section of Hematology/Oncology [H. G.] and Section of Gasteroenterology [H. G., R. S.], Tucson Veteran Affairs Medical Center and Arizona Cancer Center, Tucson, Arizona 85723, and Department of Microbiology and Immunology, University of Arizona Health Sciences Center, Tucson, Arizona 85724 [H. B., C. B. C. P.]

Dietary factors, including bile acids, are important in the causation of colorectal cancer (CRC). We have previously shown that in vitro exposure of colorectal mucosal biopsies to low concentrations of bile acids produces apoptosis selectively in goblet cells. Apopotosis is an important mechanism for clearing DNA-damaged cells. Inhibition of apoptosis would result in increasing accumulation of DNA-damaged cells, resulting in increased cancer risk. We compared the percentage of apoptosis induced by bile acids in mucosal biopsies from CRC patients with that of noncancer subjects.

Mucosal biopsies from 15 to 20 cm from the anal verge were incubated in 1 mM sodium deoxycholate, and the percentage of goblet cells undergoing apoptosis was quantitated. Seven patients with a history of CRC within the previous 5 years were compared with 18 noncancer subjects [4 neoplasia free and 14 with small (9 mm) polyps only].

The CRC patients had a significantly lower percentage of apoptosis than noncancer subjects; the mean for CRC was 10.7% (range, 0.9–26%) and for noncancer subjects was 55.9% (range, 20.3–71%; P 0.001). Two other noncancer patients had very high-risk lesions, i.e., large villous adenomas and multiple large polyps during several colonoscopies over the previous 6 years. Their percentage of apoptosis was in the cancer range, i.e., 6.2 and 10.7%.

Reduced apoptotic ability may imply increased cancer risk. By applying a quantitative bile acid-induced apoptosis assay to colorectal mucosal biopsies, the percentage of apoptosis was found to be significantly reduced in CRC patients. This assay may prove to be a useful intermediate biological marker for identifying subjects at increased risk of cancer.

¹ Supported in part by a grant from the Biomedical Research Foundation of Southern Arizona and National Institute of Environmental Health Sciences Center Grant P30-ES-06694.

² To whom requests for reprints should be addressed, at Section of Hematology-Oncology (111D), Tucson Veterans Affairs Medical Center, 3601 South 6th Avenue, Tucson, AZ 85723. Phone: (520) 792-1450, Ext. 6410; Fax: (520) 629-1861.

Received 1/15/96. Accepted 2/15/96.

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