Bernstein C, Bernstein H, Garewal H, Dinning P, Jabi R, Sampliner R E, McCuskey M K, Panda M, Roe D J, L'Heureux L, Payne C
Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson 85724, USA.
Cancer Res. 1999 May 15;59(10):2353-7.
Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk.
胆汁酸在结直肠癌的病因学中起着重要作用。在高脂肪餐后，胆汁酸诱导结肠杯状细胞凋亡的浓度与粪便水中发现的浓度相当。初步证据表明，结肠癌患者结肠上皮外观正常（无肿瘤）部分的细胞比正常个体的细胞对胆盐诱导的凋亡更具抗性。在本研究中，对68例患者进行了检查，并在距肛门边缘20厘米处、盲肠和降结肠处取活检组织。这些患者包括17例有结直肠癌病史的个体、37例有腺瘤的个体和14例无肿瘤的个体。正常个体中胆盐诱导的平均凋亡指数为57.6±3.47（标准误），与有结肠癌病史个体的平均值36.41±3.12有显著差异（P<0.05）。独立观察者之间的相关性为0.89（P<0.001），表明观察者间可靠性良好。比较个体间与个体内变异来源的方差成分表明，在有肿瘤病史的个体中，结肠不同区域之间以及相邻活检组织之间的位点间变异性大于患者间变异性。因此，在有肿瘤病史的个体中，结肠区域对胆汁酸诱导凋亡的易感性存在“斑块状”（斑块状场效应）。低凋亡指数区域与先前发现并切除肿瘤的区域之间没有明显相关性。另一方面，对于正常（即无肿瘤）个体，个体内变异相对于个体间变异相对较少。我们的检测显示，在距肛门边缘20厘米处测量的对胆汁酸诱导凋亡的抗性与结肠癌风险之间存在关联。因此，该检测可能被证明是一种有用的结肠癌风险生物标志物。
