Chang W C, Chapkin R S, Lupton J R
Faculty of Nutrition, Texas A&M University, College Station 77843-2471, USA.
Carcinogenesis. 1997 Apr;18(4):721-30. doi: 10.1093/carcin/18.4.721.
In order to determine the prognostic significance of proliferation, differentiation, and apoptosis as intermediate markers for colon tumor development, these indices were measured during the promotion phase of tumorigenesis. Two hundred and sixty male Sprague-Dawley rats were provided with one of two fats (corn oil and fish oil) and two fibers (pectin and cellulose) plus or minus the carcinogen azoxymethane (AOM) and killed at two time points (18 and 36 wk) in a 2x2x2x2 factorial design. In vivo cell proliferation was measured immunohistochemically using incorporation of bromodeoxyuridine into DNA. Differentiation was assessed by binding of Dolichos biflorus agglutinin (DBA) to colonocytes. Apoptosis was measured by immunoperoxidase detection of digoxigenin-labeled genomic DNA. Adenocarcinoma incidence results at week 36 were 70.3% for corn oil + AOM and 56.1% for fish oil + AOM treatment (P < 0.05); no main effect of fiber was observed. At week 18, AOM treatment increased the number of cells per crypt column in the proximal colon compared with saline controls (P = 0.0358) and increased the proliferative zone in the distal colon compared with controls (P = 0.0073). However, changes in cell proliferation at week 18 did not predict the beneficial effect of fish oil versus corn oil. In contrast, DBA binding (the marker for differentiation) was higher in fish oil versus corn oil fed animals in both the proximal and distal colon and in each portion of the crypt (P = 0.0001). There were a greater number of apoptotic cells/crypt column in the proximal colon (P = 0.0019) and distal colon (P = 0.0358) with fish oil compared with corn oil, and indices of apoptosis also predicted certain fat/fiber interactions. Measurements of differentiation and apoptosis had greater prognostic value to detect dietary effects on tumor incidence than did measurements of cell proliferation.
为了确定增殖、分化和凋亡作为结肠肿瘤发生中间标志物的预后意义，在肿瘤发生的促进阶段对这些指标进行了测量。给260只雄性斯普拉格-道利大鼠提供两种脂肪（玉米油和鱼油）和两种纤维（果胶和纤维素）中的一种，同时给予或不给予致癌物偶氮甲烷（AOM），并在两个时间点（18周和36周）按照2×2×2×2析因设计将大鼠处死。采用溴脱氧尿苷掺入DNA的方法，通过免疫组织化学测定体内细胞增殖。通过双花扁豆凝集素（DBA）与结肠细胞的结合评估分化情况。采用免疫过氧化物酶检测地高辛标记的基因组DNA来测量凋亡。在36周时，玉米油+AOM组腺癌发生率为70.3%，鱼油+AOM组为56.1%（P<0.05）；未观察到纤维的主要效应。在18周时，与生理盐水对照组相比，AOM处理使近端结肠每个隐窝柱中的细胞数量增加（P=0.0358），与对照组相比，使远端结肠的增殖区增加（P=0.0073）。然而，18周时细胞增殖的变化并不能预测鱼油相对于玉米油的有益作用。相反，在近端和远端结肠以及隐窝的每个部分，鱼油喂养的动物中DBA结合（分化标志物）均高于玉米油喂养的动物（P=0.0001）。与玉米油相比，鱼油组近端结肠（P=0.0019）和远端结肠（P=0.0358）中每个隐窝柱的凋亡细胞数量更多，凋亡指标也预测了某些脂肪/纤维相互作用。与细胞增殖测量相比，分化和凋亡测量对于检测饮食对肿瘤发生率的影响具有更大的预后价值。
