Cell proliferation and esophageal carcinogenesis in the zinc-deficient rat
Cell proliferation and esophageal carcinogenesis in the zinc-deficient rat
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DOI：
10.1093/carcin/17.9.1841
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发表时间：
1996-09-01
期刊：
影响因子：
4.7
通讯作者：
Magee, PN
中科院分区：
文献类型：
--
作者：
Fong, LYY;Li, JX;Magee, PN
在维持缺锌或充足锌饮食的断奶大鼠中，研究了由 N-亚硝基甲基苄胺 (NMBA) 诱导的食管癌发展过程中的靶细胞增殖。缺乏的大鼠随意喂养，而锌充足的大鼠则与缺乏的动物配对喂养或随意喂养。 5周后，每个饮食组中的一半动物被给予六次胃内剂量的NMBA（2毫克/千克；每周两次）。其余大鼠未接受致癌物治疗。首次给药后第 1、2、3、4、5、7、9 和 11 周，通过体内溴脱氧尿苷 (BrDU) 标记，然后对 S 期细胞进行免疫组织化学检测，评估各组大鼠的食管细胞增殖情况。 11周时，缺锌组、锌充足组、随意组和配对组的肿瘤发生率分别为100%、23%和6%。体内 BrDU 标记显示，在 NMBA 未处理组中，标记指数 (LI)、标记细胞数以及整个食管每个横截面的细胞总数在所有时间点均因缺锌而显着增加；在锌充足、配对喂养的大鼠中，LI 最低。在 NMBA 治疗期间（第 6、7 和 8 周），两组锌充足的食管细胞增殖均增加，但缺锌食管组仅在第 6 周出现细胞增殖增加。在停止 NMBA 治疗后的几周内，与致癌剂治疗组、锌充足配对喂养组或随意喂养组相比，缺锌食管的 LI 显着增加，标记细胞数量也更多。另一方面，与锌充足的随意喂养的大鼠相比，经 NMBA 处理的锌充足配对喂养的大鼠表现出较低的 LI 和较少数量的标记细胞。最重要的是，在实验性饮食 10-11 周后，两只未接受 NMBA 治疗的缺锌动物体内发现了食管乳头状瘤。这些数据支持细胞增殖与肿瘤发病率之间的直接关系，并且还提供了锌缺乏及其相关细胞增殖可能致癌的证据。
Target cell proliferation was investigated throughout the development of esophageal cancer induced by N-nitrosomethylbenzylamine (NMBA) in weanling rats maintained on zinc-deficient or sufficient diets. Deficient rats were fed ad libitum, while zinc-sufficient rats were either pair-fed to the deficient animals or fed ad libitum. After 5 weeks, half of the animals in each dietary group were given six intragastric doses of NMBA (2 mg/kg; twice weekly). The remaining rats were untreated by carcinogen. At weeks 1, 2, 3, 4, 5, 7, 9 and 11 post first dose, esophageal cell proliferation was assessed in rats from each group by in vivo bromodeoxyuridine (BrDU) labeling followed by immunohistochemical detection of cells in S-phase. At 11 weeks, the tumor incidence was 100, 23 and 6%, respectively, in the zinc-deficient, zinc-sufficient, ad libitum and pair-fed groups. In vivo BrDU labeling revealed that in the NMBA-untreated groups, the labeling index (LI), the number of labeled cells, and the total number of cells per cross section of entire esophagi were significantly increased by zinc deficiency at all time points; LI was lowest in zinc-sufficient, pair-fed rats. During NMBA treatment (weeks 6, 7 and 8), increased cell proliferation occurred in both groups of zinc-sufficient esophagi but only during week 6 in the deficient ones. In the weeks following the cessation of NMBA treatment, zinc-deficient esophagi showed significantly increased LI and greater number of labeled cells than the carcinogen treated, zinc-sufficient pair-fed or ad libitum fed groups. On the other hand, NMBA-treated zinc-sufficient pair-fed rats showed lower LI and smaller number of labeled cells than their zinc-sufficient ad libitum counterparts. Most importantly, esophageal papillomas were found in two zinc-deficient animals that had received no NMBA treatment, after 10-11 weeks of experimental diet. These data support a direct relationship between cell proliferation and tumor incidence, and also provide evidence that zinc deficiency and its associated cell proliferation could be carcinogenic.