Transgenic mouse models that explore the multistep hypothesis of intestinal neoplasia.
Transgenic mouse models that explore the multistep hypothesis of intestinal neoplasia.
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DOI：
10.1083/jcb.123.4.877
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发表时间：
1993-11
期刊：
影响因子：
--
通讯作者：
Gordon JI
中科院分区：
文献类型：
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作者：
Kim SH;Roth KA;Moser AR;Gordon JI
SV-40 T抗原（TAg）、人K-rasVal12和人p53的优势阴性突变体（p53Ala143）在分布于1-12岁FVB/N转基因小鼠的整个十二指肠-结肠轴的有丝分裂后肠细胞中单独表达，并以所有可能的组合表达，以评估该谱系对涉及人肠道肿瘤发病机制的基因产物的易感性。SV-40 TAg产生重新进入细胞周期。仅产生K-rasVal12、p53Ala143或K-rasVal12和p53Ala143的转基因家系没有可检测到的表型异常。然而，K-rasVal12与SV-40 TAg协同作用，在肠上皮中产生明显的增生和发育不良改变。尽管转基因持续表达，这些异常在9-12个月的时间内不会发展成腺瘤或腺癌。将p53Ala143添加到合成SV-40 TAg和K-rasVal12的肠细胞中，不会对增殖或分化产生任何进一步的变化。携带一种、两种或三种这些转基因的小鼠与携带Min的动物杂交，Min是一种与多种小肠和结肠腺瘤的发展相关的Apc基因的完全渗透性、显性突变。在单独表达SV-40 TAg、SV-40 TAg和K-rasVal12，或SV-40 TAg、K-rasVal12和p53Ala143的动物中，肿瘤数量适度增加（2-5倍）。然而，腺瘤的组织病理学特征没有改变，位于肿瘤之间的肠道上皮与没有Min的单转基因、双转基因或三转基因亲本的上皮相似。这些结果表明(a) SV-40 TAg X K-rasVal12小鼠的发育不良肠上皮无法进一步发展为腺瘤或腺癌，这是由于持续快速更新的上皮具有显著的保护作用，(b) Min小鼠的肿瘤发生通常发生在隐窝而不是绒毛相关的上皮细胞群中。(c)涉及肠细胞谱系成员的肿瘤转基因小鼠模型可能需要将与肿瘤发生有关的基因产物定向到隐窝干细胞或其直系后代。尽管如此，将K-rasVal12的产生导向小肠和结肠隐窝上下半部分的增殖和非增殖细胞并不会导致任何可检测到的异常。
SV-40 T antigen (TAg), human K-rasVal12, and a dominant negative mutant of human p53 (p53Ala143) have been expressed singly and in all possible combinations in postmitotic enterocytes distributed throughout the duodenal-colonic axis of 1-12-mo-old FVB/N transgenic mice to assess the susceptibility of this lineage to gene products implicated in the pathogenesis of human gut neoplasia. SV-40 TAg produces re-entry into the cell cycle. Transgenic pedigrees that produce K-rasVal12 alone, p53Ala143 alone, or K-rasVal12 and p53Ala143 have no detectable phenotypic abnormalities. However, K-rasVal12 cooperates with SV-40 TAg to generate marked proliferative and dysplastic changes in the intestinal epithelium. These abnormalities do not progress to form adenomas or adenocarcinomas over a 9-12-mo period despite sustained expression of the transgenes. Addition of p53Ala143 to enterocytes that synthesize SV-40 TAg and K-rasVal12 does not produce any further changes in proliferation or differentiation. Mice that carry one, two, or three of these transgenes were crossed to animals that carry Min, a fully penetrant, dominant mutation of the Apc gene associated with the development of multiple small intestinal and colonic adenomas. A modest (2-5-fold) increase in tumor number was noted in animals which express SV-40 TAg alone, SV-40 TAg and K-rasVal12, or SV-40 TAg, K-rasVal12 and p53Ala143. However, the histopathologic features of the adenomas were not altered and the gut epithelium located between tumors appeared similar to the epithelium of their single transgenic, bi-transgenic, or tri-transgenic parents without Min. These results suggest that (a) the failure of the dysplastic gut epithelium of SV-40 TAg X K-rasVal12 mice to undergo further progression to adenomas or adenocarcinomas is due to the remarkable protective effect of a continuously and rapidly renewing epithelium, (b) initiation of tumorigenesis in Min mice typically occurs in crypts rather than in villus-associated epithelial cell populations, and (c) transgenic mouse models of neoplasia involving members of the enterocytic lineage may require that gene products implicated in tumorigenesis be directed to crypt stem cells or their immediate descendants. Nonetheless, directing K-rasVal12 production to proliferating and nonproliferating cells in the lower and upper half of small intestinal and colonic crypts does not result in any detectable abnormalities.