A novel mouse colon cancer model and chemoprevention

纺锤体检查点推迟了从中期到后期的进程，直到所有浓缩的染色体 适当地附着在有丝分裂纺锤体上。检查点功能受损通常会导致基因组 不稳定性，使细胞易于恶变。了解…的分子基础 在人类癌症发展过程中，这种监测机制的功能失活，PI的实验室已经 重点是BubRl，一个关键的纺锤体检查点激酶，在维持基因组稳定性和 抑制肿瘤形成。Pi的小组已经产生了BubRl+/-小鼠以及BubRl+/-ApcMin/+ 复合突变小鼠。BubRl+/-小鼠发生肠腺癌的速度加快 偶氮甲烷处理。而ApcMin/+小鼠通常在 小肠，BubRl+/-ApcMin/+复合突变小鼠发展为更多的自发性结肠 肿瘤优于ApcMin/+小鼠。BubRl+/-ApcMin/+小鼠的结肠肿瘤临床上更晚期 而不是在ApcMin/+小鼠身上观察到的。此外，化学预防化合物，如舒林酸硫化物和 S-烯丙基硫代半胱氨酸可诱导结肠癌细胞株HT-29和SW-480发生凋亡； 缺陷细胞对这些化合物诱导的细胞凋亡更具抵抗力。考虑到BubRl和Ape 都参与了正常细胞基因组稳定性的调节，我们假设BubRl+/-ApcMin+/- 小鼠可作为评价不同抗肿瘤活性的良好啮齿动物模型。 针对结肠的化学预防化合物和了解纺锤体检查点在体内的作用 在维持基因组稳定性方面的组成部分。为了验证这一假设，PI的实验室将(I)验证和 检测舒林酸和S-烯丙基硫代半胱氨酸及其衍生物的化学预防作用 直接靶向微管或有丝分裂纺锤体对小鼠自发性肠道肿瘤的抑制作用 BubRl+/-ApcMin/+复合突变小鼠，以及(Ii)研究肠道疾病的分子基础 通过研究(A)基因组不稳定性和自发转移率在这些突变小鼠中的致癌作用 BubRl和/或Ape缺陷细胞的转化，(B)抗增殖作用的依赖性 舒林酸和S-烯丙基硫代半胱氨酸对纺锤体完整性检查点的影响，以及(C)通过 在BubRl缺陷基因中，哪些ApcMin/+小鼠的肿瘤负荷从小肠转移到结肠 背景资料。这个项目的长期目标是阐明细胞周期检查点的机制 Wnt信号通路调节细胞的增殖和分化以及基因组的稳定性。

The spindle checkpoint delays the progression from metaphase to anaphase until all condensed chromosomes are properly attached to mitotic spindles. An impaired checkpoint function often results in genomic instability, which predisposes cells to malignant transformation. To understand the molecular basis of functional inactivation of this surveillance mechanism in human cancer development, the Pi's laboratory has focused on the role of BubRl, a key spindle checkpoint kinase, in the maintenance of genomic stability and suppression of tumorigenesis. The Pi'sgroup has generated BubRl+/- mice as well as BubRl+/-ApcMin/+ compound mutant mice. BubRl+/- mice develop intestinal adenocarcinomas at an accelerated rate after azoxymethane treatment. Whereas ApcMin/+ mice develop many adenomatous polyps generally within the small intestine, BubRl+/-ApcMin/+ compound mutant mice develop significantly more spontaneous colonic tumors than ApcMin/+ mice. The colon tumors in BubRl+/-ApcMin/+ mice are clinically more advanced than those observed in ApcMin/+ mice. Moreover, chemopreventive compounds such as sulindac sulfide and S-allylmercaptocysteine are capable of inducing apoptosis in HT-29 and SW-480 colon tumor cells; BubRl - deficient cells are more resistant to apoptosis induced by these compounds. Given that both BubRl and Ape are involved in the regulation of genomic stability in normal cells, we hypothesize that BubRl+/-ApcMin+/- mice would be an excellent rodent model for evaluating the efficacy of anti-tumor activities of various chemopreventive compounds that target colon and understanding the in vivo role of spindle checkpoint components in the maintenance of genomic stability. To test this hypothesis, the Pi's lab will (i) validate and test the chemopreventive effect of sulindac and S-allylmercaptocysteine, which (or the derivative of which) directly target microtubules or mitotic spindles, on suppression of spontaneous intestinal tumorigenesis in BubRl+/- ApcMin/+ compound mutant mice, and (ii) investigate the molecular basis of intestinal carcinogenesis in these mutant mice by studying (a) the genomic instability and the rate of spontaneous transformation of cells deficient in BubRl and/or Ape, (b) the dependence of anti-proliferative effect of sulindac and S-allylmercaptocysteine on the integrity of the spindle checkpoint, and (c) the mechanism by which ApcMin/+ mice shift in tumor burden from the small intestine to colon in the BubRl-deficient genetic background. The long-term goal of this project is to elucidate the mechanism by which cell cycle checkpoints and the Wnt signaling pathway regulate cell proliferation and differentiation as well as genomic stability.