Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology & Metabolism, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology & Metabolism, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
Differentiation. 2019 Jul-Aug;108:17-23. doi: 10.1016/j.diff.2019.02.002. Epub 2019 Feb 14.
The intestinal epithelial layer is the fastest renewing tissue in the human body. Due to its incredible turnover rate, the intestine is especially prone to develop cancer, in particular in the colon. Colorectal cancer (CRC) development is characterized by the stepwise accumulation of mutations over time, of which mutations in the tumor suppressor APC are often very early to occur. Generally, mutations in this gene lead to truncated APC proteins that cannot bind to β-catenin to promote its degradation, resulting in a constant overstimulation of the Wnt pathway. The level of intrinsic Wnt activation is dependent on the number of functional β-catenin binding sites remaining within the APC proteins, and the right amount of Wnt signaling is rate-limiting in the formation of polyps. In addition, the intestinal niche provides an extensive spectrum of Wnt ligands, amplifiers and antagonists that locally regulate basal Wnt levels and consequently influence polyp formation propensity. Here we will discuss the crosstalk between transforming epithelial cells and their regional niche in the development of intestinal cancer.
肠上皮层是人体中更新速度最快的组织。由于其惊人的周转率，肠道特别容易发生癌症，特别是在结肠中。结直肠癌（CRC）的发展特征是随着时间的推移逐渐积累突变，其中肿瘤抑制因子 APC 的突变往往很早就发生。通常情况下，该基因的突变会导致 APC 蛋白截断，无法与β-连环蛋白结合以促进其降解，从而导致 Wnt 通路持续过度刺激。内在 Wnt 激活的水平取决于 APC 蛋白内剩余的功能性β-连环蛋白结合位点的数量，而适量的 Wnt 信号转导是息肉形成的限速步骤。此外，肠道龛位提供了广泛的 Wnt 配体、放大器和拮抗剂，它们可以局部调节基础 Wnt 水平，从而影响息肉形成的倾向。在这里，我们将讨论转化上皮细胞与其区域龛位在肠道癌症发展中的相互作用。
