Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Institute of Radiation Medicine, Fudan University, Shanghai, China.
JCI Insight. 2022 Mar 8;7(5):e153793. doi: 10.1172/jci.insight.153793.
Recent data establish a logarithmic expansion of leucine rich repeat containing G protein coupled receptor 5-positive (Lgr5+) colonic epithelial stem cells (CESCs) in human colorectal cancer (CRC). Complementary studies using the murine 2-stage azoxymethane-dextran sulfate sodium (AOM-DSS) colitis-associated tumor model indicate early acquisition of Wnt pathway mutations drives CESC expansion during adenoma progression. Here, subdivision of the AOM-DSS model into in vivo and in vitro stages revealed DSS induced physical separation of CESCs from stem cell niche cells and basal lamina, a source of Wnt signals, within hours, disabling the stem cell program. While AOM delivery in vivo under non-adenoma-forming conditions yielded phenotypically normal mucosa and organoids derived thereof, niche injury ex vivo by progressive DSS dose escalation facilitated outgrowth of Wnt-independent dysplastic organoids. These organoids contained 10-fold increased Lgr5+ CESCs with gain-of-function Wnt mutations orthologous to human CRC driver mutations. We posit CRC originates by niche injury-induced outgrowth of normally suppressed mutated stem cells, consistent with models of adaptive oncogenesis.
近期数据显示，富含亮氨酸重复序列的 G 蛋白偶联受体 5 阳性（Lgr5+）结肠上皮干细胞（CESCs）在人类结直肠癌（CRC）中呈对数扩增。使用小鼠 2 阶段偶氮甲烷-葡聚糖硫酸钠（AOM-DSS）结肠炎相关肿瘤模型的补充研究表明，Wnt 通路突变的早期获得驱动了腺瘤进展过程中 CESCs 的扩增。在这里，将 AOM-DSS 模型细分为体内和体外阶段，揭示了 DSS 在数小时内诱导 CESCs 与干细胞巢细胞和基底膜（Wnt 信号的来源）的物理分离，从而使干细胞程序失活。虽然在非腺瘤形成条件下体内给予 AOM 会产生表型正常的黏膜和由此衍生的类器官，但通过逐步增加 DSS 剂量进行体外巢损伤促进了 Wnt 非依赖性发育不良类器官的生长。这些类器官含有 10 倍增加的 Lgr5+CESCs，具有与人类 CRC 驱动突变同源的获得性功能 Wnt 突变。我们假设 CRC 通过巢损伤诱导的正常受抑制突变干细胞的生长而起源，这与适应性致癌模型一致。
