Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK.
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt 60596 Germany.
Cell Death Differ. 2017 Oct;24(10):1681-1693. doi: 10.1038/cdd.2017.92. Epub 2017 Jun 16.
Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of Kras mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment.
最近的研究表明，肠道中分化细胞的可塑性增加，既能作为肠干细胞（ISCs），也能作为肿瘤起始细胞。然而，人们对调节这种可塑性的过程知之甚少。我们之前的工作表明，Kras 或 NF-κB 通路的激活突变可以驱动缺乏 APC 的肠细胞去分化。为了进一步研究这个过程，我们通过基因表达分析对体外经历去分化的细胞和体内由这些细胞产生的肿瘤进行了分析。值得注意的是，在肿瘤中没有观察到明显的差异；然而，在体外去分化过程中，我们发现 TGFβ 信号通路显著上调，该通路在结直肠癌（CRC）中经常发生突变。TGFβ 型 1 受体（Tgfbr1/Alk5）的遗传失活增强了 Kras 突变驱动去分化的能力，并显著加速了肿瘤发生。从机制上讲，这与 MAPK 信号的显著激活有关。MEK 抑制强烈抑制来自分化区室的肿瘤发生。总之，我们表明，在分化区室中发生的肿瘤将暴露于不同的抑制信号，例如 TGFβ，阻断这些信号会使肿瘤发生从该区室更有效。
