IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.
IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.
复制标题
DOI：
10.1084/jem.20150576
复制
发表时间：
2015-12-14
期刊：
影响因子：
--
通讯作者：
Greten FR
中科院分区：
文献类型：
--
作者：
Pallangyo CK;Ziegler PK;Greten FR
Pallangyo等人。有报道称，在Col1a2Cre-ERT2小鼠中，成纤维细胞特异性的IKKβ缺失促进了AOM/DSS诱导的肠道肿瘤的发生，这表明该激酶具有肿瘤抑制作用。相比之下，Koliaraki等人的一项配套研究。基于IKKβ在表达Colvi的肠间充质细胞中的缺失，提示IKKβ在促进肠道肿瘤发生中的作用。这两项研究提高了人们的认识，即在肿瘤发生的背景下，IKKβ/NF-κB可能在不同的成纤维细胞亚群中具有不同的功能。肿瘤相关成纤维细胞(CAF)是肿瘤微环境中最重要的细胞类型之一。在胰腺和乳腺皮肤癌模型中，CAF中的促炎性NF-κB基因信号被认为促进了肿瘤的发生。利用结肠炎相关癌和散发性癌的本土模型，我们现在为IKKβ/NF-κB在结肠炎相关癌中的肿瘤抑制功能提供了证据。成纤维细胞限制性缺失IKKβ可刺激肠上皮细胞增殖，抑制肿瘤细胞死亡，增强CD4+Foxp3+调节性T细胞的聚集，诱导血管生成，最终促进结肠肿瘤生长。在IKKβ缺陷的成纤维细胞中，转化生长因子β信号负调控因子Smad7和S-MURF1的转录受损，导致转化生长因子β基因信号上调和肝细胞生长因子分泌增加。在IKKβ缺失的成纤维细胞中，Smad7的过表达阻止了肝细胞生长因子的分泌，而在CAC模型中对Met的药理抑制证实了促进肿瘤的增强依赖于IKKβ突变动物粘膜中的HGF-Met信号。总之，这些结果强调了在CAF中与肝细胞生长因子释放相关的IKKβ/NF-κB出人意料的肿瘤抑制功能，并引发了对IKK抑制剂在结直肠癌患者中使用的潜在担忧。
Pallangyo et al. report that fibroblast-specific IKKβ deletion in Col1a2Cre-ERT2 mice promotes AOM/DSS-induced intestinal tumorigenesis, suggesting a tumor suppressor role for this kinase. In contrast, a companion study by Koliaraki et al. based on IKKβ deletion in ColVI-expressing intestinal mesenchymal cells suggests a role for IKKβ in promoting intestinal tumorigenesis. The two studies raise the awareness that in the context of tumorigenesis, IKKβ/NF-κB may have distinct functions in different fibroblast subpopulations. Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKβ/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkβ stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4+Foxp3+ regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkβ-deficient fibroblasts, transcription of negative regulators of TGFβ signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFβ gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkβ-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF–Met signaling in mucosa of Ikkβ-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKβ/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.