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Abstract：
BACKGROUND: Colon cancer stem cells (CSCs), considered responsible for tumor initiation and cancer relapse, are constantly exposed to regulatory cues emanating from neighboring cells present in the tumor microenvironment. Among these cells are enteric glial cells (EGCs) that are potent regulators of the epithelium functions in a healthy intestine. However, whether EGCs impact CSC-driven tumorigenesis remains unknown.
METHODS: Impact of human EGC primary cultures or a non-transformed EGC line on CSCs isolated from human primary colon adenocarcinomas or colon cancer cell lines with different p53, MMR system and stemness status was determined using murine xenograft models and 3D co-culture systems. Supernatants of patient-matched human primary colon adenocarcinomas and non-adjacent healthy mucosa were used to mimic tumor versus healthy mucosa secretomes and compare their effects on EGCs.
RESULTS: Our data show that EGCs stimulate CSC expansion and ability to give rise to tumors via paracrine signaling. Importantly, only EGCs that were pre-activated by tumor epithelial cell-derived soluble factors increased CSC tumorigenicity. Pharmacological inhibition of PGE2 biosynthesis in EGCs or IL-1 knockdown in tumor epithelial cells prevented EGC acquisition of a pro-tumorigenic phenotype. Inhibition of PGE2 receptor EP4 and EGFR in CSCs inhibited the effects of tumor-activated EGCs.
CONCLUSIONS: Altogether, our results show that EGCs, once activated by the tumor, acquire a pro-tumorigenic phenotype and stimulate CSC-driven tumorigenesis via a PGE2/EP4/EGFR-dependent pathway.
BACKGROUND: This work was supported by grants from the French National Cancer Institute, La Ligue contre le Cancer, the \'Région des Pays de la Loire\' and the UNC Lineberger Comprehensive Cancer Center.
METHODS: Impact of human EGC primary cultures or a non-transformed EGC line on CSCs isolated from human primary colon adenocarcinomas or colon cancer cell lines with different p53, MMR system and stemness status was determined using murine xenograft models and 3D co-culture systems. Supernatants of patient-matched human primary colon adenocarcinomas and non-adjacent healthy mucosa were used to mimic tumor versus healthy mucosa secretomes and compare their effects on EGCs.
RESULTS: Our data show that EGCs stimulate CSC expansion and ability to give rise to tumors via paracrine signaling. Importantly, only EGCs that were pre-activated by tumor epithelial cell-derived soluble factors increased CSC tumorigenicity. Pharmacological inhibition of PGE2 biosynthesis in EGCs or IL-1 knockdown in tumor epithelial cells prevented EGC acquisition of a pro-tumorigenic phenotype. Inhibition of PGE2 receptor EP4 and EGFR in CSCs inhibited the effects of tumor-activated EGCs.
CONCLUSIONS: Altogether, our results show that EGCs, once activated by the tumor, acquire a pro-tumorigenic phenotype and stimulate CSC-driven tumorigenesis via a PGE2/EP4/EGFR-dependent pathway.
BACKGROUND: This work was supported by grants from the French National Cancer Institute, La Ligue contre le Cancer, the \'Région des Pays de la Loire\' and the UNC Lineberger Comprehensive Cancer Center.
摘要：
背景：结肠癌干细胞（CSCs），被认为是肿瘤发生和癌症复发的原因，不断暴露于肿瘤微环境中存在的邻近细胞发出的调控线索。这些细胞是肠神经胶质细胞（EGC），它们是健康肠道中上皮功能的有效调节剂。然而,EGC是否影响CSC驱动的肿瘤发生尚不清楚.
方法：使用鼠异种移植模型和3D共培养系统，确定了人EGC原代培养物或非转化EGC细胞系对从人原发性结肠腺癌或结肠癌细胞系中分离的CSC的影响。患者匹配的人原发性结肠腺癌和非邻近健康粘膜的上清液用于模拟肿瘤与健康粘膜的分泌体，并比较其对EGC的影响。
结果：我们的数据显示，EGCs刺激CSC扩增，并通过旁分泌信号产生肿瘤。重要的是,只有被肿瘤上皮细胞来源的可溶性因子预激活的EGC增加了CSC的致瘤性.EGC中PGE2生物合成的药理学抑制或肿瘤上皮细胞中IL-1敲低阻止了EGC获得促致瘤表型。CSC中PGE2受体EP4和EGFR的抑制抑制了肿瘤激活的EGC的作用。
结论：总而言之，我们的结果表明，EGCs，一旦被肿瘤激活，通过PGE2/EP4/EGFR依赖性途径获得促瘤表型并刺激CSC驱动的肿瘤发生。
背景：这项工作得到了法国国家癌症研究所的资助，LaLigueContreleCancer,“卢瓦尔河军团”和UNCLineberger综合癌症中心。
方法：使用鼠异种移植模型和3D共培养系统，确定了人EGC原代培养物或非转化EGC细胞系对从人原发性结肠腺癌或结肠癌细胞系中分离的CSC的影响。患者匹配的人原发性结肠腺癌和非邻近健康粘膜的上清液用于模拟肿瘤与健康粘膜的分泌体，并比较其对EGC的影响。
结果：我们的数据显示，EGCs刺激CSC扩增，并通过旁分泌信号产生肿瘤。重要的是,只有被肿瘤上皮细胞来源的可溶性因子预激活的EGC增加了CSC的致瘤性.EGC中PGE2生物合成的药理学抑制或肿瘤上皮细胞中IL-1敲低阻止了EGC获得促致瘤表型。CSC中PGE2受体EP4和EGFR的抑制抑制了肿瘤激活的EGC的作用。
结论：总而言之，我们的结果表明，EGCs，一旦被肿瘤激活，通过PGE2/EP4/EGFR依赖性途径获得促瘤表型并刺激CSC驱动的肿瘤发生。
背景：这项工作得到了法国国家癌症研究所的资助，LaLigueContreleCancer,“卢瓦尔河军团”和UNCLineberger综合癌症中心。
