Interaction between a tumor and its microenvironment is important for tumor initiation and progression. Cancer stem cells (CSCs) within the tumor interact with a microenvironmental niche that controls their maintenance and differentiation. We investigated the CSC‐promoting effect of factors released from myofibroblasts into the microenvironment of early colorectal cancer tumors and its molecular mechanism. By messenger RNA microarray analysis, expression of HES1, a Notch signaling target, significantly increased in Caco‐2 cells cocultured with 18Co cells (pericryptal myofibroblasts), compared to its expression in Caco‐2 cells cultured alone. Caco‐2 cells cultured in 18Co‐conditioned media (CM) showed a significant increase in CD133+CD44+ cells and HES1 expression compared to that in Caco‐2 cells cultured in regular media. Significant amounts of interleukin‐6 (IL‐6) and IL‐8 were detected in 18Co‐CM compared to levels in regular media. The 18Co‐CM‐induced increase in CD133+CD44+ cells was attenuated by IL‐6‐ and IL‐8‐neutralizing antibodies. Furthermore, these neutralizing antibodies and inhibitors of STAT3 and gamma‐secretase reduced the expression of HES1 induced in Caco‐2 cells cultured in 18Co‐CM. Immunohistochemical analysis of human tissues revealed that IL‐6, IL‐8, and HES1 expression increased from normal to adenoma, and from adenoma to cancer tissues. In addition, IL‐6 and HES1 expression was positively correlated in early colorectal cancer tissues. In conclusion, the increase of CSCs by myofibroblasts could be mediated by IL‐6/IL‐8‐induced HES1 activation in the tumor microenvironment. Based on these data, the IL‐6/IL‐8‐mediated Notch/HES1 and STAT3 pathway, through which CSCs interact with their microenvironment, might be a potential target for the prevention and treatment of colorectal tumors.

中文翻译：

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肿瘤微环境中成肌纤维细胞分泌的IL-6和IL-8激活HES1以扩大早期大肠癌的癌症干细胞群体

肿瘤与其微环境之间的相互作用对于肿瘤的发生和发展很重要。肿瘤内的癌症干细胞（CSC）与控制其维持和分化的微环境生态位相互作用。我们研究了成肌纤维细胞释放的因子对早期结直肠癌肿瘤微环境的CSC促进作用及其分子机制。通过信使RNA微阵列分析，与单独培养的Caco-2细胞相比，与18Co细胞共培养的Caco-2细胞（隐膜成肌纤维细胞）中的Notch信号靶标HES1的表达显着增加。与常规培养基中培养的Caco-2细胞相比，在18Co条件培养基（CM）中培养的Caco-2细胞显示CD133 + CD44 +细胞和HES1表达显着增加。与常规培养基中的水平相比，在18Co-CM中检测到大量白细胞介素6（IL-6）和IL-8。IL-6和IL-8中和抗体减弱了18Co-CM诱导的CD133 + CD44 +细胞的增加。此外，这些中和抗体以及STAT3和γ-分泌酶抑制剂降低了在18Co-CM中培养的Caco-2细胞中诱导的HES1的表达。人体组织的免疫组织化学分析显示，IL-6，IL-8和HES1表达从正常到腺瘤，从腺瘤到癌组织增加。此外，早期结直肠癌组织中IL-6和HES1表达呈正相关。总之，成肌纤维细胞增加的CSCs可能是由IL-6 / IL-8诱导的肿瘤微环境中HES1激活介导的。根据这些数据，