Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generated Il11 reporter mice. IL-11+ cells appeared in the colon of murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuated the development of colitis-associated colorectal cancer. IL-11+ cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis revealed that a set of genes enriched in IL-11+ fibroblasts was elevated in human colorectal cancer, and correlated with reduced recurrence-free survival. Together, IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed forward loop between tumor cells and fibroblasts in the tumor microenvironment.

白细胞介素-11（Interleukin (IL)-11）属于IL-6家族细胞因子，参与包括肿瘤发生在内的多种细胞应答过程。然而，产IL-11细胞（IL-11+细胞）的起源与功能尚未完全阐明。为在体表征IL-11+细胞，我们构建了Il11报告基因小鼠。在小鼠肿瘤与急性结肠炎模型的结肠组织中，可检测到IL-11+细胞的存在。敲除Il11ra1或Il11基因可减轻结肠炎相关结直肠癌的发生发展。IL-11+细胞表达成纤维细胞标志物，以及与细胞增殖、组织修复相关的基因。IL-11可通过STAT3磷酸化激活结肠成纤维细胞与上皮细胞。对人类癌症数据库的分析显示，在IL-11+成纤维细胞中富集的基因集在人类结直肠癌中表达上调，且与较差的无复发生存期显著相关。综上，IL-11+成纤维细胞可通过分泌IL-11激活肿瘤细胞与成纤维细胞，从而在肿瘤微环境中构建肿瘤细胞与成纤维细胞间的前馈环路。