Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer
Takashi Nishina, Yutaka Deguchi, Daisuke Ohshima, Wakami Takeda, Masato Ohtsuka, Shigeyuki Shichino, Satoshi Ueha, Soh Yamazaki, Mika Kawauchi, Eri Nakamura, Chiharu Nishiyama, Yuko Kojima, Satomi Adachi‐Akahane, Mizuho Hasegawa, Mizuho Nakayama, Masanobu Oshima, Hideo Yagita∥, Kazutoshi Shibuya, Tetuo Mikami, Naohiro Inohara, Kouji Matsushima, Norihiro Tada, Hiroyasu Nakano
Abstract
Abstract Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is 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 generate Il11 reporter mice. IL-11 + cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11 + cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11 + fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. 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.