Journal Article

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

Oshima, Masanobu, Adachi-Akahane, Satomi, Tada, Norihiro, Deguchi, Yutaka, Ohshima, Daisuke, Shichino, Shigeyuki, Kojima, Yuko, Shibuya, Kazutoshi, Takeda, Wakami, Ohtsuka, Masato, Yagita, Hideo, Matsushima, Kouji, Ueha, Satoshi, Mikami, Tetuo, Hasegawa, Mizuho, Nakamura, Eri, Yamazaki, Soh, Inohara, Naohiro, Nakayama, Mizuho, Nishiyama, Chiharu, Nishina, Takashi, Kawauchi, Mika, Nakano, Hiroyasu

2021

Overview

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. The stromal fibroblast population in the colon is composed of heterogeneous and distinct cell subtypes that play a crucial role in the development of colitis and colon cancer. Here the authors generate IL-11 reporter mice and characterize the origin and phenotype of inflammatory IL-11 + fibroblasts in colitis and colon cancer preclinical models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/2 / 13/21 / 13/31 / 13/51 / 14 / 14/19 / 38 / 38/61 / 38/77 / 38/89 / 38/91 / 631/67 / 631/67/2321 / 631/67/327 / Adenoma - genetics / Adenoma - immunology / Adenoma - mortality / Adenoma - surgery / Aged / Aged, 80 and over / Animals / Cell Line, Tumor / Cell proliferation / Colitis / Colitis - chemically induced / Colitis - immunology / Colitis - pathology / Colon / Colon - cytology / Colon - immunology / Colon - pathology / Colon - surgery / Colon cancer / Colorectal cancer / Colorectal Neoplasms - genetics / Colorectal Neoplasms - immunology / Colorectal Neoplasms - mortality / Colorectal Neoplasms - surgery / Cytokines / Dextran Sulfate - administration & dosage / Dextran Sulfate - toxicity / Disease Models, Animal / Disease-Free Survival / Epithelial cells / Epithelium / Female / Fibroblasts / Fibroblasts - immunology / Fibroblasts - metabolism / Gene expression / Gene Expression Regulation, Neoplastic - immunology / Gene Knockdown Techniques / Genes / Genes, Reporter / Green Fluorescent Proteins - genetics / Humanities and Social Sciences / Humans / Inflammation / Inflammatory bowel disease / Interleukin 1 / Interleukin 11 / Interleukin 6 / Interleukin-11 - genetics / Interleukin-11 - metabolism / Interleukin-11 Receptor alpha Subunit - genetics / Interleukin-11 Receptor alpha Subunit - metabolism / Intestinal Mucosa - cytology / Intestinal Mucosa - immunology / Intestinal Mucosa - pathology / Kaplan-Meier Estimate / Male / Medical prognosis / Mice / Mice, Knockout / Mice, Transgenic / Middle Aged / Model testing / multidisciplinary / Neoplasm Recurrence, Local - epidemiology / Neoplasm Recurrence, Local - immunology / Organoids / Phenotypes / Phosphorylation / Primary Cell Culture / Retrospective Studies / Science / Science (multidisciplinary) / Stat3 protein / Transcriptome - immunology / Tumor cells / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors