Researchers from Toho University School of Medicine, Tokyo, Japan, have discovered that Interleukin (IL)-11 (IL-11+) cells in the colon of mice have colitis-associated colorectal cancer, the IL-11+ cells were absent from the colon under normal conditions but rapidly appeared in the tissues of mice with colitis and colorectal cancer. These results were reported in the paper, ‘Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer’, published in Nature Communications.
Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. IL-11 is known to promote the development of colorectal cancer in humans and mice, but when and where IL-11 is expressed during cancer development is unknown. To address these questions experimentally, the researchers generated reporter mice that express the green fluorescent protein (EGFP) gene in interleukin 11 (IL-11)-producing (IL11+) cells in vivo.
In the study, Nishina and colleagues characterised the IL-11+ cells by flow cytometry and found that most IL-11+ cells express stromal cell surface markers, such as Thy1, podoplanin, and Sca-1, suggesting that IL-11+ cells are stromal fibroblasts. RNA-seq analysis revealed that the expression of approximately 350 genes was elevated in IL-11+ fibroblasts compared IL-11- fibroblasts, thereby constituting a feed-forward loop between tumour cells and fibroblasts in the tutor microenvironment.
These genes were also elevated in mice and human colorectal cancer tissues in vivo. IL-11 released from IL-11+ cells induced activation signals in nearby tumour cells and fibroblasts in a paracrine or autocrine manner. Thus, IL-11+ fibroblasts and tumour cells constitute the tumour microenvironment that supports tumour growth.
"We looked at human cancer databases and found that elevated expression of genes enriched in IL-11+ fibroblasts correlate with short duration of disease-free survival. We think IL-11+ fibroblasts can be new therapeutic targets for treating human colorectal cancer," said Professor Nakano, the senior author of the study.
This research was conducted in collaboration with Associate Professors Nobuhiro Tada and Hideo Yagita of Juntendo University, Professor Masato Ohtsuka of Tokai University, Professors Koji Matsushima and Chiharu Nishiyama of Tokyo University of Science, Professor Masanobu Oshima of Kanazawa University, and Naohiro Inohara of Michigan University.
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