Journal
CANCER CELL
Volume 40, Issue 2, Pages 168-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2022.01.004
Keywords
-
Categories
Funding
- Else-Kroner-Fresenius Foundation
- Georg-Speyer-Haus
- LOEWE Center Frankfurt Cancer Institute (FCI) - Hessen State Ministry for Higher Education, Research and the Arts [III L 5 - 519/03/03.001 - (0015)]
- Deutsche Forschungsgemeinschaft [FOR2438, Gr1916/11-1, SFB1292, 1479, GRK2336]
- Federal Ministry of Health
- Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK)
Ask authors/readers for more resources
The study reveals that inflammatory cancer-associated fibroblasts (iCAFs) in rectal cancer patients are associated with poor response to chemoradiotherapy. The researchers found that interleukin-1 alpha (IL-1 alpha) not only polarizes iCAFs towards an inflammatory phenotype but also triggers oxidative DNA damage, leading to p53-mediated therapy-induced senescence. This senescence of iCAFs results in chemoradiotherapy resistance and disease progression. Inhibition of IL-1 signaling or prevention of iCAFs senescence could sensitize mice to irradiation and improve therapy response.
Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer -associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1 alpha (IL-1 alpha) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available