Advanced published as a featured article in Cell Research on Apr. 14th, 2017, a team led by Prof. Bing SUN, at Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, in collaboration with Shanghai Institute of Materia Medica, defined the molecular mechanism of tumor chemotherapy-induced intestinal toxicity. This work was entitled with “Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation”.
Chemotherapies, which remain the primary treatment choice for many types of advanced cancers, are often associated with severe intestinal toxicity. CPT-11 is the first-line treatment for colorectal cancer. However, the clinical benefit of CPT-11 is limited by its adverse effect of severe diarrhoea, which occurs in ~40% of patients receiving CPT-11 treatment. Persistent or severe diarrhoea is not only a life-threatening side effect for CRC patients, but also can influence efficiency of chemotherapy through a need to reduce treatment doses or discontinue therapy.
In this work, Qiaoshi LIAN and colleagues find that the severity of diarrhea is in correlation with free dsDNA concentration in the serum of colorectal cancer patients treated with CPT-11. The authors further demonstrate that CPT-11 induces massive release of dsDNA from the intestine, which accounts for the dose-limiting intestinal toxicity. Released dsDNA through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 inflammasome. This process leads to mature IL-1β and IL-18 secretion and induces intestinal toxicity and diarrhea. These findings provide new insights into the relationship between tumor chemotherapy and immune response and strongly experimental evidence for the design of better chemotherapy strategies to avoid severe diarrhea.
This study was supported by the grants from Chinese Academy of Sciences, the Ministry of Science and Technology of China, and the National Natural Science Foundation of China.
Contact:
Bing SUN, Ph.D.
Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Email: bsun@sibs.ac.cn
Tel: +86-21-54921376
Link: https://www.nature.com/cr/journal/vaop/ncurrent/full/cr201754a.html
Legend: Model of dsDNA-mediated intestinal toxicity via activation of the inflammasome during CPT-11 administration. (Image provided by Prof. Bing SUN’s lab)
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