Necroptosis is dispensable for the development of inflammation-associated or sporadic colon cancer in mice

• Published in: Cell death and differentiation Vol. 28; no. 5; pp. 1466 - 1476
• Main Authors: Alvarez-Diaz, Silvia, Preaudet, Adele, Samson, Andre L., Nguyen, Paul M., Fung, Ka Yee, Garnham, Alexandra L., Alexander, Warren S., Strasser, Andreas, Ernst, Matthias, Putoczki, Tracy L., Murphy, James M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2021; Nature Publishing Group
• Subjects: 13/51; 631/250/256/2516; 631/67/70; 64/60; 82; 96/63; Animal models; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Colitis; Colon cancer; Colonic Neoplasms - genetics; Colorectal cancer; Colorectal carcinoma; Dextran; Disease Models, Animal; Gastrointestinal tract; Inflammation; Inflammation - genetics; Inflammatory bowel disease; Inflammatory bowel diseases; Large intestine; Life Sciences; Mice; Necroptosis; Necroptosis - genetics; Sodium sulfate; Stem Cells; Tumorigenesis
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-00673-z

Chronic inflammation of the large intestine is associated with an increased risk of developing colorectal cancer (CRC), the second most common cause of cancer-related deaths worldwide. Necroptosis has emerged as a form of lytic programmed cell death that, distinct from apoptosis, triggers an inflammatory response. Dysregulation of necroptosis has been linked to multiple chronic inflammatory diseases, including inflammatory bowel disease and cancer. Here, we used murine models of acute colitis, colitis-associated CRC, sporadic CRC, and spontaneous intestinal tumorigenesis to investigate the role of necroptosis in these gastrointestinal pathologies. In the Dextran Sodium Sulfate-induced acute colitis model, in some experiments, mice lacking the terminal necroptosis effector protein, MLKL, or its activator RIPK3, exhibited greater weight loss compared to wild-type mice, consistent with some earlier reports. However, the magnitude of weight loss and accompanying inflammatory pathology upon Mlkl deletion varied substantially between independent repeats. Such variation provides a possible explanation for conflicting literature reports. Furthermore, contrary to earlier reports, we observed that genetic deletion of MLKL had no impact on colon cancer development using several mouse models. Collectively, these data do not support an obligate role for necroptosis in inflammation or cancer within the gastrointestinal tract.