Inflammation and CRC: Necroptosis and Fibroblasts Tip the Balance
Abstract
The proposal addresses the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Area: Colorectal Cancer (CRC). Inflammation is known to promote and fuel the progression of CRC. However, the causes that trigger such inflammation and the cells that mediate tumor-promoting inflammation remain unknown. We propose that damage and inflammation is not uncommon in the gut, but that the types of inflammation in the intestine are distinct. Specifically, CRC-promoting inflammation is categorically different. Immune cell-dependent inflammation of the gut is commonplace and occurs in diseases such as gastrointestinal infection or diverticulitis, which are not associated with any increased risk of CRC. By contrast, a certain type of inflammation such as in inflammatory bowel disease (IBD) greatly increases the risk of CRC. We propose that while there may be an immune cell-dependent inflammation component in CRC, it is not the causal inflammation that increases CRC risk. Instead, inflammation of a non-immune cell known as fibroblast underlies the etiology of CRC. We also posit that a very specific form of cellular damage – the death of intestinal epithelial cell by a molecular program called necroptosis drives inflammation of fibroblasts. Thus, the scientific objective of the research project we propose is to characterize fibroblast inflammation and immune cell inflammation under conditions wherein intestinal epithelial cells die by necroptosis in mouse models of CRC, including new models developed in our laboratory. This will help determine if this specific type of damage and resulting inflammation is preferentially associated with and causes CRC. Fibroblasts are the major stromal cell or building block of most tissues, including the gut. These cells play a very important role in repair after the tissue is damaged. For example, they become myofibroblasts and generate contractile forces to physically bring the wound edges together, thereby closing open wounds during healing. The rationale behind our hypothesis is derived from our in vitro observations that exposure to necroptotic corpses causes fibroblasts to stop wound repair and become inflammatory. We posit that upon necroptosis in vivo, for example of neighboring intestinal epithelial cells, fibroblasts fail to become myofibroblasts and stop their function in wound repair. Thus, wounds such as ulcers are formed. Additionally, the fibroblasts become inflammatory and this inflammation, unlike that of immune cells during infection or diverticulitis, does not resolve. This non-resolving inflammation eventually causes CRC. There are reports that necroptosis is absent in healthy gut but is specifically associated with IBD. Yet, the significance of this finding, especially as a driver of fibroblast inflammation, is not known. Inflammatory fibroblasts have also recently been reported in IBD and CRC by a few separate publications. Again, why fibroblasts become inflammatory is not recognized. We believe that the causal link between these two heretofore unrelated observations provides an innovative rationale for why only some types of inflammation increase CRC risk. If our idea is correct, this will open a new area of investigation in our lab and in the field. If one understands the links between necroptosis, intestinal inflammation, and CRC, we can look for therapeutically tractable and amenable targets to interfere with this driver of CRC and prevent/reduce CRC risk. For example, one may be able to block necroptosis of intestinal epithelial cells. More suitable perhaps would be to understand how necroptosis drives fibroblast inflammation and disable key molecules in fibroblasts thereby restraining this inflammation. Fibroblast inflammation may have evolved as a final checkpoint to prevent systemic spread of infection when immune cell inflammation, the first line of defense, fails to protect the body. However, in CRC, it is maladaptive.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210865
Entities
People
- Carla V. Rothlin
Organizations
- United States Army
- Yale University