Scientists in Spain have discovered a mechanism that promotes inflammation-related bowel cancer and could offer new treatment targets.
The finding concerns the activity of the signaling protein p38 in the myeloid cells of the immune system and that of IGF-1, which is a hormone triggered by p38.
Much of the work was conducted in mice that had been genetically engineered to develop acute and persistent gut inflammation.
The researchers, led by Angel R. Nebreda — an ICREA professor based at the Institute for Research in Biomedicine in Barcelona, Spain — conclude that it could impact how clinicians evaluate biopsies and assess treatment options.
In a study paper now published in the journal EMBO Molecular Medicine, the authors propose that "decisions regarding therapy should take into consideration the inflammatory conditions and the levels of IGF-1 in biopsies of patients with inflammatory intestinal diseases or colitis-associated cancer."
Bowel cancer, inflammation, and immunity
Bowel cancer — which is also known as colorectal cancer or colon cancer — is now the "third most common cancer worldwide." Estimates suggest that around 1.4 million people are diagnosed with the disease every year.
In the United States, it is the second most common
Inflammatory bowel disease (IBD) is a long-term condition that inflames the gut. It is a
There are two main IBD types: Crohn's disease, which can inflame any part of the gastrointestinal tract between the mouth and the anus; and ulcerative colitis, which mainly affects the colon.
The immune system's job is to find and eliminate threats. These can come in many forms, including bacteria, viruses, fungi, and other agents.
However, the researchers explain that the evolution of the partnership between mammals and their gut microbes has led to a delicate balance — which they call "intestinal tolerance" — between immune activation and suppression.
When this balance is upset, diseases such as IBD develop. The nature of the disruption is complex and not fully understood — especially at the molecular level.
Myeloid cells and signaling
The authors cite examples in which signaling molecules known as cytokines can play a role in both the repair of gut lining and the promotion of tumors.
They decided to study myeloid cells, because they are the main type of white blood cell that enter tumors and are "known to support" their formation and development.
The researchers were particularly interested in protein p38; while it was known be involved in the recruitment of immune cells and supporting tumor development, the underlying mechanisms were poorly understood.
By studying rodents that had been engineered to develop gut inflammation, they found that p38 signaling in myeloid cells "plays a key role in inflammation‐associated colon cancer."
When they suppressed p38 — both chemically and through gene silencing — the scientists discovered that fewer inflammatory cells were recruited into the colon.
"Tumor burden" was also found to have decreased.
IGF‐1 might be suitable target
Upon further investigation, the researchers found that IGF‐1 — an insulin-like hormone triggered by p38 — might be a suitable target in "intestinal diseases associated with inflammation."
This would "preferably" be in cases in which biopsies have detected "inflammatory infiltration" and "levels of IGF-1."
Previous studies have tied IGF-1 to cancer and IBD. These have suggested that the hormone alters the immune system and plays a "multifunctional" role in the "tumor microenvironment," note the authors.
The findings may explain some of the "disappointing results" seen in trials of drugs that block p38 in patients with gut inflammation diseases and a higher risk of colon cancer.
Better results might be achieved by specifically targeting p38 in myeloid cells. "Our study," write the authors, "demonstrates that the capacity of myeloid cells to enhance tumorigenesis is determined by the protein p38."
"In particular, we have identified an important contribution of the hormone IGF-1, which is activated by p38 in myeloid cells."
Prof. Angel R. Nebreda