A breakthrough in our understanding of inflammatory bowel diseases (IBD) and colitis-associated cancer
Schematic drawing illustrating two intestinal epithelial cells (IEC) attached through α6β4 integrin to the basement membrane (BM), their specialized extracellular matrix (ECM). Loss of the integrin impairs epithelial integrity causing epithelium fragility and detachment from the BM. This cellular stress triggers an “alarm signal” in IECs (IL-18). Consequently, the mucus layer becomes altered, favoring bacterial translocation through the epithelial barrier and activation of the immune system. Infection and tissue injury then lead to a strong inflammation, mediated by the massive recruitment of innate immune cells and the secretion of IL-1β. With time, cells of the adaptive immunity sustain and perpetuate chronic inflammation, and ultimately induce the spontaneous development of cancer (CC, cancer cells).
Sept. 14, 2016
The work done by the team of Elisabeth Georges-Labouesse, with the help of Michel Labouesse at the IGBMC, has highlighted a novel and indispensable role for the extracellular matrix (ECM) which anchors cells, similar to foundations which support a house, in protecting the intestine against inflammation and secondary cancer development. These results provide new insights in the understanding of IBD and colitis-associated colorectal cancer and will help pave the way towards the development of novel therapies. This work was published on the 1st of July in the Journal Gut.
IBDs, such as Crohn's disease and ulcerative colitis, are invalidating relapsing-remitting illnesses, associated with recurring inflammation of the intestinal mucosa and severe diarrhea. IBD patients are at higher risk of developing colorectal cancer compared to the normal population, and the longer the duration and the extent of the IBD, the higher the risk.
In IBD, the intestinal homeostasis, normally ensured by the fine symbiosis between the epithelium with its mucus barrier, the bacterial flora and the immune system, is severely compromised. Most studies on IBD and colitis-associated cancer use mouse models, with or without a genetic mutation, where inflammation and cancer are induced through the use of chemical agents. Mouse models in which these processes are spontaneous and follow a progression that mimics the changes observed in humans are very rare. By focusing on the connection between the intestinal epithelium and the basement membrane (BM), the specialized ECM that supports epithelial cells, the researchers at the IGBMC have made two discoveries. Firstly, they revealed the crucial role of these "foundations" to protect the intestine against inflammation and cancer. Secondly, they established spontaneous mouse models, not based on a chemical treatment, to elicit the pathology.
Intestinal epithelial cells / extracellular matrix connection: the importance of keeping in touch
Epithelial cells of the gut form the first selective barrier facing the intestinal content and interacting with the bacterial flora. These cells sit on a specialized extracellular matrix, the basement membrane, to which they adhere through a specific receptor, the α6β4 integrin. Researchers at the IGBMC in collaboration with teams from Lille, Paris and Strasbourg1 show that in the absence of this integrin, epithelial cells send a stress signal that induces a chain reaction, starting with an acute inflammation, which becomes chronic over time and finally leads to cancer. This is the first time that the importance of the intestinal epithelial cells / basement membrane connection is demonstrated in vivo.
Mice deficient for the α6β4 integrin develop a severe colorectal inflammation whose lesions degenerate into cancer. Progression of the disease always follows the same sequence of events that can be monitored step by step. First, the loss of integrin causes epithelial cells to fail to anchor to the basement membrane, making the epithelium more fragile and sensitive to mechanical stress (e.g. food passage, muscle contractions etc.). This stress triggers, even before the clinical signs of inflammation are visible, the secretion of the pro-inflammatory cytokine interleukin-18 (IL-18). IL-18 particularly affects the properties of the protective mucus barrier, resulting in the establishment of abnormal interactions between the epithelium and the bacterial flora. In turn, it triggers a true inflammatory reaction, mediated mainly by the massive recruitment of innate immune cells that secrete another inflammatory cytokine, IL-1β. At this stage, antibiotic treatment can limit the severity of the inflammation. With time, lymphocytes and the inflammatory reaction due to the adaptive immune response progressively exacerbate the disease, inducing the transformation and tumor progression.
In addition to improving our understanding of the disease at the fundamental level, this discovery offers new perspectives for the study of IBD and colitis-associated colorectal cancer and the development of novel therapeutic solutions.
1 French laboratories involved in this work, besides the IGBMC:
• Teams of M. Chamaillard (Institut Pasteur) and I. Van Seuningen (Centre de Recherche Jean-Pierre Aubert) in Lille
• The team of S. Robine (Institut Curie) in Paris
• Teams of P. Simon Assmann (Inserm U1109) and P. Laquerriere (IPHC) in Strasbourg