Complex links between appendectomy, ulcerative colitis and colorectal cancer ⋅ Inserm, From science to health

Appendectomy – the surgery to remove the appendix – reduces intestinal inflammation associated with ulcerative colitis, a chronic colon disease. But paradoxically, this benefit is accompanied by an increased risk of developing colorectal cancer. In Rennes, the team Inserm by Éric Ogier-Denis described the underlying mechanisms, in order to better understand the phenomenon and to inform the healthcare professionals involved in the care of these patients.

The appendix definitely gives scientists a hard time. Long considered a useless vestige of evolution, this small protuberance located at the level of the colon actually plays a complex role in intestinal immunity, which researchers are trying to untangle. In particular, a link has been established between appendix and ulcerative colitis, a chronic inflammatory disease of the colon. Individuals whose appendix has been removed due to appendicitis seem to be protected from this disease. So much so that, even in the absence of appendicitis, this intervention has become a therapeutic avenue for relieving patients suffering from resistant forms of ulcerative colitis, as an alternative to total colon removal. A clinical trial conducted in the Netherlands and the United Kingdom is also underway to test this hypothesis (ACCURE trial).

But the Inserm team of Éric Ogier-Denis, at the Eugène-Marquis center in Rennes, has reservations. While they have been studying the links between inflammation and cancer for several years, the researchers have highlighted an increased risk of a particular form of colorectal cancer in the event of chronic inflammation of the colon, exacerbated by a prophylactic appendectomy. ” Be careful, these are very specific cancers, linked to inflammation. These observations cannot be extended to the majority of colorectal cancers “, tempers Éric Ogier-Denis. To understand this phenomenon, the team studied the possible mechanisms involved in this association.

Anti-tumor immunity

The researchers worked with a mouse model that exhibits chronic inflammation of the colon mimicking human ulcerative colitis. They performed an appendectomy in some of them. This intervention led to a significant reduction in intestinal inflammation, but the operated animals developed more colorectal tumors than the others. ” There difference was very significant. We are talking about an increased risk of between 15 and 20% “, specifies Éric Ogier-Denis.

The scientists went on to explore different avenues likely to explain how appendectomy increases tumor risk in these mice. Those relating to an activation of pro-oncogenes or modification of the intestinal microbiota could be ruled out, but the analysis of the immune cells was conclusive.

The researchers observed a significant deficit in CD3 T lymphocytes and CD8 in tumors of mice in which an appendectomy had been performed. However, these cells are involved in antitumor surveillance. ” They act as sentinels capable of locating and eliminating cancerous cellsexplains Éric Ogier-Denis. It would therefore seem that the appendix plays an important role in antitumor immunity in the colon, by locally promoting the entry of CD3 and CD8 T lymphocytes. “, he suggests.

These observations were then confirmed on human tumor samples from patients with ulcerative colitis. Their analysis revealed a deficit of CD3 and CD8 cells in patients who no longer had their appendix, compared to the others. ” And the rest of our experiments confirmed that appendectomy blocked the arrival of these populations of antitumor immune cells in the colon. “clarifies the researcher.

A benefit/risk ratio to be monitored

To counteract this deleterious effect of appendectomy, the researchers propose two ethically complicated avenues to implement: first trigger appendicitis, which makes it possible to skyrocket the levels of CD3 and CD8 T lymphocytes in the colon before suppressing the appendix, or re-inject CD3 and CD8 cells taken from the patient and activated in vitro to stimulate antitumor immunity. While waiting to decide on the strategy to adopt, our results are important to communicate to surgeons and gastroenterologists, because they question the risk/benefit ratio of therapeutic appendectomy in the management of ulcerative colitis. Indeed, an inflammatory disease is less debilitating than a cancer that risks metastasizing. However, we do not yet know how long it takes for these tumors to appear and this remains a major question: the benefit of an appendectomy can become greater if it provides lasting relief to patients at the cost of tumors that would appear decades later, and which can be monitored and processed. This is what motivates the investigators of the ACCURE trial to continue their work. They hope that the benefit on ulcerative colitis will be major, while remaining vigilant about the appearance of a possible cancer. concludes Éric Ogier-Denis.

Eric Ogier-Denis is researcher within the team Cell plasticityTGFβ and oncology