Researchers from IIS Aragón reveal a new inflammatory pathway that induces the development of colorectal cancer

The team led by Julián Pardo has shown that granzyme A, a protease of the immune system, is responsible for chronic inflammation in the intestine during ulcerative colitis, which ends up triggering the development of colorectal cancer.

After confirming the results in mice, they are currently developing inhibitors to analyze their effectiveness in the future in human clinical trials.

A group of scientists from the Aragón Health Research Institute (IIS Aragón) has found a new function of an immune system protease, known as granzyme A, which is responsible for the chronic inflammatory effect in the intestine observed during ulcerative colitis and, due to which induces the development of colorectal cancer. The team, coordinated by the researcher ARAID Julián Pardo has recently published these results in the prestigious journal Cell Reports and is currently developing inhibitors against human granzyme A in order to analyze their effectiveness in clinical trials.

The results have been confirmed in a mouse model in vivo of inflammatory colic carcinogenesis, which reproduces the inflammatory damage observed in patients with ulcerative colitis. In this model, mice deficient in granzyme A have been used, where great protection has been observed in terms of the severity of ulcerative colitis (the absence of granzyme A protects all mice from intestinal damage and death) and a reduction in the development of colorectal tumors of 50%. Specifically, granzyme A induces the overexpression of IL6 in macrophages, a cytokine through which granzyme A causes inflammation and transformation of the intestinal epithelium.

The relevance in humans has been confirmed by a genomic sequencing study in samples from one hundred stage II colorectal cancer patients, where the gene expression of granzyme A shows a high correlation with the presence of intestinal inflammation. Furthermore, a granzyme A inhibitor has been developed that has been effective in the treatment of colorectal cancer in mice once tumor development has begun, which reinforces that granzyme A could be used as a therapeutic target for the treatment of this disease. It is worth remembering that colorectal cancer accounts for 14% of annual deaths in Spain due to cancer, with more than 15.000 deaths, and is the most frequently diagnosed.

“The inflammatory response is key to generating an efficient immune response in eliminating infections and tumors. However, if it is not adequately regulated, it is also responsible for inflammatory diseases such as sepsis, with the example of COVID-19, autoimmunity or cancer itself,” says Pardo. "For years it has been known that chronic intestinal inflammation, as occurs in ulcerative colitis, has a high risk of developing colorectal cancer and up to 30% of patients with colitis can develop this type of cancer if it is not treated." time. However, at the moment the regulation of the chronic inflammatory response is difficult, given that the same mechanisms that regulate pathological inflammation are also responsible for the protective immune response,” he adds.

Therefore, this finding by IIS Aragón researchers represents a great advance in the knowledge of the mechanisms that regulate the generation of chronic intestinal inflammation and colorectal cancer, since for the first time it is demonstrated that a component of the granzyme family, granzyme A induces intestinal inflammation and colorectal cancer. In addition, it has a high translational component, since therapeutic inhibition of granzyme A is proven to inhibit cancer progression. This fact is of special importance, since it has been observed that the absence of granzyme A in mice does not significantly affect protective immunity. This represents an advantage over other recently developed inflammatory agents, which present, among other side effects, a greater predisposition to infections.

The study, which began four years ago and includes international collaborations, has been coordinated by Julián Pardo (ARAID researcher at the IIS Aragon and the University of Zaragoza) and Maykel Arias (Juan de la Cierva researcher at the CSIC Institute of Carbochemistry) and Its main author is Llipsy Santiago, a predoctoral researcher at the IIS Aragon and the University of Zaragoza, who will defend these results in her thesis this September.

Funded by a project of the Ministry of Science and Innovation and by funds from the Reference Group of the Government of Aragon Immunotherapy, Cytotoxicity, Inflammation and Cancer (IC2), researchers from the Lozano Blesa University Clinical Hospital/IIS Aragon, Instituto of Carbochemistry/CSIC in Zaragoza, the University of Zaragoza (Departments of Physiology and Microbiology and Preventive Medicine and Public Health), the Hospital del Mar Medical Research Institute, the Bellvitge Biomedical Research Institute and the Catalan Institute of Oncology of Barcelona, the Rey Juan Carlos I University and the Ramón y Cajal Hospital in Madrid, the Murcian Institute for Biosanitary Research IMIB-Arrixaca, XemeBiopharma and Northwestern University in Chicago, Monash University in Australia and Paris.

About IIS Aragón

The IIS Aragón is the Health Research Institute of the hospital complex formed by the Teaching and University Hospitals “Hospital Clínico Universitario Lozano Blesa” and “Hospital Universitario Miguel Servet” and Primary Health Care. The University of Zaragoza and the Aragonese Institute of Health Sciences are associated with this hospital complex through different legal instruments.

The objectives of the IIS Aragón are to bring together basic and applied, clinical and health services research; create a quality research, care and teaching environment to which health professionals, training specialists and postgraduate and undergraduate students are exposed, as well as constitute the ideal place for attracting talent and the location of large scientific facilities. technological.