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A study points to new therapeutic targets for tumours associated with chronic inflammation

Intestine of a patient with ulcerative colitis, a chronic inflammatory disease of the intestine. Macrophage marker is shown in green, activated p38 protein in red, and nucleus in blue. Author: Catrin Youssif, IRB Barcelona
Intestine of a patient with ulcerative colitis, a chronic inflammatory disease of the intestine. Macrophage marker is shown in green, activated p38 protein in red, and nucleus in blue. Author: Catrin Youssif, IRB Barcelona
  • <p>Intestine of a patient with ulcerative colitis, a chronic inflammatory disease of the intestine. Macrophage marker is shown in green, activated p38 protein in red, and nucleus in blue. Author: Catrin Youssif, IRB Barcelona</p>
  • <p>Activated macrophage isolated from mouse intestine. Macrophage marker is shown in green, inflammation marker (iNOS) in red, and nucleus in blue. Author: Catrin Youssif, IRB Barcelona</p>
  • <p>Intestine of a patient with ulcerative colitis, a chronic inflammatory disease of the intestine. Activated IGF1 receptor is shown in brown and nucleus in blue. Author: Catrin Youssif, IRB Barcelona</p>
11 Jul 2018

A new study by researchers at IRB Barcelona demonstrates that myeloid cells, which belong to the leucocyte family and form part of the innate immune system, use p38 protein signalling to support inflammation-associated colon cancer.

Published in EMBO Molecular Medicine, the study by Angel R. Nebreda suggests that inhibition of the p38 pathway in myeloid cells may be a useful therapeutic approach, especially in tumours associated with chronic inflammation.

Scientists headed by ICREA researcher Angel R. Nebreda at the Institute for Research in Biomedicine (IRB Barcelona) report a new mechanism that contributes to the development of inflammation-associated colon cancer and points to new therapeutic targets. The study has been published in the journal EMBO Molecular Medicine.

More than a million people worldwide are diagnosed with colon cancer every year. Although many of these cases are spontaneous, chronic inflammation is one of the main causes underlying the development of this disease.

“Our study 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”, explains Nebreda, head of the Cell Sigalling and Cell Cycle lab.

The research has been done using models of acute and chronic inflammation in genetically modified mice or in mice treated with pharmacological inhibitors.

IGF-1 and inflammation

IGF-1, a hormone similar to insulin, emerges as a potential therapeutic target— preferably in combination with prior detection of inflammatory infiltration in biopsies of patients and levels of IGF-1—in intestinal diseases associated with inflammation. This finding could help to address the low success rate achieved by pharmacological inhibitors of p38 in clinical trials in patients with intestinal inflammatory disease who are predisposed to colon cancer.

“We found that p38 inhibition specifically in myeloid cells protects mice against inflammation-associated colon cancer, and this protective effect is associated with a reduced production of chemokines, which are crucial for the recruitment of cells from the immune system”, explains Catrin Youssif, first author of the study and current alumnus of IRB Barcelona.

The study demonstrates that the genetic or pharmacological inhibition of IGF-1 suppresses the recruitment of inflammatory cells and reduces the burden of colon cancer tumours associated with inflammation.

“On the basis of our findings, we 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,” conclude the authors of the study.

In addition to funding from the European Research Council (ERC), the study has been supported by the “Fundació La Marató”, the Ministry of Economy and Competitiveness of Spain, and the “Agencia de Gestión de Ayudas Universitarias y de Investigación (AGAUR)” run by the Catalan Government.

The study has been done in collaboration with researchers at CNIO and Hospital Ramón y Cajal in Madrid, and has involved IRB Barcelona’s Histopathology Facility and Biostatistics and Bioinformatics Facility, as well as Jaume Comas and Teresa Rodrigo Calduch, from the University of Barcelona.

 

Reference article:

Catrin Youssif, Monica Cubillos-Rojas, Mònica Comalada, Elisabeth Llonch, Cristian Perna, Nabil Djouder, Angel R Nebreda

Myeloid p38α signaling promotes intestinal IGF‐1 production and inflammation‐associated tumorigenesis

EMBO Molecular Medicine (2018): doi: 10.15252/emmm.201708403

 

About IRB Barcelona

Created in 2005 by the Generalitat de Catalunya (Government of Catalonia) and University of Barcelona, IRB Barcelona is a Severo Ochoa Centre of Excellence, a seal that was awarded in 2011. The institute is devoted to conducting research of excellence in biomedicine and to transferring results to clinical practice, thus improving people’s quality of life, while simultaneously promoting the training of outstanding researchers, technology transfer, and public communication of science. Its 27 laboratories and seven core facilities address basic questions in biology and are orientated to diseases such as cancer, metastasis, Alzheimer’s, diabetes, and rare conditions. IRB Barcelona is an international centre that hosts 400 employees and more than 30 nationalities. It is located in the Barcelona Science Park. IRB Barcelona forms part of the Barcelona Institute of Science and Technology (BIST) and the “Xarxa de Centres de Recerca de Catalunya” (CERCA).

colon cancer
inflammation
myeloid cells
p38
IGF-1
colitis

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