In this process, stem cells in the intestine replace cells of the gut epithelium which have been lost due to injury or normal wear and tear by new cells. Scientists of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and Heidelberg University have now discovered, jointly with colleagues of the Fred Hutchinson Cancer Research Center in Seattle, that the cellular EGFR signaling pathway plays an important role in this process: It stimulates stem cells to divide so that their daughter cells replace the damaged intestinal epithelium. This signaling pathway may also be involved in the onset of human intestinal cancer.
“For the intestinal epithelium to be able to renew itself dynamically, the stem cells of the intestine need to respond to the needs of the intestinal tissue,” says Professor Bruce Edgar, who has a bridging professorship within the alliance of DKFZ and the Center for Molecular Biology (ZMBH) of Heidelberg University. “They may divide and produce new intestinal cells only to the extent in which cells of the intestinal epithelium are dying. But how the stem cells are activated has been largely unknown so far.”
The investigators have used the fruit fly Drosophila for their experiments. This insect regularly renews its intestinal epithelium with the aid of stem cells, just like man. The researchers used genetic methods to induce death of cells of the intestinal lining or fed the toxic bacterium Pseudomonas entomophila to the animals. In this way, they specifically induced self-renewal of the intestinal epithelium. The gut lining cells under attack produced an increased amount of mediator substances which activate the epidermal growth factor receptor, or EGFR for short. There was a parallel increase in the activity of the cellular EGFR signaling pathway in the intestinal stem cells.
Further experiments showed that the EGFR signaling pathway activates the stem cells using the mediators Ras, RAF und MAPK. These molecules cause the stem cells to divide and to renew the damaged intestine. “Our results show that the EGFR/Ras/MAPK signaling pathway plays a key role in the renewal and regeneration of the intestine,” summarizes Bruce Edgar.
However, this signaling pathway may also be involved in intestinal cancer. “There is mounting evidence suggesting that the signaling pathway is also activated when intestinal polyps arise,” Edgar added. Such polyps tend to turn into malignant intestinal cancer. “In intestinal cancer cells, the two signaling molecules Ras and BRAF, which are also part of the EGFR signaling pathway, are often hyperactive. However, the exact function of the EGFR signaling pathway in the onset of cancer is not yet understood,” emphasized Edgar. But there already are drugs, so-called antibodies, which are directed against EGFR and which are used, with good results, for treating intestinal cancer.
In a next step, the investigators are now planning to uncover how the EGFR signaling pathway is switched on in stem cells, in order to understand exactly what it is that causes stem cells to replace lost tissue.
Biologist and cancer researcher Bruce Edgar has recently been awarded a European Research Council Advanced Grant of 2.6 million euros for his work.
Huaqi Jiang, Marc Grenley, Maria-Jose Bravo, Rachel Blumhagen and Bruce Edgar: EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell 2010, DOI:10.1016/j.stem.2010.11.026
A picture for this press release is available on the Internet at:
Picture caption: Section through the intestine of fruit fly Drosophila (fluorescence microscopy): The intestinal epithelial cells are green with blue-green nucleus; the stem cells of the intestine are recognizable for their dark-blue nucleus.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is the largest biomedical research institute in Germany and is a member of the Helmholtz Association of National Research Centers. More than 2,200 staff members, including 1,000 scientists, are investigating the mechanisms of cancer and are working to identify cancer risk factors. They provide the foundations for developing novel approaches in the prevention, diagnosis, and treatment of cancer. In addition, the staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. The Center is funded by the German Federal Ministry of Education and Research (90%) and the State of Baden-Württemberg (10%).