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ROSCAN Report Summary

Project ID: 281967
Funded under: FP7-IDEAS-ERC
Country: Germany

Final Report Summary - ROSCAN (The role of ROS/RNS during inflammation-associated and sporadic carcinogenesis)

Chronic inflammation promotes and presumably initiates tumorigenesis. We have established several findings explaining these phenomena. We were able to provide evidence that inflammatory signalling is involved in the acquisition of stem cell properties. Post-mitotic epithelia have the capacity to dedifferentiate and to reacquire stem cell characteristics thus enabling them to initiate intestinal tumorigenesis. This concept prove that tumors do not originate from stem cells only but that basically all cells including differentiated cells have the capacity to become tumorigenic. Particularly, for patients suffering from chronic inflammatory bowel diseases this concept is of great relevance. Indeed, we were able to how that epithelial cells that were covering ulcerations as part of the wound healing expressed stem cell markers thereby increasing the pool of potential tumor initiating cells. It is reasonable to believe that such stem like cells during chronic inflammation can acquire mutations by ROS that are released for example by inflammatory cells. To prove this concept we generated mice that accumulated high levels of intracellular ROS in macrophages and neutrophils. we were able to show that HO2 released by these cells can indeed trigger DNA damage and mutations in epithelial cells which can cause tumor formation. Moreover, intestinal epithelial cells release TNFa which in an autocrine manner activates transcription of chemokines and cytokines that fuel into a feed-forward loop and stimulate recruitment of macrophages which promotes tumorigenesis even further.

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