Bad luck cancer? Not such a thing! Professor Riccardo Fodde, Laboratory for Stem Cell and Cancer Research, Cancer Institute of Erasmus University, Amsterdam.
Diet, inflammation, and stem cells: trading off regenerative response with cancer risk
Intestinal stem cells reside at the bottom of the intestinal crypt and are earmarked by expression of the Lgr5 transmembrane receptor. Lgr5+ stem cells are intermingled with Paneth cells, ie post-mitotic and terminally differentiated cells that secrete antimicrobial peptides and constitute the main epithelial component of the stem cell niche. Lgr5+ stem cells are also considered as the cell-of-origin of intestinal cancer.
Patients suffering from inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) carry an increased colon cancer risk. Of note, Paneth cells were also shown to be the site of origin of intestinal inflammation and many genes known to be associated with an increased IBD risk are specifically expressed by this secretory lineage. Moreover, metaplastic Paneth cells are often found in the colon of IBD patients, although their functional significance –if any- is yet unclear.
Based on these general observations, we set to elucidate the functional role of Paneth cells in the regenerative response to the detrimental effects of inflammation and in the onset of IBD-associate colon cancer. Previously, we have identified the Paneth-specific secreted phospholipases Pla2g2a and Pla2g10 as important niche factors that regulate stem cell activity upon inflammation (Cell Stem Cell 2016, 19:38–51). Moreover, our metabolomics characterization of Lgr5+ and Paneth cells revealed a striking dichotomy of mitochondrial (Lgr5+) and glycolytic (Paneth) profiles that are quintessential for the maintenance of the homeostatic equilibrium between self-renewal and differentiation (Nature 2017, 543:424-427).
Paneth cells specifically express the c-Kit receptor (CD117), the ligand of which, SCF (stem cell factor), is specifically secreted upon inflammation both in the DSS mouse model and in IBD patients. In view of the known effects on hematopoietic stem cell function upon interaction between SCF and cKit, we set to study the causal relationship between SCF-driven activation of Paneth cells, its functional consequences within the intestinal stem cell niche, and the onset of cancer. To this aim, we have employed a combined ex vivo/in vivo strategy by applying the conventional ‘mini-gut’ organoid assay, the more advanced ORA (organoid reconstitution assay) recently developed in our laboratory (J Vis Exp 2017, 129: e56329), and in vivo and ex vivo lineage tracing with a novel Lyz-Cre transgenic model. In short, whereas inflammation cause the rapid and dramatic ablation of Lgr5+ stem cells, activation of the SCF/cKit signaling axis in Paneth cells seems to enhance their intestinal stem cell function as part of the tissue regenerative response: upon the inflammatory insult and as a consequence of Akt and Wnt signaling activation downstream of SCK/cKit, Paneth cells re-enter the cell cycle, de-differentiate, and acquire stem cell properties. Accordingly, lineage tracing of Paneth cells during DSS-induced pan-gastroenteritis confirmed the capacity of this post-mitotic and fully differentiated secretory lineage to acquire stem-like characteristics thus contributing to the regenerative response of the intestinal epithelium to the detrimental effects of inflammation (Cell Rep 2018, 24:2312-2328). In view of these paradigm-shifting observations, it is also plausible that Paneth cells, and their cKit-expressing equivalent in the colon (Cell Stem Cell 2016, 19:38–51), may represent the cells-of-origin of intestinal cancer in the context of tissue damage (currently under investigation). Thus, the increased cancer risk in IBD patients may reflect the ‘trade-off’ effect of the reinforced regenerative response to inflammation through de-differentiation of the secretory Paneth cells into bona fide stem cells.