The origin of intestinal cancer in the context of inflammation
Verhagen, M. P.; Joosten, R.; Schmitt, M.; Valimaki, N.; Sacchetti, A.; Rajamaki, K.; Choi, J.; Procopio, P.; Silva, S.; van der Steen, B.; van den Bosch, T. P. P.; Seinstra, D.; Doukas, M.; Augenlicht, L. H.; Aaltonen, L. A.; Fodde, R.
Show abstract
According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, was shown to suppress intestinal stemness. Here, we employed Paneth cells (PCs) as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation. Upon inflammation, PC-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in inflammatory bowel disease (IBD) patients but also of a larger fraction of sporadic colon cancers. The latter is likely due to the inflammatory consequences of Western-style dietary habits, the major colon cancer risk factor. Computational methods designed to predict the cell-of-origin of cancer confirmed that, in a substantial fraction of sporadic colon cancers the cells-of-origin are secretory lineages and not stem cells. One-Sentence SummarySecretory cell lineages trigger tumor formation in the context of the major etiologic colon cancer risk factors.
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