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Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation
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Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation
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Journal Article
Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation
2024
Overview
According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific
Apc
mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.
Upon inflammation and targeted gene mutation, some fully differentiated secretory and postmitotic intestinal epithelial lineages dedifferentiate to acquire stem-like features and promote tumor formation.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 38/32
/ 38/91
/ 64/60
/ 96/100
/ 96/31
/ 96/63
/ Adenomatous Polyposis Coli Protein - genetics
/ Animal Genetics and Genomics
/ Animals
/ Biomedical and Life Sciences
/ Cell Differentiation - genetics
/ Cell Transformation, Neoplastic - genetics
/ Colonic Neoplasms - genetics
/ Colonic Neoplasms - pathology
/ Genes
/ Humans
/ Inflammatory Bowel Diseases - genetics
/ Inflammatory Bowel Diseases - pathology
/ Kinases
/ Mice
/ Mutation
/ Tumors
