Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

作者：Davis Hayley; Irshad Shazia; Bansal Mukesh; Rafferty Hannah; Boitsova Tatjana; Bardella Chiara; Jaeger Emma; Lewis Annabelle; Freeman Mills Luke; Giner Francesc C; Rodenas Cuadrado Pedro; Mallappa Sreelakshmi; Clark Susan; Thomas Huw; Jeffery Rosemary; Poulsom Richard; Rodriguez Justo Manuel; Novelli Marco; Chetty Runjan; Silver Andrew; Sansom Owen J; Greten Florian R; Wang Lai Mun; East James E; Tomlinson Ian^*; Leedham Simon J

来源：Nature Medicine, 2015, 21(1): 62-70.

DOI：10.1038/nm.3750

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

• 出版日期2015-1