Abstract
LGR5 is known to be a stem cell marker in the murine small intestine and colon, however the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have been limited by the lack of specific antibodies. Here we used in situ hybridization to specifically examine LGR5 mRNA expression in a panel of human adenoma and carcinoma samples (n = 66). We found that a small number of cells express LGR5 at the base of normal colonic crypts. We then showed that conventional adenomas widely express high levels of LGR5, and there is no evidence of stereotypic cellular hierarchy. In contrast, serrated lesions display basal localization of LGR5, and the cellular hierarchy resembles that of a normal crypt. Moreover, ectopic crypts found in traditional serrated adenomas show basal LGR5 mRNA, indicating that they replicate the stem cell organization of normal crypts with the development of a cellular hierarchy. These data imply differences in the stem cell dynamics between the serrated and conventional pathways of colorectal carcinogenesis. Furthermore we noted high LGR5 expression in invading cells, with later development of a stem cell niche in adenocarcinomas of all stages.
Highlights
LGR5 is known to be a stem cell marker in the murine small intestine and colon, the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have been limited by the lack of specific antibodies
To determine if the expression of the stem cell marker LGR5 is altered during human adenoma progression, we carried out chromogenic In situ hybridization (ISH) on a panel of human Formalin-fixed paraffin embedded (FFPE) hyperplastic polyps, adenomas and adenocarcinomas of all stages (n 5 66)
LGR5 is accepted as the most reliable intestinal stem cell marker currently in use, the expression and localization of the receptor in human adenomatous crypts or glands remains the subject of much debate
Summary
LGR5 is known to be a stem cell marker in the murine small intestine and colon, the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have been limited by the lack of specific antibodies. Recent experiments using continuous clonal labeling in mouse models indicate that each crypt contains only a small number of functional or ‘working’ stem cells[8]: and it is likely that most of the Lgr[51] population are inconsequential for long-term maintenance of the stem cell pool[9]. These observations suggest that few stem cells contribute to tumor growth: if this were true for human colorectal adenomas, it would perhaps account for their observed low growth rate[10]. A detailed analysis of the LGR5 stem cell architecture in the serrated pathway of colorectal tumorigenesis, and how it may differ from the classical adenoma/carcinoma progression has not been reported
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