Lgr5-expressing stem cells are not the cells of origin of pyloric neuroendocrine carcinomas in mice.
J Pathol
; 238(1): 42-51, 2016 Jan.
Article
in En
| MEDLINE
| ID: mdl-26333534
ABSTRACT
In intestinal and pyloric epithelia, leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-expressing cells represent long-lived adult stem cells that give rise to all epithelial cell types, including endocrine cells. Ablation of the Apc gene in Lgr5-expressing cells leads to intestinal and pyloric adenomas. To assess whether all epithelial tumours of the gastrointestinal tract are derived from LGR5-positive stem cells, we crossed Lgr5-EGFP-IRES-creER(T2) mice, which express EGFP and Cre recombinase driven by the Lgr5 promoter, with CEA424-SV40-TAg mice, which develop pyloric neuroendocrine carcinomas of epithelial origin. In 19 day-old mice, single SV40 T antigen (TAg)-positive cells were identified preferentially at the the bases of pyloric glands, close to the stem cell compartment. However, contrary to previous publications describing subpopulations of LGR5-positive cells in gastrointestinal neoplasia, we could not detect Lgr5-EGFP-positive tumour cells in malignant lesions. The lack of expression of the Wnt target gene Lgr5 is probably not caused by suppression of Wnt signalling by TAg, since ß-catenin-mediated Wnt signalling, as measured by the TOPflash assay, was not inhibited. To determine the cellular origin of CEA424-SV40-TAg tumours, we performed tracing experiments using Lgr5-EGFP-IRES-creERT2CEA424-SV40-TAgROSA26-tdRFP mice. Following tamoxifen induction, it was possible to efficiently trace the progeny of Lgr5-expressing cells in gastrointestinal tissue via red fluorescent protein (RFP) expression. No RFP-positive tumour cells were detected, even when RFP gene activation occurred in 7 day-old mice well before the appearance of TAg-positive tumour cells. Hence, we conclude that Lgr5-expressing stem cells probably do not constitute the cells of origin in CEA424-SV40-TAg mice. Consequently, not all epithelial tumours in the pyloric region are initiated by transformation of LGR5-positive stem cells. Thus, additional long-lived LGR5-negative stem cells or progenitor cells with a low turnover rate might exist in the pyloric region, which could give rise to tumours.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach Neoplasms
/
Neoplastic Stem Cells
/
Carcinoma, Neuroendocrine
/
Receptors, G-Protein-Coupled
Limits:
Animals
Language:
En
Journal:
J Pathol
Year:
2016
Type:
Article
Affiliation country:
Germany