Abstract
Although the existence of cancer stem cells in intestine tumors has been suggested, direct evidence has not been yet provided. Here, we showed, using the multicolor lineage-tracing method and mouse models of intestinal adenocarcinoma and adenoma that Bmi1- or Lgr5- positive tumorigenic cells clonally expanded in proliferating tumors. At tumor initiation and during tumor propagation in the colon, the descendants of Lgr5-positive cells clonally proliferated to form clusters. Clonal analysis using ubiquitous multicolor lineage tracing revealed that colon tumors derived from Lgr5-positive cells were monoclonal in origin but eventually merged with neighboring tumors, producing polyclonal tumors at the later stage. In contrast, the origin of small intestine tumors was likely polyclonal, and during cancer progression some clones were eliminated, resulting in the formation of monoclonal tumors, which could merge similar to colon tumors. These results suggest that in proliferating intestinal neoplasms, Bmi1- or Lgr5-positive cells represent a population of cancer stem cells, whereas Lgr5-positive cells also function as cells-of-origin for intestinal tumors.
Highlights
Addition, we created a sporadic carcinogenesis mouse model by treating mice with azoxymethane followed by DSS10
The results of this study show that all types of intestinal tumors contain Bmi1- or leucine-rich-repeat containing G-protein-coupled receptor 5 (Lgr5)-positive cells, which clonally expand to contribute to tumor propagation
To compare the ability of Lgr5- or Bmi1-positive cells to clonally expand at tumor initiation and development, we examined mice injected with tamoxifen before tumorigenesis
Summary
Addition, we created a sporadic carcinogenesis mouse model by treating mice with azoxymethane followed by DSS10. 69%, 87%, and 89.4% tumors in the FAP, two-step carcinogenesis, and sporadic carcinogenesis, respectively, models had Bmi1+ cells (Fig. 2a,c,e and Supplementary Table 1).
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