Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion

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.

LGRs receptors as peculiar GPCRs involved in cancer

“…In a colorectal cancer model using a conditional Apc loss-of-function mouse line, specific ablation of Apc function in Lgr5-expressing (Lgr5 +ve ) stem cells results in cell transformation leading to adenoma development along the small and large intestine [80]. A similar conclusion has been reached with the Apc min/+ line used as a model for human familial adenomatous polyposis [81]. In addition, overexpression of the Rspondin 3 ligand in the Lgr4 +ve/ Lgr5 +ve cells also leads to rapid adenoma and adenocarcinoma development, associated with expansion of the Lgr4 +ve/ Lgr5 +ve cells but also of Lgr4 +ve/ Lgr5 -ve cells [82].…”

Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma

“…A stem cell marker Bmi1 is involved in the regulation of cell proliferation, stem cell maintenance, tumorigenesis and tumor progression . Bmi1 is overexpressed and acts as an oncogene in several human malignancies, including HCC . The expression of another “stemness”‐related marker epithelial cell adhesion molecule (EpCAM) in HCC is associated with an aggressive biological behavior and poor clinical outcome .…”

“…(4,5) Bmi1 is overexpressed and acts as an oncogene in several human malignancies, including HCC. (6,7) The expression of another "stemness"-related marker epithelial cell adhesion molecule (EpCAM) in HCC is associated with an aggressive biological behavior and poor clinical outcome. (8) In chronic inflammation, inflammatory signaling is important for the dedifferentiation and expansion of tumorinitiating cells.…”

E‐cadherin‐Fc chimera protein matrix enhances cancer stem‐like properties and induces mesenchymal features in colon cancer cells

“…We then examined the expression of the CSC markers Lgr5, Bmi‐1, and SOX9 by RT‐PCR. ODC‐degron–transduced cells increased SOX9 mRNA expression (Figure A; P < .05), whereas Degron(+) E‐cad‐Fc(+) cells showed a significant increase in Lgr5, Bmi‐1, and SOX9 mRNA expression compared with the Degron(−) control cells (Figure A; * P < .05, ** P < .01).…”