Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion.
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.
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Hirotsugu
H
Yanai
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Naho
N
Atsumi
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Toshihiro
T
Tanaka
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Naohiro
N
Nakamura
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Urology and Andrology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Yoshihiro
Y
Komai
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Taichi
T
Omachi
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Kiyomichi
K
Tanaka
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Kazuhiko
K
Ishigaki
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Kazuho
K
Saiga
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Urology and Andrology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Haruyuki
H
Ohsugi
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Yoko
Y
Tokuyama
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Yuki
Y
Imahashi
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.|Department of Dermatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Shuichi
S
Ohe
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Hiroko
H
Hisha
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Naoko
N
Yoshida
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Keiki
K
Kumano
Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Masanori
M
Kon
Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
Hiroo
H
Ueno
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D060965:Clonal Evolution; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; C489421:Bmi1 protein, mouse; C493597:Lgr5 protein, mouse; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D063150:Polycomb Repressive Complex 1