Crypt stem cells as the cells-of-origin of intestinal cancer.
Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5(+) cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.
Barker
Nick
N
Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht & University Medical Centre Utrecht, Netherlands.
Ridgway
Rachel A
RA
van Es
Johan H
JH
van de Wetering
Marc
M
Begthel
Harry
H
van den Born
Maaike
M
Danenberg
Esther
E
Clarke
Alan R
AR
Sansom
Owen J
OJ
Clevers
Hans
H
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin