title: CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors.
abstract: Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.
authors.affiliation: Howard Hughes Medical Institute, Ansary Center for Stem Cell Therapeutics, and Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Shmelkov
authors.forename: Jason M
authors.initials: JM
authors.lastname: Butler
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Adilia
authors.initials: A
authors.lastname: Hormigo
authors.forename: Jared
authors.initials: J
authors.lastname: Kushner
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Ryan
authors.initials: R
authors.lastname: St Clair
authors.forename: Muhamed
authors.initials: M
authors.lastname: Baljevic
authors.forename: Ian
authors.initials: I
authors.lastname: White
authors.forename: David K
authors.initials: DK
authors.lastname: Jin
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Gale
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Michael
authors.initials: M
authors.lastname: D'Angelica
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis*; D007249:Inflammation; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D010455:Peptides; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse