title: CD133 and CD44 are universally overexpressed in GIST and do not represent cancer stem cell markers.
abstract: Although imatinib mesylate has been a major breakthrough in the treatment of advanced gastrointestinal stromal tumors (GIST), complete responses are rare and most patients eventually develop resistance to the drug. Thus, the possibility of an imatinib-insensitive cell subpopulation within GIST tumors, harboring stem cell characteristics, may be responsible for the clinical failures. However, the existence of a cancer stem cell component in GIST has not been yet established. This study was aimed to determine whether expression of commonly used stem cell markers in other malignancies, that is, CD133 and CD44, might identify cells with characteristics of cancer stem/progenitor cells in human GIST. CD133 and CD44 expression in GIST explants was analyzed by flow cytometry, immunofluorescence, and gene expression. Their transcription levels were correlated with clinical and molecular factors in a large, well-annotated cohort of GIST patients. FACS sorted GIST cells based on CD133 and CD44 expression were isolated and used to assess phenotypic characteristics, ability to maintain their surface expression, sensitivity to imatinib, and expression signature. The enrichment in CD133/CD44 cells in the side population (SP) assay was also investigated. CD133 expression was consistently found in GIST. CD133(-) cells formed more colonies, were more invasive in a matrigel assay, and showed enrichment in the SP cells, compared to CD133(+) cells. CD133 expression was also detected in the two imatinib-sensitive GIST cell lines, while was absent in the imatinib-resistant lines. Our results show that CD133 and CD44 are universally expressed in GIST, and may represent a lineage rather than a cancer stem cell marker.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, NY, USA.
authors.forename: Junwei
authors.initials: J
authors.lastname: Chen
authors.forename: Tianhua
authors.initials: T
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Ronald
authors.initials: R
authors.lastname: Dematteo
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000071916:AC133 Antigen; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007223:Infant; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism; D058985:Side-Population Cells / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D018960:Hyaluronan Receptors; C000606023:PROM1 protein, human; D010455:Peptides
references.citation: Am J Pathol. 2003 Aug;163(2):691-700
references.pmid: 12875988
references.citation: J Pathol. 2000 Dec;192(4):427-32
references.pmid: 11113858
references.citation: Nature. 2010 Oct 14;467(7317):849-53
references.pmid: 20927104
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12425-30
references.pmid: 9356465
references.citation: Cancer Res. 2003 Sep 15;63(18):5821-8
references.pmid: 14522905
references.citation: Cancer Res. 2005 Dec 1;65(23):10946-51
references.pmid: 16322242
references.citation: J Clin Invest. 2008 Jun;118(6):2021-4
references.pmid: 18497883
references.citation: J Clin Invest. 2008 Jun;118(6):2111-20
references.pmid: 18497886
references.citation: Blood. 2004 Dec 1;104(12):3739-45
references.pmid: 15315971
references.citation: Cancer Biol Ther. 2010 Dec 1;10(11):1182-90
references.pmid: 20948317
references.citation: Lancet. 1995 Mar 11;345(8950):615-9
references.pmid: 7534855
references.citation: Nature. 2007 Jan 4;445(7123):111-5
references.pmid: 17122771
references.citation: J Biol Chem. 2002 Feb 15;277(7):4589-92
references.pmid: 11717317
references.citation: Int J Cancer. 2011 Sep 1;129(5):1149-61
references.pmid: 21064103
references.citation: J Exp Med. 1996 Apr 1;183(4):1797-806
references.pmid: 8666936
references.citation: Blood. 1997 Dec 15;90(12):5013-21
references.pmid: 9389721
references.citation: Gastroenterology. 2005 Feb;128(2):270-9
references.pmid: 15685537
references.citation: Clin Cancer Res. 2007 Jan 1;13(1):170-81
references.pmid: 17200352
references.citation: Int J Cancer. 2010 May 1;126(9):2067-78
references.pmid: 19711346
references.citation: Eur J Cancer. 2010 May;46(7):1271-7
references.pmid: 20303742
references.citation: Lancet. 2002 Apr 13;359(9314):1301-7
references.pmid: 11965276
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1591-6
references.pmid: 21220328
references.citation: Blood. 1997 Dec 15;90(12):5002-12
references.pmid: 9389720
references.citation: Blood. 2004 Nov 1;104(9):2940-2
references.pmid: 15251980
references.citation: Cytometry B Clin Cytom. 2011 Jul-Aug;80(4):238-47
references.pmid: 21462307
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12843-8
references.pmid: 16908864
references.citation: Eur J Cardiothorac Surg. 2009 Sep;36(3):446-53
references.pmid: 19464919
references.citation: Clin Cancer Res. 2005 Jun 1;11(11):4182-90
references.pmid: 15930355
references.citation: Physiol Genomics. 2007 Nov 14;31(3):492-509
references.pmid: 17895395
references.citation: Nat Rev Cancer. 2003 Dec;3(12):895-902
references.pmid: 14737120
references.citation: Cell Cycle. 2005 Feb;4(2):203-5
references.pmid: 15655356