title: Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma.
abstract: Patients with advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis with the currently available therapy, and tumor recurrence is frequently observed. The discovery of specific membrane-associated cancer stem cell (CSC) markers is crucial for the development of novel therapeutic strategies to target these CSCs. To address this issue, we established sphere cultures to enrich CSCs and used them for plasma membrane proteomics to identify specific membrane signatures of the HNSCC spheres. Of a dataset that included a total of 376 identified proteins, 200 were bona fide membrane proteins. Among them, 123 proteins were at least 1.5-fold up- or down-regulated in the spheres relative to the adherent cultures. These proteins included cell adhesion molecules, receptors, and transporter proteins. Some of them play key roles in wnt, integrin, and TGFβ signaling pathways. When we compared our dataset with two published hESC membrane protein signatures, we found 18 proteins common to all three of the databases. CD166 and CD44 were two such proteins. Interestingly, the expression of CD166, rather than that of the well-established HNSCC CSC marker CD44, was significantly related to the malignant behavior of HNSCC. Relative to CD166(low) HNSCC cells, CD166(high) HNSCC cells had a greater sphere-formation ability in vitro and tumor formation ability in vivo. Patients whose tumors expressed high levels of CD166 had a significantly poorer clinical outcome than those whose tumors expressed low levels of CD166 (cohort 1: 96 cases, p = 0.040), whereas the level of CD44 expression had only a marginal influence on the clinical outcome of patients with HNSCC (p = 0.078). The level of CD166 expression in HNSCC tumors was also associated with the tumor recurrence rate (cohort 2: 104 cases, p = 0.016). This study demonstrates that CD166 is a valuable cell surface marker for the enrichment of HNSCC stem cells and that plasma membrane proteomics is a promising biological tool for investigating the membrane proteins of CSCs.
authors.affiliation: Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Xihu
authors.initials: X
authors.lastname: Yang
authors.forename: Lizhen
authors.initials: L
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Clark
authors.forename: Hui
authors.initials: H
authors.lastname: Zuo
authors.forename: Dongxia
authors.initials: D
authors.lastname: Ye
authors.forename: Wantao
authors.initials: W
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011379:Prognosis; D040901:Proteomics; D018874:Spheroids, Cellular / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D018960:Hyaluronan Receptors; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C497483:CD44 protein, human
references.citation: Cancer Metastasis Rev. 2005 Jun;24(2):223-36
references.pmid: 15986133
references.citation: Stem Cells. 2005 Nov-Dec;23(10):1560-70
references.pmid: 16081669
references.citation: Int J Cancer. 2012 Jul 15;131(2):396-405
references.pmid: 21858815
references.citation: Nature. 2009 Jan 29;457(7229):608-11
references.pmid: 19092804
references.citation: Mol Cell Proteomics. 2009 May;8(5):959-70
references.pmid: 19151416
references.citation: Prostate. 2003 Jan 1;54(1):34-43
references.pmid: 12481253
references.citation: Oncology. 2005;68(4-6):462-70
references.pmid: 16024937
references.citation: PLoS One. 2008;3(10):e3360
references.pmid: 18852874
references.citation: Clin Cancer Res. 2008 Mar 15;14(6):1726-33
references.pmid: 18347173
references.citation: PLoS One. 2011 Jan 27;6(1):e16466
references.pmid: 21304586
references.citation: Oral Oncol. 2002 Dec;38(8):763-71
references.pmid: 12570055
references.citation: PLoS One. 2011 May 03;6(5):e19386
references.pmid: 21559292
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10158-63
references.pmid: 17548814
references.citation: N Engl J Med. 2006 Sep 21;355(12):1253-61
references.pmid: 16990388
references.citation: Oral Oncol. 2010 May;46(5):393-8
references.pmid: 20371201
references.citation: Anticancer Res. 2010 Apr;30(4):1163-8
references.pmid: 20530423
references.citation: Mod Pathol. 2007 Jan;20(1):102-7
references.pmid: 17143262
references.citation: J Clin Endocrinol Metab. 2003 Jul;88(7):3437-43
references.pmid: 12843199
references.citation: J Biol Chem. 2002 Nov 22;277(47):45299-305
references.pmid: 12235144
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Cancer Immunol Immunother. 2010 Nov;59(11):1665-74
references.pmid: 20635083
references.citation: Nat Med. 1997 Jul;3(7):730-7
references.pmid: 9212098
references.citation: Int J Cancer. 2009 May 1;124(9):2098-105
references.pmid: 19142865
references.citation: Breast Cancer Res. 2004;6(5):R478-87
references.pmid: 15318930
references.citation: Arthritis Rheum. 2004 May;50(5):1522-32
references.pmid: 15146422
references.citation: J Clin Oncol. 2007 Jun 20;25(18):2586-93
references.pmid: 17577038
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
references.pmid: 17210912
references.citation: Nat Med. 2011 Mar;17(3):313-9
references.pmid: 21386835
references.citation: Mol Cell Proteomics. 2007 Nov;6(11):1997-2011
references.pmid: 17656355
references.citation: Cancer Res. 2007 May 1;67(9):4010-5
references.pmid: 17483311
references.citation: Mol Cell Proteomics. 2009 Jun;8(6):1436-49
references.pmid: 19321434
references.citation: Cancer Cell. 2010 Nov 16;18(5):510-23
references.pmid: 21075313
references.citation: Cell. 2010 Jan 8;140(1):62-73
references.pmid: 20074520
references.citation: Mol Cell Proteomics. 2011 Dec;10(12):M111.011353
references.pmid: 21788403
references.citation: Int J Cancer. 2009 Jul 1;125(1):9-14
references.pmid: 19322904
references.citation: Br J Cancer. 2009 Aug 4;101(3):457-64
references.pmid: 19603023
references.citation: Nat Genet. 2008 May;40(5):499-507
references.pmid: 18443585
references.citation: J Pathol. 2005 Feb;205(3):359-76
references.pmid: 15532095
references.citation: Gastroenterology. 2010 Dec;139(6):2072-2082.e5
references.pmid: 20826154
references.citation: J Clin Pathol. 2011 Feb;64(2):146-52
references.pmid: 21262777
references.citation: J Surg Oncol. 2010 Jun 1;101(7):564-9
references.pmid: 20461761