title: CD44v8-10 is a cancer-specific marker for gastric cancer stem cells.
abstract: The surface marker CD44 has been identified as one of several markers associated with cancer stem cells (CSC) in solid tumors, but its ubiquitous expression in many cell types, including hematopoietic cells, has hindered its use in targeting CSCs. In this study, 28 paired primary tumor and adjacent nontumor gastric tissue samples were analyzed for cell surface protein expression. Cells that expressed pan-CD44 were found to occur at significantly higher frequency in gastric tumor tissues. We identified CD44v8-10 as the predominant CD44 variant expressed in gastric cancer cells and verified its role as a gastric CSC marker by limiting dilution and serial transplantation assays. Parallel experiments using CD133 failed to enrich for gastric CSCs. Analyses of another 26 primary samples showed significant CD44v8-10 upregulation in gastric tumor sites. Exogenous expression of CD44v8-10 but not CD44 standard (CD44s) increased the frequency of tumor initiation in immunocompromised mice. Reciprocal silencing of total CD44 resulted in reduced tumor-initiating potential of gastric cancer cells that could be rescued by CD44v8-10 but not CD44s expression. Our findings provide important functional evidence that CD44v8-10 marks human gastric CSCs and contributes to tumor initiation, possibly through enhancing oxidative stress defense. In addition, we showed that CD44v8-10 expression is low in normal tissues. Because CD44 also marks CSCs of numerous human cancers, many of which may also overexpress CD44v8-10, CD44v8-10 may provide an avenue to target CSCs in other human cancers.
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Surgery, National University of Singapore, Singapore, Singapore; and Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, Ireland, United Kingdom.
authors.forename: Wen Min
authors.initials: WM
authors.lastname: Lau
authors.forename: Eileen
authors.initials: E
authors.lastname: Teng
authors.forename: Hui Shan
authors.initials: HS
authors.lastname: Chong
authors.forename: Kirsten Anne Pagaduan
authors.initials: KA
authors.lastname: Lopez
authors.forename: Amy Yuh Ling
authors.initials: AY
authors.lastname: Tay
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.forename: Jimmy Bok Yan
authors.initials: JB
authors.lastname: So
authors.forename: Shing Leng
authors.initials: SL
authors.lastname: Chan
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D020033:Protein Isoforms