title: Stem Cells Antigen-1 Enriches for a Cancer Stem Cell-Like Subpopulation in Mouse Gastric Cancer.
abstract: There is a strong need to identify markers to enrich gastric cancer stem cells (CSCs). However, CSC enrichment markers for mouse gastric cancers have not yet been determined. In our previous study, we generated primary mouse gastric cancer cell line NCC-S1 (S1) established from a Villin-cre;Smad4(F/F) ;Trp53(F/F) ;Cdh1(F/wt) mouse and its metastatic variant cell line NCC-S1M (S1M). Interestingly, S1M cells exhibited CSC-like features, such as increased tumorigenic potential and chemoresistance. By comparing gene expression profiles between S1 and S1M cells, we identified Stem Cells Antigen-1 (Sca-1) as a cell surface marker, which was mostly upregulated in S1M. Sca-1 was upregulated in tumorspheres from S1 cells or after cisplatin treatment in S1 cells. Immunofluorescence (IF) analysis showed that approximately 7% of cancer cells exhibited positivity for Sca-1 in primary mouse gastric cancer tissues. An in vivo-limiting dilution assay showed that Sca-1(high) mouse gastric cancer cells demonstrated increased tumorigenicity compared with Sca-1(negative) cells. The Sca-1 expression was downregulated by TGF-β pathway activation and Wnt pathway inhibition in mouse gastric cancer cells. Sca-1(high) cells showed relatively low TGF-β reporter activity and high TCF/LEF1 reporter activity compared with Sca-1(negative) cells. A chromatin immunoprecipitation analysis demonstrated that Sca-1 was a β-catenin/LEF1 target gene. Sca-1(high) allografts were more resistant to cisplatin/fluorouracil chemotherapy than Sca-1(negative) allografts, and overexpressed Bcl-xL. Eighty-five mouse genes overexpressed in Sca-1(high) S1 cells compared with Sca-1(negative) cells clustered 123 pretreatment gastric cancer patient samples according to survival following chemotherapy. Taken together, Sca-1 is a novel CSC enrichment marker that mediates TGF-β and Wnt/β-catenin signaling in mouse gastric cancer. Stem Cells 2016;34:1177-1187.
authors: Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.|Department of Veterinary Pathology, Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Jun Won
authors: JW
authors: Park
authors: Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
authors: Jung Min
authors: JM
authors: Park
authors: Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
authors: Dong Min
authors: DM
authors: Park
authors: Department of Veterinary Pathology, Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Dae-Yong
authors: DY
authors: Kim
authors: Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
authors: Hark Kyun
authors: HK
authors: Kim
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta
keywords: Chemoresistance; Stomach; TGF-β pathway; Wnt/β-Catenin pathway