title: Tumor-initiating cells are enriched in CD44(hi) population in murine salivary gland tumor.
abstract: Tumor-initiating cells (T-ICs) discovered in various tumors have been widely reported. However, T-IC populations in salivary gland tumors have yet to be elucidated. Using the established Pleomorphic Adenoma Gene-1 (Plag1) transgenic mouse model of a salivary gland tumor, we identified CD44(high) (CD44(hi)) tumor cells, characterized by high levels of CD44 cell surface expression, as the T-ICs for pleomorphic adenomas. These CD44(hi) tumor cells incorporated 5-bromo-2-deoxyuridine (BrdU), at a lower rate than their CD44(negative) (CD44(neg)) counterparts, and also retained BrdU for a long period of time. Cell surface maker analysis revealed that 25% of the CD44(hi) tumor cells co-express other cancer stem cell markers such as CD133 and CD117. As few as 500 CD44(hi) tumor cells were sufficient to initiate pleomorphic adenomas in one third of the wildtype mice, whereas more than 1×10(4) CD44(neg) cells were needed for the same purpose. In NIH 3T3 cells, Plag1 was capable of activating the gene transcription of Egr1, a known upregulator for CD44. Furthermore, deletion of sequence 81-96 in the Egr1 promoter region abolished the effect of Plag1 on Egr1 upregulation. Our results establish the existence of T-ICs in murine salivary gland tumors, and suggest a potential molecular mechanism for CD44 upregulation.
authors.affiliation: Department of Oral and Maxillofacial Surgery, College of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Shukun
authors.initials: S
authors.lastname: Shen
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yang
authors.forename: Zhugang
authors.initials: Z
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.forename: Liqun
authors.initials: L
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Lizhen
authors.initials: L
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yu
authors.forename: Xinhong
authors.initials: X
authors.lastname: Zhang
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.forename: Xuelai
authors.initials: X
authors.lastname: Yin
authors.forename: Chenping
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000071916:AC133 Antigen; D008949:Adenoma, Pleomorphic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012468:Salivary Gland Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D010455:Peptides; C491264:Plag1 protein, mouse; C000606024:Prom1 protein, mouse; D019009:Proto-Oncogene Proteins c-kit