title: CD44+ cancer stem-like cells in EBV-associated nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is a unique EBV-associated epithelial malignancy, showing highly invasive and metastatic phenotype. Despite increasing evidence demonstrating the critical role of cancer stem-like cells (CSCs) in the maintenance and progression of tumors in a variety of malignancies, the existence and properties of CSC in EBV-associated NPC are largely unknown. Our study aims to elucidate the presence and role of CSCs in the pathogenesis of this malignant disease. Sphere-forming cells were isolated from an EBV-positive NPC cell line C666-1 and its tumor-initiating properties were confirmed by in vitro and in vivo assays. In these spheroids, up-regulation of multiple stem cell markers were found. By flow cytometry, we demonstrated that both CD44 and SOX2 were overexpressed in a majority of sphere-forming C666-1 cells. The CD44+SOX2+ cells was detected in a minor population in EBV-positive xenografts and primary tumors and considered as potential CSC in NPC. Notably, the isolated CD44+ NPC cells were resistant to chemotherapeutic agents and with higher spheroid formation efficiency, showing CSC properties. On the other hand, microarray analysis has revealed a number of differentially expressed genes involved in transcription regulation (e.g. FOXN4, GLI1), immune response (CCR7, IL8) and transmembrane transport (e.g. ABCC3, ABCC11) in the spheroids. Among these genes, increased expression of CCR7 in CD44+ CSCs was confirmed in NPC xenografts and primary tumors. Importantly, blocking of CCR7 abolished the sphere-forming ability of C666-1 in vitro. Expression of CCR7 was associated with recurrent disease and distant metastasis. The current study defined the specific properties of a CSC subpopulation in EBV-associated NPC. Our findings provided new insights into developing effective therapies targeting on CSCs, thereby potentiating treatment efficacy for NPC patients.
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Samantha Wei-Man
authors.initials: SW
authors.lastname: Lun
authors.forename: Siu Tim
authors.initials: ST
authors.lastname: Cheung
authors.forename: Phyllis Fung Yi
authors.initials: PF
authors.lastname: Cheung
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: John Kong-Sang
authors.initials: JK
authors.lastname: Woo
authors.forename: Kwong-Wai
authors.initials: KW
authors.lastname: Choy
authors.forename: Chit
authors.initials: C
authors.lastname: Chow
authors.forename: Chartia Ching-Mei
authors.initials: CC
authors.lastname: Cheung
authors.forename: Grace Tin-Yun
authors.initials: GT
authors.lastname: Chung
authors.forename: Alice Suk-Hang
authors.initials: AS
authors.lastname: Cheng
authors.forename: Chun-Wai
authors.initials: CW
authors.lastname: Ko
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: Margaret Heung-Ling
authors.initials: MH
authors.lastname: Ng
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009500:Neutralization Tests; D054400:Receptors, CCR7 / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C515370:CCR7 protein, human; D018960:Hyaluronan Receptors; D054400:Receptors, CCR7; D055748:SOXB1 Transcription Factors