title: ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas.
abstract: A small sub-population of cells characterized by increased tumorigenic potential, ability to self-renew and to differentiate into cells that make up the tumor bulk, has been characterized in some (but not all) tumor types. These unique cells, namedcancer stem cells, are considered drivers of tumor progression in these tumors. The purpose of this work is to understand if cancer stem cells play a functional role in the tumorigenesis of salivary gland mucoepidermoid carcinomas. Here, we investigated the expression of putative cancer stem cell markers (ALDH, CD10, CD24, CD44) in primary human mucoepidermoid carcinomas by immunofluorescence, in vitro salisphere assays, and in vivo tumorigenicity assays in immunodeficient mice. Human mucoepidermoid carcinoma cells (UM-HMC-1, UM-HMC-3A, UM-HMC-3B) sorted for high levels of ALDH activity and CD44 expression (ALDHhighCD44high) consistently formed primary and secondary salispheres in vitro, and showed enhanced tumorigenic potential in vivo (defined as time to tumor palpability, tumor growth after palpability), when compared to ALDHlowCD44low cells. Cells sorted for CD10/CD24, and CD10/CD44 showed varying trends of salisphere formation, but consistently low in vivo tumorigenic potential. And finally, cells sorted for CD44/CD24 showed inconsistent results in salisphere formation and tumorigenic potential assays when different cell lines were evaluated. Collectively, these data demonstrate that salivary gland mucoepidermoid carcinomas contain a small population of cancer stem cells with enhanced tumorigenic potential and that are characterized by high ALDH activity and CD44 expression. These results suggest that patients with mucoepidermoid carcinoma might benefit from therapies that ablate these highly tumorigenic cells.
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors.forename: April
authors.initials: A
authors.lastname: Adams
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Warner
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.|Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Pearson
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors.forename: Zhaocheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors.forename: Hong Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors.forename: Daiki
authors.initials: D
authors.lastname: Mochizuki
authors.affiliation: Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Basura
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Helman
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.|Department of Oral Pathology, University of Sao Paulo School of Dentistry, São Paulo, Brazil, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mantesso
authors.affiliation: Department Periodontics Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors.forename: Rogério M
authors.initials: RM
authors.lastname: Castilho
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.|Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.|Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D018277:Carcinoma, Mucoepidermoid / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D012468:Salivary Gland Neoplasms / Q000378:metabolism*
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D015260:Neprilysin
keywords: multipotency; salivary gland cancer; self-renewal; tumor initiating cells; tumorigenesis