title: Anchorage-dependent multicellular aggregate formation induces CD44 high cancer stem cell-like ATL cells in an NF-κB- and vimentin-dependent manner.
abstract: Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy accompanied by massive invasion of lymphoma cells into various tissues. We demonstrate here that ATL cells cultured on a layer of epithelial-like feeder cells form anchorage-dependent multicellular aggregates (Ad-MCAs) and that a fraction of MCA-forming ATL cells acquire CD44 high cancer stem cell-like phenotypes. ATL cells forming Ad-MCAs displayed extracellular microvesicles with enhanced expression of CD44v9 at cell synapses, augmented expression of multidrug resistance protein 1, and increased NF-κB activity. Blockade of the NF-κB pathway dramatically reduced Ad-MCA formation by ATL cells and the emergence of CD44 high ATL cells, but left a considerable number of ATL cells adhering to the feeder layer. Disruption of vimentin cytoskeleton by treatment with withaferin A, a natural steroidal lactone, suppressed not only the adhesion of ATL cells to the feeder layer but also subsequent Ad-MCA formation by ATL cells, suggesting the involvement of vimentin in anchoring ATL cells to the feeder layer. Ad-MCA formation by ATL cells on a layer of epithelial-like feeder cells may mimic critical events that occur in metastatic colonization.
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland. Electronic address: yukimiya@med.hokudai.ac.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyatake
authors.affiliation: Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
authors.forename: Noreen
authors.initials: N
authors.lastname: Sheehy
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Ikeshita
authors.affiliation: Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
authors.forename: William W
authors.initials: WW
authors.lastname: Hall
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kasahara
mesh_terms: D017209:Apoptosis / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000378:metabolism*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D014746:Vimentin
keywords: CD44; Cancer stem cells; Coculture; Vimentin, ATL