title: Protective roles of epithelial cells in the survival of adult T-cell leukemia/lymphoma cells.
abstract: Adult T-cell leukemia/lymphoma (ATL) is a highly invasive and intractable T-cell malignancy caused by human T-cell leukemia virus-1 infection. We demonstrate herein that normal tissue-derived epithelial cells (NECs) exert protective effects on the survival of leukemic cells, which may partially account for high resistance to antileukemic therapies in patients with ATL. Viral gene-silenced, ATL-derived cell lines (ATL cells) dramatically escaped from histone deacetylase inhibitor-induced apoptosis by direct co-culture with NECs. Adhesions to NECs suppressed p21(Cip1) expression and increased a proportion of resting G0/G1 phase cells in trichostatin A (TSA)-treated ATL cells. ATL cells adhering to NECs down-regulated CD25 expression and enhanced vimentin expression, suggesting that most ATL cells acquired a quiescent state by cell-cell interactions with NECs. ATL cells adhering to NECs displayed highly elevated expression of the cancer stem cell marker CD44. Blockade of CD44 signaling diminished the NEC-conferred resistance of ATL cells to TSA-induced apoptosis. Co-culture with NECs also suppressed the expression of NKG2D ligands on TSA-treated ATL cells, resulting in decreased natural killer cell-mediated cytotoxicity. Combined evidence suggests that interactions with normal epithelial cells augment the resistance of ATL cells to TSA-induced apoptosis and facilitate immune evasion by ATL cells.
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. yukimiya@med.hokudai.ac.jp
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyatake
authors.forename: André L A
authors.initials: AL
authors.lastname: Oliveira
authors.forename: Mohamed Ali
authors.initials: MA
authors.lastname: Jarboui
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ota
authors.forename: Utano
authors.initials: U
authors.lastname: Tomaru
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.forename: William W
authors.initials: WW
authors.lastname: Hall
authors.forename: Masanori
authors.initials: M
authors.lastname: Kasahara
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: D056572:Histone Deacetylase Inhibitors; D018960:Hyaluronan Receptors; D006877:Hydroxamic Acids; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; C012589:trichostatin A