title: Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation.
abstract: The transplantation of human cancer cells into immunodeficient NOD/SCID/IL-2Rγc(null) (NOG) mice often causes highly malignant cell populations like cancer stem cells to emerge. Here, by serial transplantation in NOG mice, we established two highly tumorigenic adult T-cell leukemia-derived cell lines, ST1-N6 and TL-Om1-N8. When transplanted s.c., these cells formed tumors significantly earlier and from fewer initial cells than their parental lines ST1 and TL-Om1. We found that protein kinase B (AKT) signaling was upregulated in ST1-N6 and TL-Om1-N8 cells, and that this upregulation was due to the decreased expression of a negative regulator, INPP5D. Furthermore, the introduction of a constitutively active AKT mutant expression vector into ST1 cells augmented the tumorigenicity of the cells, whereas treatment with the AKT inhibitor MK-2206 attenuated the progression of tumors induced by ST1-N6 cells. Collectively, our results reveal that the AKT signaling pathway plays a critical role in the malignancy of adult T-cell leukemia-derived cells.
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.|Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Takanashi
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.|Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nasu
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamai
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.|Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Mochizuki
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Pathology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Satoh
authors.affiliation: Division of Hematology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ine
authors.affiliation: Division of Hematology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sasaki
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Cancer Stem Cells, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; C000715470:MAS1 protein, human; C000606430:INPP5D protein, human
keywords: Adult T-cell leukemia; proto-oncogene protein Akt; severe combined immunodeficient mice; tumor-initiating cells; xenotransplantation