title: Induction of cancerous stem cells during embryonic stem cell differentiation.
abstract: Stem cell maintenance depends on their surrounding microenvironment, and aberrancies in the environment have been associated with tumorigenesis. However, it remains to be elucidated whether an environmental aberrancy can act as a carcinogenic stress for cellular transformation of differentiating stem cells into cancer stem cells. Here, utilizing mouse embryonic stem cells as a model, it was illustrated that environmental aberrancy during differentiation leads to the emergence of pluripotent cells showing cancerous characteristics. Analogous to precancerous stages, DNA lesions were spontaneously accumulated during embryonic stem cell differentiation under aberrational environments, which activates barrier responses such as senescence and apoptosis. However, overwhelming such barrier responses, piled-up spheres were subsequently induced from the previously senescent cells. The sphere cells exhibit aneuploidy and dysfunction of the Arf-p53 module as well as enhanced tumorigenicity and a strong self-renewal capacity, suggesting development of cancerous stem cells. Our current study suggests that stem cells differentiating in an aberrational environment are at risk of cellular transformation into malignant counterparts.
authors.affiliation: Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.forename: Mima
authors.initials: M
authors.lastname: Shikanai
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Teraoka
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshioka
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence; D003470:Culture Media; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010455:Peptides / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D003470:Culture Media; D006023:Glycoproteins; D010455:Peptides; D016159:Tumor Suppressor Protein p53