title: In vitro transformation of mesenchymal stem cells by oncogenic H-rasVal12.
abstract: Tissue stem cells may serve as progenitors for malignant tumors derived from the same tissue. Here, we report the establishment of immortalized human mesenchymal stem cells (ihMSC) and tested the feasibility of using ihMSC as presarcomatous cells. Immortalization was achieved by introducing the genes for human telomerase reverse transcriptase and Bmi1. ihMSC retained the potential for multi-directional differentiation of the original MSC. To transform ihMSC, we introduced an oncogenic H-ras(Val12) gene, and established the cell line ihMSC-ras. ihMSC-ras had the phenotype of fully transformed cells and retained adipogenic and chondrogenic, but not osteogenic, potential. Interestingly, ihMSC-ras demonstrated morphological features of autophagy, and inhibition of the ERK pathway suppressed the production of autophagosomes, indicating that ras/ERK signaling is responsible for the induction of autophagy. Thus ihMSC will serve as a material with which to analyze the tumorigenic and differentiation-modifying effects of candidate oncogenes involved in the development of sarcomas.
authors.affiliation: Institute for Frontier Medical Sciences, Kyoto University, Shogoin, Kyoto 606-8507, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Shima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okamoto
authors.forename: Tomoki
authors.initials: T
authors.lastname: Aoyama
authors.forename: Ko
authors.initials: K
authors.lastname: Yasura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishibe
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishijo
authors.forename: Kotaro R
authors.initials: KR
authors.lastname: Shibata
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kohno
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fukiage
authors.forename: Seiji
authors.initials: S
authors.lastname: Otsuka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uejima
authors.forename: Tomitaka
authors.initials: T
authors.lastname: Nakayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018631:ras Proteins