title: Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation.
abstract: Human mesenchymal stem cells (hMSC) aid in tissue maintenance and repair by differentiating into specialized cell types. Due to this ability, hMSC are currently being evaluated for cell-based therapies of tissue injury and degenerative diseases. However, extensive expansion ex vivo is a prerequisite to obtain the cell numbers required for human cell-based therapy protocols. Recent studies indicate that hMSC may contribute to cancer development and progression either by acting as cancer-initiating cells or through interactions with stromal elements. If spontaneous transformation ex vivo occurs, this may jeopardize the use of hMSC as therapeutic tools. Whereas murine MSC readily undergo spontaneous transformation, there are conflicting reports about spontaneous transformation of hMSC. We have addressed this controversy in a two-center study by growing bone marrow-derived hMSC in long-term cultures (5-106 weeks). We report for the first time spontaneous malignant transformation to occur in 45.8% (11 of 24) of these cultures. In comparison with hMSC, the transformed mesenchymal cells (TMC) showed a significantly increased proliferation rate and altered morphology and phenotype. In contrast to hMSC, TMC grew well in soft agar assays and were unable to undergo complete differentiation. Importantly, TMC were highly tumorigenic, causing multiple fast-growing lung deposits when injected into immunodeficient mice. We conclude that spontaneous malignant transformation may represent a biohazard in long-term ex vivo expansion of hMSC. On the other hand, this spontaneous transformation process may represent a unique model for studying molecular pathways initiating malignant transformation of hMSC.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen N-5009, Norway.
authors.forename: Gro Vatne
authors.initials: GV
authors.lastname: Røsland
authors.forename: Agnete
authors.initials: A
authors.lastname: Svendsen
authors.forename: Anja
authors.initials: A
authors.lastname: Torsvik
authors.forename: Ewa
authors.initials: E
authors.lastname: Sobala
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.forename: Heike
authors.initials: H
authors.lastname: Immervoll
authors.forename: Josef
authors.initials: J
authors.lastname: Mysliwietz
authors.forename: Joerg-Christian
authors.initials: JC
authors.lastname: Tonn
authors.forename: Roland
authors.initials: R
authors.lastname: Goldbrunner
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Christian
authors.initials: C
authors.lastname: Schichor
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000473:pathology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D012016:Reference Values; D013045:Species Specificity; D013997:Time Factors; D055815:Young Adult