Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation

Gro Vatne Røsland, Agnete Svendsen, Anja Torsvik, Ewa Sobala, Emmet McCormack, Heike Immervoll, Josef Mysliwietz, Joerg Christian Tonn, Roland Goldbrunner, Per Eystein Lønning, Rolf Bjerkvig*, Christian Schichor

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

541 Citations (Scopus)

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 fastgrowing 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.

Original languageEnglish
Pages (from-to)5331-5339
Number of pages9
JournalCancer Research
Volume69
Issue number13
DOIs
Publication statusPublished - 1 Jul 2009
Externally publishedYes

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