Carcinogenesis Advance Access originally published online on October 9, 2008
Carcinogenesis 2009 30(1):150-157; doi:10.1093/carcin/bgn234
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Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds
1 Department of Oncology, Biology and Genetics, University of Genova
2 Laboratory of Regenerative Medicine, National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genova, Italy
3 Department of Pathology, Ospedale di Circolo, Viale Borri 57, 20121 Varese, Italy
4 Embryogenesis and Tumorigenesis in Animal Models, National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genova, Italy
5 Department of Experimental Medicine, University of Genova, Via Leon Battista Alberti 2, 16132 Genova, Italy
6 Department of Diagnostic Technologies, National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genova, Italy
7 Present address: Stem Cells Laboratory, Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genova, Italy
* To whom correspondence should be addressed. Tel: +39 010 5737511; Fax: +39 010 5737505; Email: pina.pennesi{at}istge.it
Bone marrow-derived mesenchymal stem cells (MSCs) are precursors of bone, cartilage and fat tissue. MSC can also regulate the immune response. For these properties, they are tested in clinical trials for tissue repair in combination with bioscaffolds or injected as cell suspension for immunosuppressant therapy. Experimental data, however, indicate that MSC can undergo or induce a tumorigenic process in determined circumstances. We used a modified model of ectopic bone formation in mice by subcutaneously implanting porous ceramic seeded with murine MSC. In this new model, host-derived sarcomas developed when we implanted MSC/bioscaffold constructs into syngeneic and immunodeficient recipients, but not in allogeneic hosts or when MSCs were injected as cell suspensions. The bioscaffold provided a tridimensional support for MSC to aggregate, thus producing the stimulus for triggering the process eventually leading to the transformation of surrounding cells and creating a surrogate tumor stroma. The chemical and physical characteristics of the bioscaffold did not affect tumor formation; sarcomas developed either when a stiff porous ceramic was used or when the scaffold was a smooth collagen sponge. The immunoregulatory function of MSC contributed to tumor development. Implanted MSC expanded clones of CD4+CD25+ T regulatory lymphocytes that suppressed host’s antitumor immune response.
Abbreviations: GFP-Tg, green fluorescent protein transgenic; FISH, fluorescence in situ hybridization; HA, hydroxyapatite; MSC, mesenchymal stem cell; s.c., subcutaneously; Treg, regulatory T lymphocyte
Received May 12, 2008; revised September 11, 2008; accepted October 3, 2008.