Efficacy assessment of interferon-alpha-engineered mesenchymal stromal cells in a mouse plasmacytoma model.
Bone marrow mesenchymal stromal cells (BM-MSCs) may survive and proliferate in the presence of cycling neoplastic cells. Exogenously administered MSCs are actively incorporated in the tumor as stromal fibroblasts, thus competing with the local mesenchymal cell precursors. For this reason, MSCs have been suggested as a suitable carrier for gene therapy strategies, as they can be genetically engineered with genes encoding for biologically active molecules that can inhibit tumor cell proliferation and enhance the antitumor immune response. We used BM-MSCs engineered with the murine interferon-alpha (IFN-α) gene (BM-MSCs/IFN-α) to assess in a mouse plasmacytoma model the efficacy of this approach toward neoplastic plasma cells. We found that IFN-α can be efficiently produced and delivered inside the tumor microenvironment. Subcutaneous multiple administration of BM-MSCs/IFN-α significantly hampered the tumor growth in vivo and prolonged the overall survival of mice. The antitumor effect was associated with enhanced apoptosis of tumor cells, reduction in microvessel density, and ischemic necrosis. By contrast, intravenous administration of BM-MSCs/IFN-α did not significantly modify the survival of mice, mainly as a consequence of an excessive entrapment of injected cells in the pulmonary vessels. In conclusion, BM-MSCs/IFN-α are effective in inhibiting neoplastic plasma cell growth; however, systemic administration of engineered MSCs needs to be improved to make this approach potentially suitable for the treatment of multiple myeloma.
Sartoris
Silvia
S
Department of Pathology and Diagnostics, University of Verona, Verona, Italy. silvia.sartoris@univr.it
Mazzocco
Marta
M
Tinelli
Martina
M
Martini
Matteo
M
Mosna
Federico
F
Lisi
Veronica
V
Indraccolo
Stefano
S
Moserle
Lidia
L
Cestari
Tiziana
T
Riviera
Anna Pia
AP
Bifari
Francesco
F
Tridente
Giuseppe
G
Pizzolo
Giovanni
G
Krampera
Mauro
M
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D015316:Genetic Therapy; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy; D010950:Plasma Cells / Q000473:pathology; D010954:Plasmacytoma / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins / Q000378:metabolism; D018800:Thy-1 Antigens / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D016898:Interferon-alpha; D011994:Recombinant Proteins; D018800:Thy-1 Antigens