Systemically administered allogeneic mesenchymal stem cells do not aggravate the progression of precancerous lesions: a new biosafety insight

Background: Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal cells currently tested for multiple therapeutic purposes. Their potential to home into tumors, to secrete trophic/vasculogenic factors, and to suppress immune response raises questions regarding their biosafety. Our aim was to evaluate whether systemically administered allogeneic MSCs modify the natural progression of precancerous lesions and whether their putative effect depends on cancer stage and/or cell dose. Methods: Oral squamous cell carcinoma (OSCC) was induced in Syrian golden hamsters by topical application of 7,12-dimethylbenz[a] anthracene in one buccal pouch. At hyperplasia, dysplasia, or papilloma stage, animals received intracardially the vehicle or 0.7 x 10(6), 7 x 10(6), or 21 x 10(6) allogeneic bone marrow-derived MSCs/kg. OSCC progression was assessed according to the presence of erythroplakia and leukoplakia, extent of inflammation and vascularization, and appearance, volume, and staging of tumors. Also, the homing of donor cells was studied. Results: Precancerous lesions progressed from hyperplasia to dysplasia in 2 weeks, from dysplasia to papilloma in 3 weeks, and from papilloma to carcinoma in 4 weeks. This time course was unmodified by the systemic administration of MSCs at hyperplasia or dysplasia stages. When MSCs were administered at papilloma stage, lesions did not progress to carcinoma stage. Tumors developed in hamsters receiving 0.7 x 10(6) or 7 x 10(6) MSCs/kg at hyperplasia stage were significantly smaller than those found in control animals (25 +/- 4 or 23 +/- 4 mm(3) versus 72 +/- 19 mm(3), p < 0.05). Similar results were obtained when 0.7 x 10(6), 7 x 10(6), or 21 x 10(6) MSCs/kg were administered at papilloma stage (44 +/- 15, 28 +/- 7, or 28 +/- 5 mm(3) versus 104 +/- 26 mm(3), p < 0.05). For dysplasia stage, only the lower concentration of MSCs reached statistical significance (21 +/- 9 mm(3) versus 94 +/- 39 mm(3), p < 0.05). Animals receiving 21 x 10(6) MSCs/kg at hyperplasia stage developed tumors larger than those found in animals that received the vehicle (147 +/- 47 mm(3) versus 72 +/- 19 mm(3), p < 0.05). Donor cells were rarely found in precancerous lesions. Conclusions: Systemically administered allogeneic MSCs do not aggravate the progression of precancerous lesions. Moreover, they preclude cancer progression and tumor growth.