Abstract
BackgroundMesenchymal 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.MethodsOral 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 × 106, 7 × 106, or 21 × 106 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.ResultsPrecancerous 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 × 106 or 7 × 106 MSCs/kg at hyperplasia stage were significantly smaller than those found in control animals (25 ± 4 or 23 ± 4 mm3 versus 72 ± 19 mm3, p < 0.05). Similar results were obtained when 0.7 × 106, 7 × 106, or 21 × 106 MSCs/kg were administered at papilloma stage (44 ± 15, 28 ± 7, or 28 ± 5 mm3 versus 104 ± 26 mm3, p < 0.05). For dysplasia stage, only the lower concentration of MSCs reached statistical significance (21 ± 9 mm3 versus 94 ± 39 mm3, p < 0.05). Animals receiving 21 × 106 MSCs/kg at hyperplasia stage developed tumors larger than those found in animals that received the vehicle (147 ± 47 mm3 versus 72 ± 19 mm3, p < 0.05). Donor cells were rarely found in precancerous lesions.ConclusionsSystemically administered allogeneic MSCs do not aggravate the progression of precancerous lesions. Moreover, they preclude cancer progression and tumor growth.
Highlights
Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal cells currently tested for multiple therapeutic purposes
Administered allogeneic MSCs do not accelerate the progression of precancerous lesions Four weeks after the first DMBA exposure, buccal pouches of animals that received the vehicle were retracted, and erythroplakia, leukoplakia, or both were evident (Fig. 2)
Four weeks later (13 weeks after the first DMBA exposure), buccal pouches retracted and stiffened, presenting features of necrosis and larger tumors. This time course was unchanged in animals receiving MSCs at hyperplasia (Fig. 2) or dysplasia (Fig. 3) stage
Summary
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. MSCs can be procured from living donors, can be efficiently expanded ex vivo [2], are hypoimmunogenic so a conditioning regimen is not required before their transplantation [3], home into injured tissues and tumors [4, 5], differentiate into tissue cells [6], secrete trophic factors [7], promote neovascularization [8], reduce oxidative stress [9], and modulate the immune response [10]. Results of clinical trials are promising, safety issues regarding MSC-based therapies are still unproven [12]
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