The administration of multipotent stromal cells at precancerous stage precludes tumor growth and epithelial dedifferentiation of oral squamous cell carcinoma

Abstract

Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3×10 allogenic bone marrow-derived MSCs were locally administered. Four weeks later, the lesions were studied according to: volume, stratification (histology), proliferation (Ki-67), apoptosis (Caspase 3 cleaved), vasculature (ASMA), inflammation (Leukocyte infiltrate), differentiation (CK1 and CK4) and gene expression profile (mRNA). Tumors found in individuals that received MSCs were smaller than those presented in the vehicle group (87±80 versus 54±62mm, p<0.05). The rate of proliferation was two times lower and the apoptosis was 2.5 times higher in lesions treated with MSCs than in untreated ones. While the laters presented dedifferentiated cells, the former maintained differentiated cells (cytokeratin and gene expression profile similar to normal tissue). Thus, MSC administration at papilloma stage precludes tumor growth and epithelial dedifferentiation of OSCC.

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

“…As tumor growth restriction was not an expected outcome of the present work, our original study design did not consider exploration of the putative mechanisms behind it. Previously, we showed that local administration of allogeneic MSCs at dysplasia or papilloma stage precludes OSCC tumor growth (unpublished results, [ 19 ]). While at dysplasia stage MSCs impede mast cell infiltration and diminish tissue vascularization, at papilloma stage donor cells diminish proliferation, increase apoptosis, and reduce epithelial dedifferentiation.…”

“…Images were captured with a digital camera (DFC295; Leica). Samples were classified as hyperplasia, dysplasia, papilloma, or carcinoma as described previously [ 18 , 19 ].…”

“…The aim of our work 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. For this, we used a preclinical model of oral squamous cell carcinoma (OSCC) that reproduces the etiology, malignant features, and dynamics of human oral epithelial tumors [ 18 , 19 ].…”

SPINK7 Expression Changes Accompanied by HER2, P53 and RB1 may be Potential Biomarkers to Predict Oral Squamous Cell Carcinoma at Molecular Level

“…Samples were classified according to the revised criteria given by the World Health Organization (2005). Three independent observers performed histological analyses blind; one of them is a pathologist expert in oral diseases (42,43).…”

“…Five representative optical sections by sample (n=6/group) were photographed using 60X magnification. The images obtained per field of each sample, were processed with the same conditions and the positive protein signal (pixels intensity) was analyzed and quantified using Fiji Image J software (NIH, USA) (42,43).…”