Mesenchymal stem cells derived from normal gingival tissue inhibit the proliferation of oral cancer cells in vitro and in vivo

Abstract

The interplay between tumor cells and mesenchymal stem cells (MSCs) within tumor microenvironment plays a significant role in tumor development, and thus might be exploited for therapeutic intervention. In this study, we isolated MSCs from normal gingival tissue (GMSCs), and detected the effect of GMSCs on oral cancer cells via direct co-culture and indirect co-culture systems. The cell proliferation assay of direct co-culture showed that GMSCs could inhibit the growth of oral cancer cells. Conditioned medium derived from GMSCs (GMSCs-CM) also exerted an anticancer effect, which indicates that soluble factors in GMSCs-CM played a dominant role in GMSCs-induced cancer cell growth inhibition. To investigate the mechanism, we performed apoptosis assay by flow cytometry, and confirmed that cancer cell apoptosis induced by GMSCs could be a reason for the effect of GMSCs on the growth of oral cancer cells. Western blotting also confirmed that GMSCs could upregulate expression of pro-apoptotic genes including p-JNK, cleaved PARP, cleaved caspase-3, Bax expression and downregulate proliferation- and anti-apoptosis-related gene expression such as p-ERK1/2, Bcl-2, CDK4, cyclin D1, PCNA and survivin. Importantly, the inhibitory effect of GMSCs on cancer cells can partially be restored by blockade of JNK pathway. Moreover, animal studies showed that GMSCs exerted an anticancer effect after oral cancer cells and GMSCs were co-injected with oral cancer cells. Taken together, our data suggest that GMSCs can suppress oral cancer cell growth in vitro and in vivo via altering the surrounding microenvironment of oral cancer cells, which indicates that GMSCs have a potential use in the management of oral dysplasia and oral cancer in future.

Oral mucosal mesenchymal stem cell‑derived exosomes: A potential therapeutic target in oral premalignant lesions

“…Human MSCs were isolated and identified according to a previous study (26). Briefly, the primary tissues were treated by dispase (2 mg/ml; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) in sterile PBS and the mesenchyme part was separated and cut into 2 mm 3 , and then cultured in a 60-mm dish in MSC medium (Sciencell Research Laboratories, Inc., San Diego, CA, USA) for 5-7 days at 37°C.…”

Stemness Potency of Human Gingival Cells—Application in Anticancer Therapies and Clinical Trials

“…The reason of such discrepancies in terms of MSCs influence on cancer is probably due to the fact that MSCs from different sources may exert various effects on cancer cells. Ji et al [62] suggested that MSCs for anticancer therapy should be derived from the same tissue/organ origin as tumor cells and that they would restore altered homeostasis, exerting anticancer effect.…”

“…Moreover, up to 30% of patients with TSCC exhibit metastatic lesions in the lymph nodes, even without the clinical signs of metastasis [64], clearly suggesting that another approaches must be undertaken to enhance the efficiency of cancer treatment. Ji et al [62] cocultured GMSCs with two oral cancer cell lines-CAL27 and WSU-HN6, revealing that MSCs inhibited oral cancer cell growth in vitro. Moreover, their conditioned medium exerted the same effect, suggesting that soluble factors secreted by GMSCs (including IL-6, IL-8, and GM-CSF) may be responsible for such antiproliferative properties.…”

“…Additionally, Western blotting revealed that GMSCs downregulated the proliferation-related gene expression in cancer cells (Bcl-2 and survivin), while upregulating apoptosis-related genes (Bax, cleaved caspase-3, and PARP). It was also suggested that GMSCs' conditioned medium deactivated the JNK, ERK, and STAT3 pathways associated with proliferation [62].…”

The Potential of Different Origin Stem Cells in Modulating Oral Bone Regeneration Processes

“…A recent study has demonstrated that MSCs derived from normal gingival tissue secrete soluble factors which inhibit the development of oral cancer. At the molecular level, overexpression of the pro-apoptotic genes p-JNK, cleaved PARP, cleaved caspase-3 and Bax was observed and down-regulation of anti-apoptotic genes: p-ERK1/2, Bcl-2, CDK4, cyclin D1, PCNA and survivin [105].…”