Oral-specific microenvironments regulate cell behavior and anticancer drug sensitivity of tongue squamous cell carcinoma

Squamous cell carcinoma (SCC) is the most major malignant tumor of the tongue. The tongue exists at the air-liquid interface and is covered with saliva. In addition, the tongue constituent cells and tongue cancer are present under fluid flow stimulation due to the abundant capillary network and contraction of muscle tissue. Therefore, replicating both cell-cell interactions (the cellular microenvironment) and the aforementioned physical microenvironment is very important for understanding the kinetics of tongue SCC. To elucidate the effects of the cellular and physical microenvironment on tongue SCC and to investigate the relationships between these factors, we developed a collagen cell disc, with double dish under a rotational culture method to generate cancer-stroma interactions and to create fluid flow stimulation. Mesenchymal cells, NIH-3T3 cells and tongue-derived fibroblasts influenced the proliferative potential. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by cellular interactions and fluid flow stimulation, depending on the SCC cell type. The cell-cell interactions and fluid flow stimulation independently, synergistically or contradictorily affected the behavior of tongue SCC. Fluid flow stimulation synergistically enhanced the antiproliferative effect of cis-diamminedichloroplatinum on tongue SCC cells, but mesenchymal cells abolished the synergistic antiproliferative effect related to fluid flow stimulation. In conclusion, a reconstructed model was established to investigate the cellular and physical microenvironments of tongue SCC in vitro. The newly established system is a promising model for the development of further regimes to treat general oral cancer.

Automated summary

Squamous cell carcinoma (SCC) is the most common malignant tumor of the tongue, and understanding the cellular and physical microenvironments of tongue SCC is important. In this study, a collagen cell disc was developed to simulate cancer-stroma interactions and fluid flow stimulation in vitro. The behavior of tongue SCC was found to be influenced by cell-cell interactions and fluid flow stimulation, with the latter enhancing the anti-proliferative effect of cisplatin on SCC cells. The newly established model could be a promising tool for studying tongue SCC and developing treatment strategies for oral cancer.