The objective of this study is to design a cancer invasion model based on an interaction between cancer cells and cancer-associated fibroblasts (CAF) aggregates. The strength of this study is to incorporate gelatin hydrogel microspheres (GM) containing pifithrin-α (PFT) of a p53 inhibitor (GM-PFT) with the CAF aggregates. Incorporation of GM-PFT allowed CAF aggregates to enhance the alpha-smooth muscle actin expression level at a high concentration of PFT. When the cancer cells were cocultured with the CAF aggregates incorporating GM-PFT, the invasion rate of cancer cells was significantly high compared with CAF aggregates or CAF aggregates incorporating GM with or without the same dose of free PFT as well as two-dimension cultured CAF with or without the same dose of PFT. In addition, an inhibitor of matrix metalloproteinase decreased the cancer invasion rate for the CAF aggregates incorporating GM-PFT. It is concluded that the interaction between cancer cells and CAF aggregates incorporating GM-PFT of biological activation needs to realize the invasion of cancer cells even in vitro. The strength of this study is to combine with a three-dimensional cell culture system and a drug delivery system technology for a cancer invasion model. The combination enabled cancer-associated fibroblasts to enhance the biological functions. This cancer invasion model is a promising tool to mimic the tumor microenvironment for anticancer drug screening.
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