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Purpose Cancer cells are known to exhibit a cancer-associated fibroblast (CAF)-dependent invasive mode in the presence of CAFs. The purpose of this study was to investigate whether intrinsic factors of cancer cells influence the CAF-dependent invasive mode of cancer cells. Methods We observed the dynamic movement of CAFs and cancer cells by time-lapse imaging of 2-D and 3-D collagen invasion models and evaluated the invasion modes of gastric cancer cell lines (MKN-7, MKN-45, and HSC44PE). We further examined whether modification of the invasive capacity of CAFs can alter the invasive mode of MKN-7 and HSC44PE cells. Results When MKN-7 and MKN-45 were co-cultured with CAFs, CAFs first invade collagen matrix followed by cancer cells (CAF-dependent invasion), whereas HSC44PE invaded collagen matrix independently of CAFs invasion. Overexpression or suppression of podoplanin in CAFs, respectively increased or decreased the invasive capacity of CAFs themselves and significantly increased or decreased the number of invading MKN-7, respectively. CAFs overexpressing a podoplanin mutant lacking the cytoplasmic domain had a significantly reduced invasive capacity compared to CAFs overexpressing wild-type podoplanin, and it also reduced the number of invading MKN-7 cells significantly. When HSC44PE and CAFs were co-cultured, changes in the podoplanin expression in CAFs similarly altered the invasive capacity of CAFs themselves, but it did not affect the number of invading HSC44PE cells. Conclusion These results indicate that in the presence of CAFs, there are CAF-dependent and -independent modes of cancer cell invasion, the determinants of which may depend on the intrinsic properties of cancer cells. |
