Effects of LPA receptor-mediated signaling on the modulation of cellular functions of pancreatic cancer cells cultured in fibroblast supernatants under hypoxic conditions.

The tumor microenvironment (TME) consists of various cell types, including fibroblasts. The TME plays a central role in the promotion of tumor progression. In the present study, we investigated whether lysophosphatidic acid (LPA) receptor-mediated signaling regulates cellular functions by the TME of pancreatic cancer PANC-1 cells. To obtain fibroblast 3T3 cell supernatants, 3T3 cells were cultured in 5% charcoal stripped FCS-DMEM for 48 h. LPAR2 and LPAR3 expression levels were elevated in PANC-1 cells cultured in 3T3 cell supernatants. While PANC-1 cell motility was decreased by 3T3 cell supernatants, the cell survival to cisplatin (CDDP) of PANC-1 cells was markedly enhanced. Moreover, the cell survival to CDDP of PANC-1 cells cultured in 3T3 cell supernatants was increased by GRI-977,143 (LPA₂ agonist) and (2 S)-OMPT (LPA₃ agonist). Since hypoxia is caused by the restriction of adequate vascular networks to deliver oxygen into solid tumors, PANC-1 cells were cultured in 3T3 cell supernatants at 1% O₂ conditions. The cell survival to CDDP of PANC-1 cells cultured in 3T3 cell supernatants at 1% O₂ was significantly elevated, correlating with LPAR2 and LPAR3 expressions. These results suggest that LPA signaling via LPA₂ and LPA₃ is involved in the promotion of malignant properties by the TME in PANC-1 cells.