The role of LPA receptor signaling in modulating cellular responses of colon cancer cells co-cultured with lymphoid endothelial cells under hypoxic stress

Abstract

Solid tumors are formed by cancer cells and the surrounding non-cancer stromal cells under hypoxic conditions, collectively referred to as the tumor microenvironment (TME). Lysophosphatidic acid (LPA) receptor (LPA1 to LPA6) signaling is crucial in regulating tumor progression. This study investigated the impact of LPA receptor signaling on the biological behaviors of colon cancer DLD-1 cells co-cultured with lymphatic endothelial SVEC4–10 cells under hypoxic conditions. Expression levels of LPAR1, LPAR2 and LPAR5 genes were significantly higher in DLD-1 cells co-cultured with SVEC4–10 cells compared to those cultured alone. Co-culturing with SVEC4–10 cells increased the motility of DLD-1 cells at 21 % O2. LPA stimulated the motility of DLD-1 cells co-cultured with SVEC4–10 cells but had no effect on DLD-1 cells cultured alone. Furthermore, under 1 % O2 conditions, expression levels of LPAR1, LPAR2, and LPAR5 genes were markedly elevated in DLD-1 cells co-cultured with SVEC4–10 cells compared to 21 % O2. The motility of DLD-1 cells co-cultured with SVEC4–10 cells was enhanced under 1 % O2 conditions. Viability of DLD-1 cells to fluorouracil (5-FU) in SVEC4–10 cell supernatants increased at 21 % O2 and decreased at 1 % O2. Additionally, the LPA2 agonist GRI-977143 increased viability to 5-FU. These findings indicate that LPA receptor signaling plays a critical role in regulating the biological behaviors of DLD-1 cells co-cultured with SVEC4–10 cells under hypoxic conditions.