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

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.