Kusumoto Yuka, Nagano Shion, Tamura Moemi, Shimomura Nanami, Yashiro Narumi, Yamamoto Mao, Takai Miwa, Tsujiuchi Toshifumi
Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan.
Cell Biochem Biophys. 2025 Jul 10. doi: 10.1007/s12013-025-01828-w.
Lysophosphatidic acid (LPA) receptors (LPA to LPA) are implicated in cancer pathogenesis. Stromal cells within the tumor microenvironment contribute to the malignant progression of cancer cells. Given that stromal cells can contribute to the malignant behavior of tumor cells, this study investigated the role of LPA receptor-mediated signaling in modulating stromal cell-induced cancer cell growth. Lung cancer A549 cells were co-cultured with lymphatic endothelial SVEC4-10 cells and/or fibroblast 3T3 cells, or cultured in their respective supernatant. Co-culture with SVEC4-10 and/or 3T3 cells altered the expression of LPAR1, LPAR2, and LPAR5 genes in A549 cells. LPA enhanced A549 cell growth in the supernatant derived from co-cultured SVEC4-10 and 3T3 cells, exceeding the effects observed in the supernatant from SVEC4-10 or 3T3 cells alone. A549 cell growth was suppressed by AM966 (LPA antagonist) and TC LPA5 4 (LPA antagonist), and promoted by GRI-977143 (LPA agonist). Autotaxin (ATX) expression was upregulated in A549 cells co-cultured with SVEC4-10 and/or 3T3 cells, and lysophosphatidylcholine (LPC) treatment enhanced A549 cell growth in the co-culture supernatant of both cell types. Mouse lung cancer LL/2 cells also showed increased growth in response to LPA when cultured with the co-culture supernatant, and this effect was inhibited by AM966 and TC LPA5 4, and promoted by GRI-977143. These findings suggest that co-culture of SVEC4-10 and 3T3 cells more effectively promotes lung cancer cell growth through LPA receptor signaling than either cell type alone.
溶血磷脂酸（LPA）受体（从LPA1到LPA6）与癌症发病机制有关。肿瘤微环境中的基质细胞有助于癌细胞的恶性进展。鉴于基质细胞可促成肿瘤细胞的恶性行为，本研究调查了LPA受体介导的信号传导在调节基质细胞诱导的癌细胞生长中的作用。肺癌A549细胞与淋巴管内皮SVEC4-10细胞和/或成纤维细胞3T3细胞共培养，或在它们各自的上清液中培养。与SVEC4-10和/或3T3细胞共培养改变了A549细胞中LPAR1、LPAR2和LPAR5基因的表达。LPA增强了来自共培养的SVEC4-10和3T3细胞的上清液中A549细胞的生长，超过了单独在SVEC4-10或3T3细胞的上清液中观察到的效果。A549细胞的生长受到AM966（LPA拮抗剂）和TC-LPA5-4（LPA拮抗剂）的抑制，并受到GRI-977143（LPA激动剂）的促进。自分泌运动因子（ATX）的表达在与SVEC4-10和/或3T3细胞共培养的A549细胞中上调，溶血磷脂酰胆碱（LPC）处理增强了两种细胞类型共培养上清液中A549细胞的生长。小鼠肺癌LL/2细胞在用共培养上清液培养时对LPA的反应也显示出生长增加，并且这种作用受到AM966和TC-LPA5-4的抑制，并受到GRI-977143的促进。这些发现表明，与单独的任何一种细胞类型相比，SVEC4-10和3T3细胞的共培养通过LPA受体信号传导更有效地促进肺癌细胞生长。
