Laboratory of Angiology, Vascular Biology and Inflammation, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain.
J Lipid Res. 2012 Apr;53(4):630-42. doi: 10.1194/jlr.M019695. Epub 2012 Feb 4.
Prostaglandin (PG)E(2) is relevant in tumor biology, and interactions between tumor and stroma cells dramatically influence tumor progression. We tested the hypothesis that cross-talk between head and neck squamous cell carcinoma (HNSCC) cells and fibroblasts could substantially enhance PGE(2) biosynthesis. We observed an enhanced production of PGE(2) in cocultures of HNSCC cell lines and fibroblasts, which was consistent with an upregulation of COX-2 and microsomal PGE-synthase-1 (mPGES-1) in fibroblasts. In cultured endothelial cells, medium from fibroblasts treated with tumor cell-conditioned medium induced in vitro angiogenesis, and in tumor cell induced migration and proliferation, these effects were sensitive to PGs inhibition. Proteomic analysis shows that tumor cells released IL-1, and tumor cell-induced COX-2 and mPGES-1 were suppressed by the IL-1-receptor antagonist. IL-1α levels were higher than those of IL-1β in the tumor cell-conditioning medium and in the secretion from samples obtained from 20 patients with HNSCC. Fractionation of tumor cell-conditioning media indicated that tumor cells secreted mature and unprocessed forms of IL-1. Our results support the concept that tumor-associated fibroblasts are a relevant source of PGE(2) in the tumor mass. Because mPGES-1 seems to be essential for a substantial biosynthesis of PGE(2), these findings also strengthen the concept that mPGES-1 may be \a target for therapeutic intervention in patients with HNSCC.
前列腺素(PG)E(2)与肿瘤生物学有关,肿瘤细胞与基质细胞之间的相互作用会显著影响肿瘤的进展。我们检验了这样一个假设,即头颈部鳞状细胞癌(HNSCC)细胞与成纤维细胞之间的串扰可以显著增强 PGE(2)的生物合成。我们观察到头颈部鳞状细胞癌细胞系和成纤维细胞的共培养物中 PGE(2)的产生明显增加,这与成纤维细胞中 COX-2 和微粒体 PGE-合酶-1(mPGES-1)的上调一致。在培养的内皮细胞中,来自用肿瘤细胞条件培养基处理的成纤维细胞的培养基在体外诱导血管生成,并诱导肿瘤细胞迁移和增殖,这些作用对 PG 抑制敏感。蛋白质组学分析表明,肿瘤细胞释放了白细胞介素 1(IL-1),并且肿瘤细胞诱导的 COX-2 和 mPGES-1 被白细胞介素 1 受体拮抗剂抑制。肿瘤细胞条件培养基中的 IL-1α 水平高于 IL-1β,并且在来自 20 名 HNSCC 患者的样本中分泌的水平也高于 IL-1β。肿瘤细胞条件培养基的分级表明,肿瘤细胞分泌成熟和未加工形式的 IL-1。我们的研究结果支持这样一个概念,即肿瘤相关成纤维细胞是肿瘤组织中 PGE(2)的一个相关来源。由于 mPGES-1 似乎对于 PGE(2)的大量生物合成是必不可少的,因此这些发现也加强了 mPGES-1 可能成为 HNSCC 患者治疗干预的一个目标的概念。