In tumors, cancer cells coexist and communicate with macrophages that can promote tumorigenesis via pro-inflammatory signals. Lipid mediators (LMs), produced mainly by cyclooxygenases (COXs) or lipoxygenases (LOs), display a variety of biological functions with advantageous or deleterious consequences for tumors. Here, we investigated how the communication between human monocyte-derived M2-like macrophages (MDM) and cancer cells affects LM biosynthesis using LM metabololipidomics. Coculture of human MDM with human A549 epithelial lung carcinoma cells, separated by a semipermeable membrane, increased LM formation by MDM upon subsequent activation. Strongest effects were observed on 5-LO-derived LM. While expression of the 5-LO pathway was not altered, p38 MAPK and the downstream MAPKAPK-2 that phosphorylates and stimulates 5-LO were more susceptible for activation in MDM upon precedent coculture with A549 cells as compared to monocultures. Accordingly, the p38 MAPK inhibitor Skepinone-L selectively prevented this increase in 5-LO product formation. Also, 5-LO-/15-LO-derived LM including lipoxin A4, resolvin D2 and D5 were elevated after coculture with A549 cells, correlating to increased 15-LO-1 protein levels. In contrast to cancer cells, coincubation with non-transformed human umbilical vein endothelial cells (HUVEC) did not affect LM production in MDM. Vice versa, MDM increased COX-2 protein expression and COX-mediated prostanoid formation in cancer cells. Conclusively, our data reveal that the communication between MDM and cancer cells can strikingly modulate the biosynthetic capacities to produce bioactive LM with potential relevance for tumor biology.

中文翻译：

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人类巨噬细胞和上皮癌细胞系之间的通讯决定了脂质介质的生物合成。

在肿瘤中，癌细胞与巨噬细胞共存并交流，巨噬细胞可以通过促炎信号促进肿瘤发生。脂质介质 (LMs) 主要由环氧合酶 (COX) 或脂加氧酶 (LO) 产生，显示出多种生物学功能，对肿瘤具有有利或有害的后果。在这里，我们研究了人类单核细胞衍生的 M2 样巨噬细胞 (MDM) 和癌细胞之间的通讯如何使用 LM 代谢脂质组学影响 LM 生物合成。人 MDM 与人 A549 上皮肺癌细胞的共培养，由半透膜隔开，在随后的激活后增加了 MDM 的 LM 形成。在 5-LO 衍生的 LM 上观察到最强的影响。虽然 5-LO 通路的表达没有改变，与单培养相比，p38 MAPK 和下游的 MAPKAPK-2 磷酸化和刺激 5-LO 在与 A549 细胞共培养后更容易在 MDM 中激活。因此，p38 MAPK 抑制剂 Skepinone-L 选择性地阻止了 5-LO 产物形成的这种增加。此外，5-LO-/15-LO 衍生的 LM 包括脂氧素 A4、resolvin D2 和 D5 在与 A549 细胞共培养后升高，这与 15-LO-1 蛋白水平增加有关。与癌细胞相反，与未转化的人脐静脉内皮细胞 (HUVEC) 共培养不影响 MDM 中 LM 的产生。反之亦然，MDM 增加了癌细胞中 COX-2 蛋白的表达和 COX 介导的前列腺素形成。最后，