Skip to main content

Advertisement

Log in

mPGES-1 and ALOX5/-15 in tumor-associated macrophages

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The tumor immune landscape gained considerable interest based on the knowledge that genetic aberrations in cancer cells alone are insufficient for tumor development. Macrophages are basically supporting all hallmarks of cancer and owing to their tremendous plasticity they may exert a whole spectrum of anti-tumor and pro-tumor activities. As part of the innate immune response, macrophages are armed to attack tumor cells, alone or in concert with distinct T cell subsets. However, in the tumor microenvironment, they sense nutrient and oxygen gradients, receive multiple signals, and respond to this incoming information with a phenotype shift. Often, their functional output repertoire is shifted to become tumor-supportive. Incoming and outgoing signals are chemically heterogeneous but also comprise lipid mediators. Here, we review the current understanding whereby arachidonate metabolites derived from the cyclooxygenase and lipoxygenase pathways shape the macrophage phenotype in a tumor setting. We discuss these findings in the context of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) expression and concomitant prostaglandin E2 (PGE2) formation. We elaborate the multiple actions of this lipid in affecting macrophage biology, which are sensors for and generators of this lipid. Moreover, we summarize properties of 5-lipoxygenases (ALOX5) and 15-lipoxygenases (ALOX15, ALOX15B) in macrophages and clarify how these enzymes add to the role of macrophages in a dynamically changing tumor environment. This review will illustrate the potential routes how COX-2/mPGES-1 and ALOX5/-15 in macrophages contribute to the development and progression of a tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Balkwill, F. R., Capasso, M., & Hagemann, T. (2012). The tumor microenvironment at a glance. Journal of Cell Science, 125, 5591–5596. https://doi.org/10.1242/jcs.116392.

    Article  PubMed  CAS  Google Scholar 

  2. Gentles, A. J., Newman, A. M., Liu, C. L., Bratman, S. V., Feng, W., Kim, D., et al. (2015). The prognostic landscape of genes and infiltrating immune cells across human cancers. Nature Medicine, 21, 938–945. https://doi.org/10.1038/nm.3909.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Fridman, W. H., Zitvogel, L., Sautès-Fridman, C., & Kroemer, G. (2017). The immune contexture in cancer prognosis and treatment. Nature Reviews. Clinical Oncology, 14, 717–734. https://doi.org/10.1038/nrclinonc.2017.101.

    Article  PubMed  CAS  Google Scholar 

  4. Tran, E., Robbins, P. F., & Rosenberg, S. A. (2017). 'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations. Nature Immunology, 18, 255–262. https://doi.org/10.1038/ni.3682.

    Article  PubMed  CAS  Google Scholar 

  5. Yarchoan, M., Johnson, B. A., Lutz, E. R., Laheru, D. A., & Jaffee, E. M. (2017). Targeting neoantigens to augment antitumour immunity. Nature Reviews. Cancer, 17, 209–222. https://doi.org/10.1038/nrc.2016.154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Lim, W. A., & June, C. H. (2017). The principles of engineering immune cells to treat cancer. Cell, 168, 724–740. https://doi.org/10.1016/j.cell.2017.01.016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Engblom, C., Pfirschke, C., & Pittet, M. J. (2016). The role of myeloid cells in cancer therapies. Nature Reviews. Cancer, 16, 447–462. https://doi.org/10.1038/nrc.2016.54.

    Article  PubMed  CAS  Google Scholar 

  8. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L., & Allavena, P. (2017). Tumour-associated macrophages as treatment targets in oncology. Nature Reviews. Clinical Oncology, 14, 399–416. https://doi.org/10.1038/nrclinonc.2016.217.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zheng, X., Turkowski, K., Mora, J., Brüne, B., Seeger, W., Weigert, A., & Savai, R. (2017). Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget, 8, 48436–48452. https://doi.org/10.18632/oncotarget.17061.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Klug, F., Prakash, H., Huber, P. E., Seibel, T., Bender, N., Halama, N., et al. (2013). Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell, 24, 589–602. https://doi.org/10.1016/j.ccr.2013.09.014.

    Article  PubMed  CAS  Google Scholar 

  11. Ruffell, B., Chang-Strachan, D., Chan, V., Rosenbusch, A., Ho, C. M. T., Pryer, N., et al. (2014). Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell, 26, 623–637. https://doi.org/10.1016/j.ccell.2014.09.006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Rath, M., Müller, I., Kropf, P., Closs, E. I., & Munder, M. (2014). Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Frontiers in Immunology, 5, 532. https://doi.org/10.3389/fimmu.2014.00532.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kuang, D.-M., Zhao, Q., Peng, C., Xu, J., Zhang, J.-P., Wu, C., & Zheng, L. (2009). Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. The Journal of Experimental Medicine, 206, 1327–1337. https://doi.org/10.1084/jem.20082173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 10, 942–949. https://doi.org/10.1038/nm1093.

    Article  PubMed  CAS  Google Scholar 

  15. Willingham, S. B., Volkmer, J.-P., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., et al. (2012). The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Sciences of the United States of America, 109, 6662–6667. https://doi.org/10.1073/pnas.1121623109.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Barkal, A. A., Weiskopf, K., Kao, K. S., Gordon, S. R., Rosental, B., Yiu, Y. Y., et al. (2018). Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nature Immunology, 19, 76–84. https://doi.org/10.1038/s41590-017-0004-z.

    Article  PubMed  CAS  Google Scholar 

  17. Gordon, S. R., Maute, R. L., Dulken, B. W., Hutter, G., George, B. M., McCracken, M. N., et al. (2017). PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 545, 495–499. https://doi.org/10.1038/nature22396.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. de, P. M., Biziato, D., & Petrova, T. V. (2017). Microenvironmental regulation of tumour angiogenesis. Nature Reviews. Cancer, 17, 457–474. https://doi.org/10.1038/nrc.2017.51.

    Article  CAS  Google Scholar 

  19. Weichand, B., Popp, R., Dziumbla, S., Mora, J., Strack, E., Elwakeel, E., et al. (2017). S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. The Journal of Experimental Medicine, 214, 2695–2713. https://doi.org/10.1084/jem.20160392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Liu, Y., & Cao, X. (2016). Characteristics and significance of the pre-metastatic niche. Cancer Cell, 30, 668–681. https://doi.org/10.1016/j.ccell.2016.09.011.

    Article  PubMed  CAS  Google Scholar 

  21. Franklin, R. A., & Li, M. O. (2016). Ontogeny of tumor-associated macrophages and its implication in cancer regulation. Trends Cancer, 2, 20–34. https://doi.org/10.1016/j.trecan.2015.11.004.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tymoszuk, P., Evens, H., Marzola, V., Wachowicz, K., Wasmer, M.-H., Datta, S., et al. (2014). In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors. European Journal of Immunology, 44, 2247–2262. https://doi.org/10.1002/eji.201344304.

    Article  PubMed  CAS  Google Scholar 

  23. Zhu, Y., Herndon, J. M., Sojka, D. K., Kim, K.-W., Knolhoff, B. L., Zuo, C., et al. (2017). Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity, 47, 597. https://doi.org/10.1016/j.immuni.2017.08.018.

    Article  PubMed  CAS  Google Scholar 

  24. Madsen, D. H., Jürgensen, H. J., Siersbæk, M. S., Kuczek, D. E., Grey Cloud, L., Liu, S., et al. (2017). Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake. Cell Reports, 21, 3662–3671. https://doi.org/10.1016/j.celrep.2017.12.011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Franklin, R. A., Liao, W., Sarkar, A., Kim, M. V., Bivona, M. R., Liu, K., et al. (2014). The cellular and molecular origin of tumor-associated macrophages. Science, 344, 921–925. https://doi.org/10.1126/science.1252510.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Qian, B.-Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L. R., et al. (2011). CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature, 475, 222–225. https://doi.org/10.1038/nature10138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Ries, C. H., Cannarile, M. A., Hoves, S., Benz, J., Wartha, K., Runza, V., et al. (2014). Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell, 25, 846–859. https://doi.org/10.1016/j.ccr.2014.05.016.

    Article  PubMed  CAS  Google Scholar 

  28. Cannarile, M. A., Weisser, M., Jacob, W., Jegg, A.-M., Ries, C. H., & Rüttinger, D. (2017). Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. Journal for Immunotherapy of Cancer, 5, 53. https://doi.org/10.1186/s40425-017-0257-y.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., et al. (2017). Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. https://doi.org/10.1136/gutjnl-2017-313738.

  30. Kumar, V., Donthireddy, L., Marvel, D., Condamine, T., Wang, F., Lavilla-Alonso, S., et al. (2017). Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell, 32, 654–668.e5. https://doi.org/10.1016/j.ccell.2017.10.005.

    Article  PubMed  CAS  Google Scholar 

  31. Biswas, S. K., & Mantovani, A. (2010). Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunology, 11, 889–896. https://doi.org/10.1038/ni.1937.

    Article  PubMed  CAS  Google Scholar 

  32. Müller, E., Christopoulos, P. F., Halder, S., Lunde, A., Beraki, K., Speth, M., et al. (2017). Toll-like receptor ligands and interferon-γ synergize for induction of antitumor M1 macrophages. Frontiers in Immunology, 8, 1383. https://doi.org/10.3389/fimmu.2017.01383.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436–444. https://doi.org/10.1038/nature07205.

    Article  PubMed  CAS  Google Scholar 

  34. Cooks, T., Pateras, I. S., Jenkins, L. M., Patel, K. M., Robles, A. I., Morris, J., et al. (2018). Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nature Communications, 9, 771. https://doi.org/10.1038/s41467-018-03224-w.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Cavnar, M. J., Zeng, S., Kim, T. S., Sorenson, E. C., Ocuin, L. M., Balachandran, V. P., et al. (2013). KIT oncogene inhibition drives intratumoral macrophage M2 polarization. The Journal of Experimental Medicine, 210, 2873–2886. https://doi.org/10.1084/jem.20130875.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Weigert, A., Mora, J., Sekar, D., Syed, S., Brüne, B., & Killing, I. (2016). Not enough: how apoptosis hijacks tumor-associated macrophages to promote cancer progression. Advances in Experimental Medicine and Biology, 930, 205–239. https://doi.org/10.1007/978-3-319-39406-0_9.

    Article  PubMed  CAS  Google Scholar 

  37. Gregory, C. D., & Paterson, M. (2018). An apoptosis-driven 'onco-regenerative niche': roles of tumour-associated macrophages and extracellular vesicles. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. https://doi.org/10.1098/rstb.2017.0003.

  38. Biswas, S. K. (2015). Metabolic reprogramming of immune cells in cancer progression. Immunity, 43, 435–449. https://doi.org/10.1016/j.immuni.2015.09.001.

    Article  PubMed  CAS  Google Scholar 

  39. Dehne, N., Mora, J., Namgaladze, D., Weigert, A., & Brüne, B. (2017). Cancer cell and macrophage cross-talk in the tumor microenvironment. Current Opinion in Pharmacology, 35, 12–19. https://doi.org/10.1016/j.coph.2017.04.007.

    Article  PubMed  CAS  Google Scholar 

  40. Laoui, D., Movahedi, K., van Overmeire, E., van den Bossche, J., Schouppe, E., Mommer, C., et al. (2011). Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. The International Journal of Developmental Biology, 55, 861–867. https://doi.org/10.1387/ijdb.113371dl.

    Article  PubMed  Google Scholar 

  41. Olesch, C., Sha, W., Angioni, C., Sha, L. K., Açaf, E., Patrignani, P., et al. (2015). MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. Oncotarget, 6, 10284–10296. https://doi.org/10.18632/oncotarget.3581.

    Article  PubMed  PubMed Central  Google Scholar 

  42. van Overmeire, E., Stijlemans, B., Heymann, F., Keirsse, J., Morias, Y., Elkrim, Y., et al. (2016). M-CSF and GM-CSF receptor signaling differentially regulate monocyte maturation and macrophage polarization in the tumor microenvironment. Cancer Research, 76, 35–42. https://doi.org/10.1158/0008-5472.CAN-15-0869.

    Article  PubMed  CAS  Google Scholar 

  43. Weigert, A., Schiffmann, S., Sekar, D., Ley, S., Menrad, H., Werno, C., et al. (2009). Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype. International Journal of Cancer, 125, 2114–2121. https://doi.org/10.1002/ijc.24594.

    Article  PubMed  CAS  Google Scholar 

  44. Helm, O., Held-Feindt, J., Grage-Griebenow, E., Reiling, N., Ungefroren, H., Vogel, I., et al. (2014). Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. International Journal of Cancer, 135, 843–861. https://doi.org/10.1002/ijc.28736.

    Article  PubMed  CAS  Google Scholar 

  45. Reinartz, S., Schumann, T., Finkernagel, F., Wortmann, A., Jansen, J. M., Meissner, W., et al. (2014). Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. International Journal of Cancer, 134, 32–42. https://doi.org/10.1002/ijc.28335.

    Article  PubMed  CAS  Google Scholar 

  46. Movahedi, K., Laoui, D., Gysemans, C., Baeten, M., Stangé, G., van den Bossche, J., et al. (2010). Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Research, 70, 5728–5739. https://doi.org/10.1158/0008-5472.CAN-09-4672.

    Article  PubMed  CAS  Google Scholar 

  47. Lavin, Y., Kobayashi, S., Leader, A., Amir, E.-A. D., Elefant, N., Bigenwald, C., et al. (2017). Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell, 169, 750–765.e17. https://doi.org/10.1016/j.cell.2017.04.014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Chevrier, S., Levine, J. H., Zanotelli, V. R. T., Silina, K., Schulz, D., Bacac, M., et al. (2017). An immune atlas of clear cell renal cell carcinoma. Cell, 169, 736–749.e18. https://doi.org/10.1016/j.cell.2017.04.016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kiss, M., van Gassen, S., Movahedi, K., Saeys, Y., & Laoui, D. (2018). Myeloid cell heterogeneity in cancer: not a single cell alike. Cellular Immunology. https://doi.org/10.1016/j.cellimm.2018.02.008.

  50. Hoves, S., Ooi, C.-H., Wolter, C., Sade, H., Bissinger, S., Schmittnaegel, M., et al. (2018). Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. The Journal of Experimental Medicine, 215, 859–876. https://doi.org/10.1084/jem.20171440.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Perry, C. J., Muñoz-Rojas, A. R., Meeth, K. M., Kellman, L. N., Amezquita, R. A., Thakral, D., et al. (2018). Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. The Journal of Experimental Medicine, 215, 877–893. https://doi.org/10.1084/jem.20171435.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Nagahashi, M., Yamada, A., Katsuta, E., Aoyagi, T., Huang, W.-C., Terracina, K. P., et al. (2018). Targeting the SphK1/S1P/S1PR1 axis that links obesity, chronic inflammation and breast cancer metastasis. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-17-1423.

  53. Liang, J., Nagahashi, M., Kim, E. Y., Harikumar, K. B., Yamada, A., Huang, W.-C., et al. (2013). Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell, 23, 107–120. https://doi.org/10.1016/j.ccr.2012.11.013.

    Article  PubMed  CAS  Google Scholar 

  54. Seo, M.-J., & Oh, D.-K. (2017). Prostaglandin synthases: molecular characterization and involvement in prostaglandin biosynthesis. Progress in Lipid Research, 66, 50–68. https://doi.org/10.1016/j.plipres.2017.04.003.

    Article  PubMed  CAS  Google Scholar 

  55. Alexanian, A., & Sorokin, A. (2017). Cyclooxygenase 2: protein-protein interactions and posttranslational modifications. Physiological Genomics, 49, 667–681. https://doi.org/10.1152/physiolgenomics.00086.2017.

    Article  PubMed  Google Scholar 

  56. Larsson, K., & Jakobsson, P.-J. (2015). Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostaglandins & Other Lipid Mediators, 120, 161–165. https://doi.org/10.1016/j.prostaglandins.2015.06.002.

    Article  CAS  Google Scholar 

  57. Sampey, A. V., Monrad, S., & Crofford, L. J. (2005). Microsomal prostaglandin E synthase-1: the inducible synthase for prostaglandin E2. Arthritis Research & Therapy, 7, 114–117. https://doi.org/10.1186/ar1748.

    Article  CAS  Google Scholar 

  58. Koeberle, A., & Werz, O. (2015). Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders. Biochemical Pharmacology, 98, 1–15. https://doi.org/10.1016/j.bcp.2015.06.022.

    Article  PubMed  CAS  Google Scholar 

  59. Xiao, L., Ornatowska, M., Zhao, G., Cao, H., Yu, R., Deng, J., et al. (2012). Lipopolysaccharide-induced expression of microsomal prostaglandin E synthase-1 mediates late-phase PGE2 production in bone marrow derived macrophages. PLoS One, 7, e50244. https://doi.org/10.1371/journal.pone.0050244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Díaz-Muñoz, M. D., Osma-García, I. C., Fresno, M., & Iñiguez, M. A. (2012). Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. The Biochemical Journal, 443, 451–461. https://doi.org/10.1042/BJ20111052.

    Article  PubMed  CAS  Google Scholar 

  61. Li, X., Yu, Y., & Funk, C. D. (2013). Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). The FASEB Journal, 27, 4987–4997. https://doi.org/10.1096/fj.13-235333.

    Article  PubMed  CAS  Google Scholar 

  62. Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998). Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. The Journal of Clinical Investigation, 101, 890–898. https://doi.org/10.1172/JCI1112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Johann, A. M., Weigert, A., Eberhardt, W., Kuhn, A.-M., Barra, V., von Knethen, A., et al. (2008). Apoptotic cell-derived sphingosine-1-phosphate promotes HuR-dependent cyclooxygenase-2 mRNA stabilization and protein expression. Journal of Immunology, 180, 1239–1248.

    Article  CAS  Google Scholar 

  64. Brecht, K., Weigert, A., Hu, J., Popp, R., Fisslthaler, B., Korff, T., et al. (2011). Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E2. The FASEB Journal, 25, 2408–2417. https://doi.org/10.1096/fj.10-179473.

    Article  PubMed  CAS  Google Scholar 

  65. Tong, M., Ding, Y., & Tai, H.-H. (2006). Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells. Carcinogenesis, 27, 2170–2179. https://doi.org/10.1093/carcin/bgl053.

    Article  PubMed  CAS  Google Scholar 

  66. Kochel, T. J., & Fulton, A. M. (2015). Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer. Prostaglandins & Other Lipid Mediators, 116-117, 99–103. https://doi.org/10.1016/j.prostaglandins.2014.11.003.

    Article  CAS  Google Scholar 

  67. Arima, K., Komohara, Y., Bu, L., Tsukamoto, M., Itoyama, R., Miyake, K., et al. (2018). Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer. Cancer Science, 109, 462–470. https://doi.org/10.1111/cas.13467.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Eruslanov, E., Kaliberov, S., Daurkin, I., Kaliberova, L., Buchsbaum, D., Vieweg, J., & Kusmartsev, S. (2009). Altered expression of 15-hydroxyprostaglandin dehydrogenase in tumor-infiltrated CD11b myeloid cells: a mechanism for immune evasion in cancer. Journal of Immunology, 182, 7548–7557. https://doi.org/10.4049/jimmunol.0802358.

    Article  CAS  Google Scholar 

  69. O'Callaghan, G., & Houston, A. (2015). Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? British Journal of Pharmacology, 172, 5239–5250. https://doi.org/10.1111/bph.13331.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Ikegami, R., Sugimoto, Y., Segi, E., Katsuyama, M., Karahashi, H., Amano, F., et al. (2001). The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by lipopolysaccharide in C3H/HeN peritoneal macrophages. Journal of Immunology, 166, 4689–4696.

    Article  CAS  Google Scholar 

  71. Wang, D., & Dubois, R. N. (2010). Eicosanoids and cancer. Nature Reviews. Cancer, 10, 181–193. https://doi.org/10.1038/nrc2809.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Xia, D., Wang, D., Kim, S.-H., Katoh, H., & Dubois, R. N. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nature Medicine, 18, 224–226. https://doi.org/10.1038/nm.2608.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Kalinski, P. (2012). Regulation of immune responses by prostaglandin E2. Journal of Immunology, 188, 21–28. https://doi.org/10.4049/jimmunol.1101029.

    Article  CAS  Google Scholar 

  74. Sha, W., Brüne, B., & Weigert, A. (2012). The multi-faceted roles of prostaglandin E2 in cancer-infiltrating mononuclear phagocyte biology. Immunobiology, 217, 1225–1232. https://doi.org/10.1016/j.imbio.2012.05.001.

    Article  PubMed  CAS  Google Scholar 

  75. Hooper, K. M., Yen, J.-H., Kong, W., Rahbari, K. M., Kuo, P.-C., Gamero, A. M., & Ganea, D. (2017). Prostaglandin E2 inhibition of IL-27 production in murine dendritic cells: a novel mechanism that involves IRF1. Journal of Immunology, 198, 1521–1530. https://doi.org/10.4049/jimmunol.1601073.

    Article  CAS  Google Scholar 

  76. Zasłona, Z., Pålsson-McDermott, E. M., Menon, D., Haneklaus, M., Flis, E., Prendeville, H., et al. (2017). The induction of pro-IL-1β by lipopolysaccharide requires endogenous prostaglandin E2 production. Journal of Immunology, 198, 3558–3564. https://doi.org/10.4049/jimmunol.1602072.

    Article  CAS  Google Scholar 

  77. Chen, E. P., & Smyth, E. M. (2011). COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins & Other Lipid Mediators, 96, 14–20. https://doi.org/10.1016/j.prostaglandins.2011.08.005.

    Article  CAS  Google Scholar 

  78. Zaslona, Z., Serezani, C. H., Okunishi, K., Aronoff, D. M., & Peters-Golden, M. (2012). Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling. Blood, 119, 2358–2367. https://doi.org/10.1182/blood-2011-08-374207.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Lee, S. P., Serezani, C. H., Medeiros, A. I., Ballinger, M. N., & Peters-Golden, M. (2009). Crosstalk between prostaglandin E2 and leukotriene B4 regulates phagocytosis in alveolar macrophages via combinatorial effects on cyclic AMP. Journal of Immunology, 182, 530–537.

    Article  CAS  Google Scholar 

  80. Bystrom, J., Evans, I., Newson, J., Stables, M., Toor, I., van Rooijen, N., et al. (2008). Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. Blood, 112, 4117–4127. https://doi.org/10.1182/blood-2007-12-129767.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Peters-Golden, M. (2009). Putting on the brakes: cyclic AMP as a multipronged controller of macrophage function. Science Signaling, 2, pe37. https://doi.org/10.1126/scisignal.275pe37.

    Article  PubMed  CAS  Google Scholar 

  82. Sokolowska, M., Chen, L.-Y., Liu, Y., Martinez-Anton, A., Qi, H.-Y., Logun, C., et al. (2015). Prostaglandin E2 inhibits NLRP3 inflammasome activation through EP4 receptor and intracellular cyclic AMP in human macrophages. Journal of Immunology, 194, 5472–5487. https://doi.org/10.4049/jimmunol.1401343.

    Article  CAS  Google Scholar 

  83. Nakatsuji, M., Minami, M., Seno, H., Yasui, M., Komekado, H., Higuchi, S., et al. (2015). EP4 receptor-associated protein in macrophages ameliorates colitis and colitis-associated tumorigenesis. PLoS Genetics, 11, e1005542. https://doi.org/10.1371/journal.pgen.1005542.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Ruffell, D., Mourkioti, F., Gambardella, A., Kirstetter, P., Lopez, R. G., Rosenthal, N., & Nerlov, C. (2009). A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proceedings of the National Academy of Sciences of the United States of America, 106, 17475–17480. https://doi.org/10.1073/pnas.0908641106.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Luan, B., Yoon, Y.-S., Le Lay, J., Kaestner, K. H., Hedrick, S., & Montminy, M. (2015). CREB pathway links PGE2 signaling with macrophage polarization. Proceedings of the National Academy of Sciences of the United States of America, 112, 15642–15647. https://doi.org/10.1073/pnas.1519644112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Qian, X., Zhang, J., & Liu, J. (2011). Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP/PKA signaling pathway. The Journal of Biological Chemistry, 286, 2111–2120. https://doi.org/10.1074/jbc.M110.154971.

    Article  PubMed  CAS  Google Scholar 

  87. Hangai, S., Ao, T., Kimura, Y., Matsuki, K., Kawamura, T., Negishi, H., et al. (2016). PGE2 induced in and released by dying cells functions as an inhibitory DAMP. Proceedings of the National Academy of Sciences of the United States of America, 113, 3844–3849. https://doi.org/10.1073/pnas.1602023113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Zelenay, S., van der Veen, A. G., Böttcher, J. P., Snelgrove, K. J., Rogers, N., Acton, S. E., et al. (2015). Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell, 162, 1257–1270. https://doi.org/10.1016/j.cell.2015.08.015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Prima, V., Kaliberova, L. N., Kaliberov, S., Curiel, D. T., & Kusmartsev, S. (2017). COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proceedings of the National Academy of Sciences of the United States of America, 114, 1117–1122. https://doi.org/10.1073/pnas.1612920114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Sasaki, Y., Kamei, D., Ishikawa, Y., Ishii, T., Uematsu, S., Akira, S., et al. (2012). Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis. Oncogene, 31, 2943–2952. https://doi.org/10.1038/onc.2011.472.

    Article  PubMed  CAS  Google Scholar 

  91. Eruslanov, E., Daurkin, I., Ortiz, J., Vieweg, J., & Kusmartsev, S. (2010). Pivotal advance: tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE2 catabolism in myeloid cells. Journal of Leukocyte Biology, 88, 839–848. https://doi.org/10.1189/jlb.1209821.

    Article  PubMed  CAS  Google Scholar 

  92. Janakiram, N. B., Mohammed, A., Bryant, T., Ritchie, R., Stratton, N., Jackson, L., et al. (2017). Loss of natural killer T cells promotes pancreatic cancer in LSL-KrasG12D/+mice. Immunology, 152, 36–51. https://doi.org/10.1111/imm.12746.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Gregory, C. D., & Pound, J. D. (2011). Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. The Journal of Pathology, 223, 177–194. https://doi.org/10.1002/path.2792.

    Article  PubMed  CAS  Google Scholar 

  94. Kamata, H., Hosono, K., Suzuki, T., Ogawa, Y., Kubo, H., Katoh, H., et al. (2010). mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice. Biomedicine & Pharmacotherapy, 64, 409–416. https://doi.org/10.1016/j.biopha.2010.01.017.

    Article  CAS  Google Scholar 

  95. Rong, X., Huang, B., Qiu, S., Li, X., He, L., & Peng, Y. (2016). Tumor-associated macrophages induce vasculogenic mimicry of glioblastoma multiforme through cyclooxygenase-2 activation. Oncotarget, 7, 83976–83986. https://doi.org/10.18632/oncotarget.6930.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Nandi, P., Girish, G. V., Majumder, M., Xin, X., Tutunea-Fatan, E., & Lala, P. K. (2017). PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells. BMC Cancer, 17, 11. https://doi.org/10.1186/s12885-016-3018-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Gan, L., Qiu, Z., Huang, J., Li, Y., Huang, H., Xiang, T., et al. (2016). Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway. International Journal of Biological Sciences, 12, 1533–1543. https://doi.org/10.7150/ijbs.15943.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Khan, K. M. F., Kothari, P., Du, B., Dannenberg, A. J., & Falcone, D. J. (2012). Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-α and the EP4 prostanoid receptor. Journal of Immunology, 188, 1970–1980. https://doi.org/10.4049/jimmunol.1102383.

    Article  CAS  Google Scholar 

  99. Rådmark, O., & Samuelsson, B. (2009). 5-Lipoxygenase: mechanisms of regulation. Journal of Lipid Research, 50(Suppl), S40–S45. https://doi.org/10.1194/jlr.R800062-JLR200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Yokomizo, T., Kato, K., Terawaki, K., Izumi, T., & Shimizu, T. (2000). A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. The Journal of Experimental Medicine, 192, 421–432.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Yokomizo, T., Kato, K., Hagiya, H., Izumi, T., & Shimizu, T. (2001). Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2. The Journal of Biological Chemistry, 276, 12454–12459. https://doi.org/10.1074/jbc.M011361200.

    Article  PubMed  CAS  Google Scholar 

  102. Ogasawara, H., Ishii, S., Yokomizo, T., Kakinuma, T., Komine, M., Tamaki, K., et al. (2002). Characterization of mouse cysteinyl leukotriene receptors mCysLT1 and mCysLT2: differential pharmacological properties and tissue distribution. The Journal of Biological Chemistry, 277, 18763–18768. https://doi.org/10.1074/jbc.M109447200.

    Article  PubMed  CAS  Google Scholar 

  103. Heise, C. E., O'Dowd, B. F., Figueroa, D. J., Sawyer, N., Nguyen, T., Im, D. S., et al. (2000). Characterization of the human cysteinyl leukotriene 2 receptor. The Journal of Biological Chemistry, 275, 30531–30536. https://doi.org/10.1074/jbc.M003490200.

    Article  PubMed  CAS  Google Scholar 

  104. Lötzer, K., Funk, C. D., & Habenicht, A. J. R. (2005). The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. Biochimica et Biophysica Acta, 1736, 30–37. https://doi.org/10.1016/j.bbalip.2005.07.001.

    Article  PubMed  CAS  Google Scholar 

  105. Dahlén, S.-E. (2006). Treatment of asthma with antileukotrienes: first line or last resort therapy? European Journal of Pharmacology, 533, 40–56. https://doi.org/10.1016/j.ejphar.2005.12.070.

    Article  PubMed  CAS  Google Scholar 

  106. Hammamieh, R., Sumaida, D., Zhang, X., Das, R., & Jett, M. (2007). Control of the growth of human breast cancer cells in culture by manipulation of arachidonate metabolism. BMC Cancer, 7, 138. https://doi.org/10.1186/1471-2407-7-138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Barresi, V., Grosso, M., Vitarelli, E., Tuccari, G., & Barresi, G. (2007). 5-Lipoxygenase is coexpressed with Cox-2 in sporadic colorectal cancer: a correlation with advanced stage. Diseases of the Colon and Rectum, 50, 1576–1584. https://doi.org/10.1007/s10350-007-0311-9.

    Article  PubMed  Google Scholar 

  108. Matsuyama, M., Hayama, T., Funao, K., Kawahito, Y., Sano, H., Takemoto, Y., et al. (2007). Overexpression of cysteinyl LT1 receptor in prostate cancer and CysLT1R antagonist inhibits prostate cancer cell growth through apoptosis. Oncology Reports, 18, 99–104.

    PubMed  CAS  Google Scholar 

  109. Sarveswaran, S., Varma, N., Morisetty, S., & Ghosh, J. (2016). Inhibition of 5-lipoxygenase downregulates stemness and kills prostate cancer stem cells by triggering apoptosis via activation of c-Jun N-terminal kinase*. Oncotarget. https://doi.org/10.18632/oncotarget.13422.

  110. Ghosh, J., & Myers, C. E. (1998). Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 95, 13182–13187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Meng, Z., Cao, R., Yang, Z., Liu, T., Wang, Y., & Wang, X. (2013). Inhibitor of 5-lipoxygenase, zileuton, suppresses prostate cancer metastasis by upregulating E-cadherin and paxillin. Urology, 82, 1452.e7–1452.14. https://doi.org/10.1016/j.urology.2013.08.060.

    Article  Google Scholar 

  112. Sarveswaran, S., Chakraborty, D., Chitale, D., Sears, R., & Ghosh, J. (2015). Inhibition of 5-lipoxygenase selectively triggers disruption of c-Myc signaling in prostate cancer cells. The Journal of Biological Chemistry, 290, 4994–5006. https://doi.org/10.1074/jbc.M114.599035.

    Article  PubMed  CAS  Google Scholar 

  113. Shen, J., Li, W. X., Xiao, Z. G., Zhang, L., Li, M. X., Li, L. F., et al. (2016). The co-regulatory role of 5-lipoxygenase and cyclooxygenase-2 in the carcinogenesis and their promotion by cigarette smoking in colons. Current Medicinal Chemistry, 23, 1131–1138.

    Article  PubMed  CAS  Google Scholar 

  114. Moore, G. Y., & Pidgeon, G. P. (2017). Cross-talk between cancer cells and the tumour microenvironment: the role of the 5-lipoxygenase pathway. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms18020236.

  115. Boger, P. C., Shutt, J. D., Neale, J. R., Wilson, S. J., Bateman, A. C., Holloway, J. W., et al. (2012). Increased expression of the 5-lipoxygenase pathway and its cellular localization in Barrett's adenocarcinoma. Histopathology, 61, 509–517. https://doi.org/10.1111/j.1365-2559.2012.04258.x.

    Article  PubMed  Google Scholar 

  116. Reinartz, S., Finkernagel, F., Adhikary, T., Rohnalter, V., Schumann, T., Schober, Y., et al. (2016). A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome. Genome Biology, 17, 108. https://doi.org/10.1186/s13059-016-0956-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Brenner, C., Galluzzi, L., Kepp, O., & Kroemer, G. (2013). Decoding cell death signals in liver inflammation. Journal of Hepatology, 59, 583–594. https://doi.org/10.1016/j.jhep.2013.03.033.

    Article  PubMed  CAS  Google Scholar 

  118. Poczobutt, J. M., Gijon, M., Amin, J., Hanson, D., Li, H., Walker, D., et al. (2013). Eicosanoid profiling in an orthotopic model of lung cancer progression by mass spectrometry demonstrates selective production of leukotrienes by inflammatory cells of the microenvironment. PLoS One, 8, e79633. https://doi.org/10.1371/journal.pone.0079633.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Poczobutt, J. M., De, S., Yadav, V. K., Nguyen, T. T., Li, H., Sippel, T. R., et al. (2016). Expression profiling of macrophages reveals multiple populations with distinct biological roles in an immunocompetent orthotopic model of lung cancer. Journal of Immunology, 196, 2847–2859. https://doi.org/10.4049/jimmunol.1502364.

    Article  CAS  Google Scholar 

  120. Wen, Z., Liu, H., Li, M., Li, B., Gao, W., Shao, Q., et al. (2015). Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumor-associated macrophage infiltration. Oncogene, 34, 1241–1252. https://doi.org/10.1038/onc.2014.85.

    Article  PubMed  CAS  Google Scholar 

  121. Cheon, E. C., Strouch, M. J., Krantz, S. B., Heiferman, M. J., & Bentrem, D. J. (2012). Genetic deletion of 5-lipoxygenase increases tumor-infiltrating macrophages in Apc(Δ468) mice. Journal of Gastrointestinal Surgery, 16, 389–393. https://doi.org/10.1007/s11605-011-1761-x.

    Article  PubMed  Google Scholar 

  122. Gounaris, E., Heiferman, M. J., Heiferman, J. R., Shrivastav, M., Vitello, D., Blatner, N. R., et al. (2015). Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PLoS One, 10, e0121402. https://doi.org/10.1371/journal.pone.0121402.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Nosaka, T., Baba, T., Tanabe, Y., Sasaki, S., Nishimura, T., Imamura, Y., et al. (2018). Alveolar macrophages drive hepatocellular carcinoma lung metastasis by generating leukotriene B4. Journal of Immunology. https://doi.org/10.4049/jimmunol.1700544.

  124. Kitamura, T., Qian, B.-Z., Soong, D., Cassetta, L., Noy, R., Sugano, G., et al. (2015). CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. The Journal of Experimental Medicine, 212, 1043–1059. https://doi.org/10.1084/jem.20141836.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Poczobutt, J. M., Nguyen, T. T., Hanson, D., Li, H., Sippel, T. R., Weiser-Evans, Mary, C. M., et al. (2016). Deletion of 5-lipoxygenase in the tumor microenvironment promotes lung cancer progression and metastasis through regulating T cell recruitment. Journal of Immunology, 196, 891–901. https://doi.org/10.4049/jimmunol.1501648.

    Article  CAS  Google Scholar 

  126. Ringleb, J., Strack, E., Angioni, C., Geisslinger, G., Steinhilber, D., Weigert, A., & Brüne, B. (2018). Apoptotic cancer cells suppress 5-lipoxygenase in tumor-associated macrophages. Journal of Immunology, 200, 857–868. https://doi.org/10.4049/jimmunol.1700609.

    Article  CAS  Google Scholar 

  127. Rossi, A., Pergola, C., Koeberle, A., Hoffmann, M., Dehm, F., Bramanti, P., et al. (2010). The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. British Journal of Pharmacology, 161, 555–570. https://doi.org/10.1111/j.1476-5381.2010.00930.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Park, S.-W., Heo, D.-S., & Sung, M.-W. (2012). The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells. Cellular Oncology (Dordrecht), 35, 1–8. https://doi.org/10.1007/s13402-011-0051-7.

    Article  Google Scholar 

  129. Weigert, A., von, K. A., Fuhrmann, D., Dehne, N., & Brüne, B. (2018). Redox-signals and macrophage biology (for the upcoming issue of molecular aspects of medicine on signaling by reactive oxygen species). Molecular Aspects of Medicine. https://doi.org/10.1016/j.mam.2018.01.003.

  130. Edelman, M. J., Watson, D., Wang, X., Morrison, C., Kratzke, R. A., Jewell, S., et al. (2008). Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy—Cancer and Leukemia Group B Trial 30203. Journal of Clinical Oncology, 26, 848–855. https://doi.org/10.1200/JCO.2007.13.8081.

    Article  PubMed  CAS  Google Scholar 

  131. Kuhn, H., Banthiya, S., & van Leyen, K. (2015). Mammalian lipoxygenases and their biological relevance. Biochimica et Biophysica Acta, 1851, 308–330. https://doi.org/10.1016/j.bbalip.2014.10.002.

    Article  PubMed  CAS  Google Scholar 

  132. Ivanov, I., Kuhn, H., & Structural, H. D. (2015). functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15). Gene, 573, 1–32. https://doi.org/10.1016/j.gene.2015.07.073.

    Article  PubMed  CAS  Google Scholar 

  133. Wuest, S. J. A., Crucet, M., Gemperle, C., Loretz, C., & Hersberger, M. (2012). Expression and regulation of 12/15-lipoxygenases in human primary macrophages. Atherosclerosis, 225, 121–127. https://doi.org/10.1016/j.atherosclerosis.2012.07.022.

    Article  PubMed  CAS  Google Scholar 

  134. Ackermann, J. A., Hofheinz, K., Zaiss, M. M., & Krönke, G. (2017). The double-edged role of 12/15-lipoxygenase during inflammation and immunity. Biochimica et Biophysica Acta, 1862, 371–381. https://doi.org/10.1016/j.bbalip.2016.07.014.

    Article  PubMed  CAS  Google Scholar 

  135. Bender, G., Schexnaydre, E. E., Murphy, R. C., Uhlson, C., & Newcomer, M. E. (2016). Membrane-dependent activities of human 15-LOX-2 and its murine counterpart: implications for murine models of atherosclerosis. The Journal of Biological Chemistry, 291, 19413–19424. https://doi.org/10.1074/jbc.M116.741454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Hammond, V. J., & O'Donnell, V. B. (2012). Esterified eicosanoids: generation, characterization and function. Biochimica et Biophysica Acta, 1818, 2403–2412. https://doi.org/10.1016/j.bbamem.2011.12.013.

    Article  PubMed  CAS  Google Scholar 

  137. O'Donnell, V. B., & Murphy, R. C. (2012). New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions. Blood, 120, 1985–1992. https://doi.org/10.1182/blood-2012-04-402826.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Morgan, A. H., Hammond, V. J., Sakoh-Nakatogawa, M., Ohsumi, Y., Thomas, C. P., Blanchet, F., et al. (2015). A novel role for 12/15-lipoxygenase in regulating autophagy. Redox Biology, 4, 40–47. https://doi.org/10.1016/j.redox.2014.11.005.

    Article  PubMed  CAS  Google Scholar 

  139. Kagan, V. E., Mao, G., Qu, F., Angeli, J. P. F., Doll, S., Croix, C. S., et al. (2017). Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology, 13, 81–90. https://doi.org/10.1038/nchembio.2238.

    Article  PubMed  CAS  Google Scholar 

  140. Ou, Y., Wang, S.-J., Li, D., Chu, B., & Gu, W. (2016). Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proceedings of the National Academy of Sciences of the United States of America, 113, E6806–E6812. https://doi.org/10.1073/pnas.1607152113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Shureiqi, I., Jiang, W., Zuo, X., Wu, Y., Stimmel, J. B., Leesnitzer, L. M., et al. (2003). The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 9968–9973. https://doi.org/10.1073/pnas.1631086100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Su, C. G., Wen, X., Bailey, S. T., Jiang, W., Rangwala, S. M., Keilbaugh, S. A., et al. (1999). A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. The Journal of Clinical Investigation, 104, 383–389. https://doi.org/10.1172/JCI7145.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Tanaka, T., Kohno, H., Yoshitani, S., Takashima, S., Okumura, A., Murakami, A., & Hosokawa, M. (2001). Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Research, 61, 2424–2428.

    PubMed  CAS  Google Scholar 

  144. Zuo, X., Wu, Y., Morris, J. S., Stimmel, J. B., Leesnitzer, L. M., Fischer, S. M., et al. (2006). Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene, 25, 1225–1241. https://doi.org/10.1038/sj.onc.1209160.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Powell, W. S., & Rokach, J. (2015). Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid. Biochimica et Biophysica Acta, 1851, 340–355. https://doi.org/10.1016/j.bbalip.2014.10.008.

    Article  PubMed  CAS  Google Scholar 

  146. Marcheselli, V. L., Hong, S., Lukiw, W. J., Tian, X. H., Gronert, K., Musto, A., et al. (2003). Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. The Journal of Biological Chemistry, 278, 43807–43817. https://doi.org/10.1074/jbc.M305841200.

    Article  PubMed  CAS  Google Scholar 

  147. Kumar, N., Gupta, G., Anilkumar, K., Fatima, N., Karnati, R., Reddy, G. V., et al. (2016). 15-Lipoxygenase metabolites of α-linolenic acid, 13-(S)-HPOTrE and 13-(S)-HOTrE, mediate anti-inflammatory effects by inactivating NLRP3 inflammasome. Scientific Reports, 6, 31649. https://doi.org/10.1038/srep31649.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Pham, H., Banerjee, T., & Ziboh, V. A. (2004). Suppression of cyclooxygenase-2 overexpression by 15S-hydroxyeicosatrienoic acid in androgen-dependent prostatic adenocarcinoma cells. International Journal of Cancer, 111, 192–197. https://doi.org/10.1002/ijc.20245.

    Article  PubMed  CAS  Google Scholar 

  149. Klil-Drori, A. J., & Ariel, A. (2013). 15-Lipoxygenases in cancer: a double-edged sword? Prostaglandins & Other Lipid Mediators, 106, 16–22. https://doi.org/10.1016/j.prostaglandins.2013.07.006.

    Article  CAS  Google Scholar 

  150. Moreno, J. J. (2009). New aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development. Biochemical Pharmacology, 77, 1–10. https://doi.org/10.1016/j.bcp.2008.07.033.

    Article  PubMed  CAS  Google Scholar 

  151. Kang, K.-H., Ling, T.-Y., Liou, H.-H., Huang, Y.-K., Hour, M.-J., Liou, H.-C., & Fu, W.-M. (2013). Enhancement role of host 12/15-lipoxygenase in melanoma progression. European Journal of Cancer, 49, 2747–2759. https://doi.org/10.1016/j.ejca.2013.03.030.

    Article  PubMed  CAS  Google Scholar 

  152. Pidgeon, G. P., Kandouz, M., Meram, A., & Honn, K. V. (2002). Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. Cancer Research, 62, 2721–2727.

    PubMed  CAS  Google Scholar 

  153. Chabane, N., Zayed, N., Benderdour, M., Martel-Pelletier, J., Pelletier, J.-P., Duval, N., & Fahmi, H. (2009). Human articular chondrocytes express 15-lipoxygenase-1 and -2: potential role in osteoarthritis. Arthritis Research & Therapy, 11, R44. https://doi.org/10.1186/ar2652.

    Article  CAS  Google Scholar 

  154. Chiurchiù, V., Leuti, A., & Maccarrone, M. (2018). Bioactive lipids and chronic inflammation: managing the fire within. Frontiers in Immunology, 9, 38. https://doi.org/10.3389/fimmu.2018.00038.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Wu, R.-F., Huang, Z.-X., Ran, J., Dai, S.-J., Lin, D.-C., Ng, T.-W., et al. (2018). Lipoxin A4 suppresses estrogen-induced epithelial-mesenchymal transition via ALXR-dependent manner in endometriosis. Reproductive Sciences, 25, 566–578. https://doi.org/10.1177/1933719117718271.

    Article  PubMed  CAS  Google Scholar 

  156. Schnittert, J., Heinrich, M. A., Kuninty, P. R., Storm, G., & Prakash, J. (2018). Reprogramming tumor stroma using an endogenous lipid lipoxin A4 to treat pancreatic cancer. Cancer Letters, 420, 247–258. https://doi.org/10.1016/j.canlet.2018.01.072.

    Article  PubMed  CAS  Google Scholar 

  157. Serhan, C. N., Chiang, N., Dalli, J., & Levy, B. D. (2014). Lipid mediators in the resolution of inflammation. Cold Spring Harbor Perspectives in Biology, 7, a016311. https://doi.org/10.1101/cshperspect.a016311.

    Article  PubMed  CAS  Google Scholar 

  158. Zhang, Q., Zhu, B., & Li, Y. (2017). Resolution of cancer-promoting inflammation: a new approach for anticancer therapy. Frontiers in Immunology, 8, 71. https://doi.org/10.3389/fimmu.2017.00071.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Sulciner, M. L., Serhan, C. N., Gilligan, M. M., Mudge, D. K., Chang, J., Gartung, A., et al. (2018). Resolvins suppress tumor growth and enhance cancer therapy. The Journal of Experimental Medicine, 215, 115–140. https://doi.org/10.1084/jem.20170681.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Tian, R., Zuo, X., Jaoude, J., Mao, F., Colby, J., & Shureiqi, I. (2017). ALOX15 as a suppressor of inflammation and cancer: lost in the link. Prostaglandins & Other Lipid Mediators, 132, 77–83. https://doi.org/10.1016/j.prostaglandins.2017.01.002.

    Article  CAS  Google Scholar 

  161. Chung, W., Eum, H. H., Lee, H.-O., Lee, K.-M., Lee, H.-B., Kim, K.-T., et al. (2017). Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer. Nature Communications, 8, 15081. https://doi.org/10.1038/ncomms15081.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Zuo, X., Peng, Z., Wu, Y., Moussalli, M. J., Yang, X. L., Wang, Y., et al. (2012). Effects of gut-targeted 15-LOX-1 transgene expression on colonic tumorigenesis in mice. Journal of the National Cancer Institute, 104, 709–716. https://doi.org/10.1093/jnci/djs187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Deguchi, A., Xing, S. W., Shureiqi, I., Yang, P., Newman, R. A., Lippman, S. M., et al. (2005). Activation of protein kinase G up-regulates expression of 15-lipoxygenase-1 in human colon cancer cells. Cancer Research, 65, 8442–8447. https://doi.org/10.1158/0008-5472.CAN-05-1109.

    Article  PubMed  CAS  Google Scholar 

  164. Mao, F., Xu, M., Zuo, X., Yu, J., Xu, W., Moussalli, M. J., et al. (2015). 15-Lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway. The FASEB Journal, 29, 2359–2370. https://doi.org/10.1096/fj.14-264515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Moussalli, M. J., Wu, Y., Zuo, X., Yang, X. L., Wistuba, I. I., Raso, M. G., et al. (2011). Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion. Cancer Prevention Research (Philadelphia, Pa.), 4, 1961–1972. https://doi.org/10.1158/1940-6207.CAPR-10-0280.

    Article  CAS  Google Scholar 

  166. Schif-Zuck, S., Gross, N., Assi, S., Rostoker, R., Serhan, C. N., & Ariel, A. (2011). Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids. European Journal of Immunology, 41, 366–379. https://doi.org/10.1002/eji.201040801.

    Article  PubMed  CAS  Google Scholar 

  167. Uderhardt, S., Herrmann, M., Oskolkova, O. V., Aschermann, S., Bicker, W., Ipseiz, N., et al. (2012). 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. Immunity, 36, 834–846. https://doi.org/10.1016/j.immuni.2012.03.010.

    Article  PubMed  CAS  Google Scholar 

  168. Kwon, H.-J., Kim, S.-N., Kim, Y.-A., & Lee, Y.-H. (2016). The contribution of arachidonate 15-lipoxygenase in tissue macrophages to adipose tissue remodeling. Cell Death & Disease, 7, e2285. https://doi.org/10.1038/cddis.2016.190.

    Article  CAS  Google Scholar 

  169. Wang. (2010). Downregulation of 15-lipoxygenase 2 by glucocorticoid receptor in prostate cancer cells. International Journal of Oncology. https://doi.org/10.3892/ijo_00000641.

  170. Schneider, C., & Pozzi, A. (2011). Cyclooxygenases and lipoxygenases in cancer. Cancer Metastasis Reviews, 30, 277–294. https://doi.org/10.1007/s10555-011-9310-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Abrial, C., Grassin-Delyle, S., Salvator, H., Brollo, M., Naline, E., & Devillier, P. (2015). 15-Lipoxygenases regulate the production of chemokines in human lung macrophages. British Journal of Pharmacology, 172, 4319–4330. https://doi.org/10.1111/bph.13210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Ruffell, B., Affara, N. I., & Coussens, L. M. (2012). Differential macrophage programming in the tumor microenvironment. Trends in Immunology, 33, 119–126. https://doi.org/10.1016/j.it.2011.12.001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Daurkin, I., Eruslanov, E., Stoffs, T., Perrin, G. Q., Algood, C., Gilbert, S. M., et al. (2011). Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. Cancer Research, 71, 6400–6409. https://doi.org/10.1158/0008-5472.CAN-11-1261.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We apologize to researchers whose primary observations could not be cited due to space limitations or were cited indirectly by referring to current reviews. Our work is supported by grants from Deutsche Forschungsgemeinschaft (projects B04 and B06 of the CRC 1039, projects 1 and 6 of the GRK 2336, project 8 of FOR 2438), Deutsche Krebshilfe (111576, 70112451), Else Kröner-Fresenius-Graduiertenkolleg (project P2), and the German Cancer Consortium (DKTK).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernhard Brüne.

Additional information

Cancer and Metastasis Reviews: Special issue “Bioactive lipids in Cancer”

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weigert, A., Strack, E., Snodgrass, R.G. et al. mPGES-1 and ALOX5/-15 in tumor-associated macrophages. Cancer Metastasis Rev 37, 317–334 (2018). https://doi.org/10.1007/s10555-018-9731-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-018-9731-3

Keywords

Navigation