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Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumor-associated macrophage infiltration

Oncogene volume 34, pages 1241–1252 (2015)Cite this article

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Abstract

5-lipoxygenase (5-LOX), a member of the lipoxygenase gene family, is a key enzyme assisting in the conversion of arachidonic acid to 5-HETE and leukotrienes. Tumor-associated macrophages (TAMs) have a critical role in the progression and metastasis of many tumors, including ovarian tumors. Moreover, TAMs are often found in a high density in the hypoxic areas of tumors. However, the relevant mechanisms have not been studied explicitly until now. In this study, we found that the expression of 5-LOX strongly correlated with the density of TAMs in hypoxic areas of human ovarian tumor tissues. In cultured ovarian cancer cells, 5-LOX metabolites were increased under hypoxic conditons. Increased 5-LOX metabolites from hypoxic ovarian cancer cells promoted migration and invasion of macrophages, which was further demonstrated to be mediated by the upregulation of matrix metalloproteinase (MMP)-7 expression through the p38 pathway. Besides, we also showed that 5-LOX metabolites enhanced the release of tumor necrosis factor (TNF-α) and heparin-binding epidermal growth factor-like growth factor through upregulation of MMP-7. Furthermore, in animal models, Zileuton (a selective and specific 5-LOX inhibitor) reduced the MMP-7 expression and the number of macrophages infiltrating in the xenograft. Our findings suggest for the first time that increased metabolites of 5-LOX from hypoxic ovarian cancer cells promote TAM infiltration. These results of this study have immediate translational implications for the therapeutic exploitation of TAMs.

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References

  1. Balkwill F, Mantovani A . Inflammation and cancer: back to Virchow? Lancet 2001; 357: 539–545.

    Article  CAS  PubMed  Google Scholar 

  2. Coussens LM, Werb Z . Inflammation and cancer. Nature 2002; 420: 860–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Meng Y, Beckett MA, Liang H, Mauceri HJ, van Rooijen N, Cohen KS et al. Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy. Cancer Res 2010; 70: 1534–1543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pollard JW . Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4: 71–78.

    Article  CAS  PubMed  Google Scholar 

  5. Allavena P, Sica A, Solinas G, Porta C, Mantovani A . The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 2008; 66: 1–9.

    Article  PubMed  Google Scholar 

  6. Murdoch C, Giannoudis A, Lewis CE . Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 2004; 104: 2224–2234.

    Article  CAS  PubMed  Google Scholar 

  7. Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 2011; 19: 31–44.

    Article  CAS  PubMed  Google Scholar 

  8. Ruhrberg C, De Palma M . A double agent in cancer: deciphering macrophage roles in human tumors. Nat Med 2010; 16: 861–862.

    Article  CAS  PubMed  Google Scholar 

  9. Bingham BA, Hatef DA, Chevez-Barrios P, Blackmon SH, Kim MP . Increased FDG activity in a dermatofibroma in esophageal cancer patient. Clin Nucl Med 2013; 38: e140–e142.

    Article  PubMed  Google Scholar 

  10. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013; 73: 1128–1141.

    Article  CAS  PubMed  Google Scholar 

  11. Reinartz S, Schumann T, Finkernagel F, Wortmann A, Jansen JM, Meissner W et al. Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer 2014; 134: 32–42.

    Article  PubMed  Google Scholar 

  12. Bingle L, Brown NJ, Lewis CE . The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002; 196: 254–265.

    Article  CAS  PubMed  Google Scholar 

  13. Lewis JS, Landers RJ, Underwood JC, Harris AL, Lewis CE . Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 2000; 192: 150–158.

    Article  CAS  PubMed  Google Scholar 

  14. Maniecki MB, Etzerodt A, Ulhoi BP, Steiniche T, Borre M, Dyrskjot L et al. Tumor-promoting macrophages induce the expression of the macrophage-specific receptor CD163 in malignant cells. Int J Cancer 2012; 131: 2320–2331.

    Article  CAS  PubMed  Google Scholar 

  15. Negus RP, Stamp GW, Hadley J, Balkwill FR . Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am J Pathol 1997; 150: 1723–1734.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin EY, Nguyen AV, Russell RG, Pollard JW . Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 2001; 193: 727–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Negus RP, Stamp GW, Relf MG, Burke F, Malik ST, Bernasconi S et al. The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer. J Clin Invest 1995; 95: 2391–2396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haeggstrom JZ, Funk CD . Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem Rev 2011; 111: 5866–5898.

    Article  PubMed  Google Scholar 

  19. Freedman RS, Wang E, Voiculescu S, Patenia R, Bassett Jr. RL, Deavers M et al. Comparative analysis of peritoneum and tumor eicosanoids and pathways in advanced ovarian cancer. Clin Cancer Res 2007; 13: 5736–5744.

    Article  CAS  PubMed  Google Scholar 

  20. Rocconi RP, Kirby TO, Seitz RS, Beck R, Straughn Jr. JM, Alvarez RD et al. Lipoxygenase pathway receptor expression in ovarian cancer. Reprod Sci 2008; 15: 321–326.

    Article  PubMed  Google Scholar 

  21. Bonizzi G, Piette J, Schoonbroodt S, Greimers R, Havard L, Merville MP et al. Reactive oxygen intermediate-dependent NF-kappaB activation by interleukin-1beta requires 5-lipoxygenase or NADPH oxidase activity. Mol Cell Biol 1999; 19: 1950–1960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 1990; 343: 282–284.

    Article  CAS  PubMed  Google Scholar 

  23. Yamaguchi T, Baba K, Doi Y, Yano K . Effect of adrenomedullin on aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. Life Sci 1995; 56: 379–387.

    Article  CAS  PubMed  Google Scholar 

  24. Funk CD . Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001; 294: 1871–1875.

    Article  CAS  PubMed  Google Scholar 

  25. Sitia G, Isogawa M, Iannacone M, Campbell IL, Chisari FV, Guidotti LG . MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J Clin Invest 2004; 113: 1158–1167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kessenbrock K, Plaks V, Werb Z . Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141: 52–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dunsmore SE, Saarialho-Kere UK, Roby JD, Wilson CL, Matrisian LM, Welgus HG et al. Matrilysin expression and function in airway epithelium. J Clin Invest 1998; 102: 1321–1331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Halpert I, Sires UI, Roby JD, Potter-Perigo S, Wight TN, Shapiro SD et al. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci USA 1996; 93: 9748–9753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gonsalves CS, Kalra VK . Hypoxia-mediated expression of 5-lipoxygenase-activating protein involves HIF-1alpha and NF-kappaB and microRNAs 135a and 199a-5p. J Immunol 2010; 184: 3878–3888.

    Article  CAS  PubMed  Google Scholar 

  30. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. New Engl J Med 2010; 362: 875–885.

    Article  CAS  PubMed  Google Scholar 

  31. Lee SK, Han YM, Yun J, Lee CW, Shin DS, Ha YR et al. Phosphatase of regenerating liver-3 promotes migration and invasion by upregulating matrix metalloproteinases-7 in human colorectal cancer cells. Int J Cancer 2012; 131: E190–E203.

    Article  CAS  PubMed  Google Scholar 

  32. Schroder A, Kirwan TP, Jiang JX, Aitken KJ, Bagli DJ . Rapamycin attenuates bladder hypertrophy during long-term outlet obstruction in vivo: tissue, matrix and mechanistic insights. J Urol 2013; 189: 2377–2384.

    Article  CAS  PubMed  Google Scholar 

  33. Megias J, Busserolles J, Alcaraz MJ . The carbon monoxide-releasing molecule CORM-2 inhibits the inflammatory response induced by cytokines in Caco-2 cells. Br J Pharmacol 2007; 150: 977–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH et al. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature 1994; 370: 555–557.

    Article  CAS  PubMed  Google Scholar 

  35. Yu WH, Woessner Jr. JF, McNeish JD, Stamenkovic I . CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 2002; 16: 307–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chu J, Pratico D . Pharmacologic blockade of 5-lipoxygenase improves the amyloidotic phenotype of an Alzheimer's disease transgenic mouse model involvement of gamma-secretase. Am J Pathol 2011; 178: 1762–1769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Keith B, Simon MC . Hypoxia-inducible factors, stem cells, and cancer. Cell 2007; 129: 465–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Negus RP, Turner L, Burke F, Balkwill FR . Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors. J Leukoc Biol 1998; 63: 758–765.

    Article  CAS  PubMed  Google Scholar 

  39. Horiuchi A, Hayashi T, Kikuchi N, Hayashi A, Fuseya C, Shiozawa T et al. Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1alpha to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene. Int J Cancer 2012; 131: 1755–1767.

    Article  CAS  PubMed  Google Scholar 

  40. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 2003; 163: 1437–1447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kummer NT, Nowicki TS, Azzi JP, Reyes I, Iacob C, Xie S et al. Arachidonate 5 lipoxygenase expression in papillary thyroid carcinoma promotes invasion via MMP-9 induction. J Cell Biochem 2012; 113: 1998–2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chang MC, Chen CA, Chen PJ, Chiang YC, Chen YL, Mao TL et al. Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. Biochem J 2012; 442: 293–302.

    Article  CAS  PubMed  Google Scholar 

  43. Ashwell JD . The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 2006; 6: 532–540.

    Article  CAS  PubMed  Google Scholar 

  44. Wagner EF, Nebreda AR . Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 2009; 9: 537–549.

    Article  CAS  PubMed  Google Scholar 

  45. Murdoch C, Lewis CE . Macrophage migration and gene expression in response to tumor hypoxia. Int J Cancer 2005; 117: 701–708.

    Article  CAS  PubMed  Google Scholar 

  46. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L et al. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 2003; 163: 1233–1243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kioi M, Yamamoto K, Higashi S, Koshikawa N, Fujita K, Miyazaki K . Matrilysin (MMP-7) induces homotypic adhesion of human colon cancer cells and enhances their metastatic potential in nude mouse model. Oncogene 2003; 22: 8662–8670.

    Article  CAS  PubMed  Google Scholar 

  48. Charles KA, Kulbe H, Soper R, Escorcio-Correia M, Lawrence T, Schultheis A et al. The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest 2009; 119: 3011–3023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5: 828–831.

    Article  CAS  PubMed  Google Scholar 

  50. Wen ZH, Su YC, Lai PL, Zhang Y, Xu YF, Zhao A et al. Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis. Oncogene 2013; 32: 160–170.

    Article  CAS  PubMed  Google Scholar 

  51. Pidgeon GP, Lysaght J, Krishnamoorthy S, Reynolds JV, O'Byrne K, Nie D et al. Lipoxygenase metabolism: roles in tumor progression and survival. Cancer Metastasis Rev 2007; 26: 503–524.

    Article  CAS  PubMed  Google Scholar 

  52. Camp RL, Rimm EB, Rimm DL . Met expression is associated with poor outcome in patients with axillary lymph node negative breast carcinoma. Cancer 1999; 86: 2259–2265.

    Article  CAS  PubMed  Google Scholar 

  53. Brigatte P, Cury Y, de Souza BM, Baptista-Saidemberg NB, Saidemberg DM, Gutierrez VP et al. Hyperalgesic and edematogenic effects of peptides isolated from the venoms of honeybee (Apis mellifera) and neotropical social wasps (Polybia paulista and Protonectarina sylveirae). Amino Acids 2011; 40: 101–111.

    Article  CAS  PubMed  Google Scholar 

  54. Johnson N, Li YC, Walton ZE, Cheng KA, Li D, Rodig SJ et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med 2011; 17: 875–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Phuangsab A, Lorence RM, Reichard KW, Peeples ME, Walter RJ . Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett 2001; 172: 27–36.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Colin D Funk, Department of Physiology and Biochemistry, Queen’s University for providing us with essential material and a technical guide. This study was supported by National Natural Science Foundation of China (Nos. 31270971, 81072406).

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Authors and Affiliations

  1. Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR, China

    Z Wen, H Liu, W Gao, Q Shao, Q Wang, Q Xie, Y Yang & X Qu

  2. Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR, China

    M Li, B Li, B Fan, F Zhao & J Yu

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

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