Cross-talk between cancer cells and the tumour microenvironment: The role of the 5-lipoxygenase pathway

International Journal of Molecular Sciences

Volumn 18, Issue 2, 2017, Pages

  Moore, Gillian Y ^a   Pidgeon, Graham P ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

5 lipoxygenase; Adipose tissue; Angiogenesis; Immune cells; Leukotrienes; Tumour microenvironment

Indexed keywords

3 [3 TERT BUTYLTHIO 1 (4 CHLOROBENZYL) 5 ISOPROPYL 2 INDOLYL] 2,2 DIMETHYLPROPIONIC ACID; 5 HYDROXYICOSATETRAENOIC ACID; ALPHA PENTYL 3 (2 QUINOLYLMETHOXY)BENZYL ALCOHOL; ALPHA SMOOTH MUSCLE ACTIN; ARACHIDONATE 5 LIPOXYGENASE; ARACHIDONATE 5 LIPOXYGENASE ACTIVATING PROTEIN; ARACHIDONIC ACID; CYCLOOXYGENASE 2; GLUTATHIONE PEROXIDASE; INTERLEUKIN 10; INTERLEUKIN 1BETA; LEUKOTRIENE; LEUKOTRIENE A4 HYDROLASE; MATRILYSIN; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; MONOCYTE CHEMOTACTIC PROTEIN 1; PEPTIDES AND PROTEINS; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOLIPASE A2; PROSTAGLANDIN SYNTHASE; PROTEIN BAX; PROTEIN BCL 2; PROTEIN KINASE B; TUMOR NECROSIS FACTOR; VASCULOTROPIN; VASCULOTROPIN A;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; CANCER CELL; CANCER GROWTH; CANCER STAGING; CARCINOGENESIS; CELL INFILTRATION; CELL PROLIFERATION; COLORECTAL CARCINOMA; ENZYME ACTIVITY; ENZYME LINKED IMMUNOSORBENT ASSAY; ENZYME PHOSPHORYLATION; GENETIC TRANSCRIPTION; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; IMMUNOREGULATION; INFLAMMATION; LIPOGENESIS; NONHUMAN; PROSTATE CANCER; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; UPREGULATION; ADIPOSE TISSUE; ANIMAL; BIOSYNTHESIS; BONE MARROW CELL; CELL COMMUNICATION; DRUG EFFECTS; FIBROBLAST; IMMUNOLOGY; IMMUNOMODULATION; LIPID METABOLISM; LYMPHOCYTE; METABOLISM; NEOPLASM; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY;

ADIPOSE TISSUE; ANIMALS; ARACHIDONATE 5-LIPOXYGENASE; BIOSYNTHETIC PATHWAYS; CELL COMMUNICATION; CYCLOOXYGENASE 2; FIBROBLASTS; HUMANS; IMMUNOMODULATION; LEUKOTRIENES; LIPID METABOLISM; LYMPHOCYTES; MYELOID CELLS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 85011024226     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms18020236     Document Type: Review

References (192)

1. Albini, A., Sporn, M.B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 2007, 7, 139-147.
2. Chen, F., Zhuang, X., Lin, L., Yu, P., Wang, Y., Shi, Y., Hu, G., Sun, Y. New horizons in tumor microenvironment biology: Challenges and opportunities. BMC Med. 2015, 13, 45.
3. Quail, D.F., Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 2013, 19, 1423-1437.
4. Wang, D., DuBois, R.N. Eicosanoids and cancer. Nat. Rev. Cancer 2010, 10, 181-193.
5. Khan, R., Spagnoli, V., Tardif, J.C., L’Allier, P.L. Novel anti-inflammatory therapies for the treatment of atherosclerosis. Atherosclerosis 2015, 240, 497-509.
6. Joshi, Y.B., Pratico, D. The 5-lipoxygenase pathway: Oxidative and inflammatory contributions to the Alzheimer’s disease phenotype. Front. Cell Neurosci. 2014, 8, 436.
7. Tersey, S.A., Bolanis, E., Holman, T.R., Maloney, D.J., Nadler, J.L., Mirmira, R.G. Minireview: 12-Lipoxygenase and Islet beta-Cell Dysfunction in Diabetes. Mol. Endocrinol. 2015, 29, 791-800.
8. Knab, L.M., Grippo, P.J., Bentrem, D.J. Involvement of eicosanoids in the pathogenesis of pancreatic cancer: The roles of cyclooxygenase-2 and 5-lipoxygenase. World J. Gastroenterol. 2014, 20, 10729-10739.
9. Kuhn, H., Walther, M., Kuban, R.J. Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. Prostaglandins Other Lipid Mediat. 2002, 68-69, 263-290.
10. Klil-Drori, A.J., Ariel, A. 15-Lipoxygenases in cancer: A double-edged sword? Prostaglandins Other Lipid Mediat. 2013, 106, 16-22.
11. Kelavkar, U.P., Cohen, C. 15-lipoxygenase-1 expression upregulates and activates insulin-like growth factor-1 receptor in prostate cancer cells. Neoplasia 2004, 6, 41-52.
12. Kelavkar, U.P., Nixon, J.B., Cohen, C., Dillehay, D., Eling, T.E., Badr, K.F. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis. Carcinogenesis 2001, 22, 1765-1773.
13. Middleton, M.K., Zukas, A.M., Rubinstein, T., Jacob, M., Zhu, P., Zhao, L., Blair, I., Pure, E. Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease. J. Exp. Med. 2006, 203, 2529-2540.
14. Nixon, J.B., Kim, K.S., Lamb, P.W., Bottone, F.G., Eling, T.E. 15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer. Prostaglandins Leukot. Essent. Fatty Acids 2004, 70, 7-15.
15. Shureiqi, I., Wojno, K.J., Poore, J.A., Reddy, R.G., Moussalli, M.J., Spindler, S.A., Greenson, J.K., Normolle, D., Hasan, A.A., Lawrence, T.S., et al. Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis 1999, 20, 1985-1995.
16. Shureiqi, I., Wu, Y., Chen, D., Yang, X.L., Guan, B., Morris, J.S., Yang, P., Newman, R.A., Broaddus, R., Hamilton, S.R., et al. The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Cancer Res. 2005, 65, 11486-11492.
17. Natarajan, R., Esworthy, R., Bai, W., Gu, J.L., Wilczynski, S., Nadler, J. Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor. J. Clin. Endocrinol. Metab. 1997, 82, 1790-1798.
18. Jiang, W.G., Watkins, G., Douglas-Jones, A., Mansel, R.E. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot. Essent. Fatty Acids 2006, 74, 235-245.
19. Suraneni, M.V., Moore, J.R., Zhang, D., Badeaux, M., Macaluso, M.D., DiGiovanni, J., Kusewitt, D., Tang, D.G. Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer. Cell Cycle 2014, 13, 1798-1810.
20. Guo, Y., Nie, D. Tumor-suppressing 15-lipoxygenase-2: Time for prime time? Cell Cycle 2014, 13, 1836-1837.
21. Gao, X., Grignon, D.J., Chbihi, T., Zacharek, A., Chen, Y.Q., Sakr, W., Porter, A.T., Crissman, J.D., Pontes, J.E., Powell, I.J., et al. Elevated 12-lipoxygenase mRNA expression correlates with advanced stage and poor differentiation of human prostate cancer. Urology 1995, 46, 227-237.
22. Nithipatikom, K., Isbell, M.A., See, W.A., Campbell, W.B. Elevated 12-and 20-hydroxyeicosatetraenoic acid in urine of patients with prostatic diseases. Cancer Lett. 2006, 233, 219-225.
23. Jiang, W.G., Douglas-Jones, A., Mansel, R.E. Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer. Prostaglandins Leukot. Essent. Fatty Acids 2003, 69, 275-281.
24. Mohammad, A.M., Abdel, H.A., Abdel, W., Ahmed, A.M., Wael, T., Eiman, G. Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: Impact on prognosis and therapy. Indian J. Cancer 2006, 43, 163-168.
25. Matsuyama, M., Yoshimura, R., Mitsuhashi, M., Hase, T., Tsuchida, K., Takemoto, Y., Kawahito, Y., Sano, H., Nakatani, T. Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors. Int. J. Oncol. 2004, 24, 821-827.
26. Matsuyama, M., Hayama, T., Funao, K., Kawahito, Y., Sano, H., Takemoto, Y., Nakatani, T., Yoshimura, R. Overexpression of cysteinyl LT1 receptor in prostate cancer and CysLT1R antagonist inhibits prostate cancer cell growth through apoptosis. Oncol. Rep. 2007, 18, 99-104.
27. Jiang, W.G., Douglas-Jones, A.G., Mansel, R.E. Aberrant expression of 5-lipoxygenase-activating protein (5-LOXAP) has prognostic and survival significance in patients with breast cancer. Prostaglandins Leukot. Essent. Fatty Acids 2006, 74, 125-134.
28. Hennig, R., Ding, X.Z., Tong, W.G., Schneider, M.B., Standop, J., Friess, H., Buchler, M.W., Pour, P.M., Adrian, T.E. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am. J. Pathol. 2002, 161, 421-428.
29. Barresi, V., Grosso, M., Vitarelli, E., Tuccari, G., Barresi, G. 5-Lipoxygenase is coexpressed with Cox-2 in sporadic colorectal cancer: A correlation with advanced stage. Dis. Colon Rectum 2007, 50, 1576-1584.
30. Ding, X.Z., Iversen, P., Cluck, M.W., Knezetic, J.A., Adrian, T.E. Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells. Biochem. Biophys. Res. Commun. 1999, 261, 218-223.
31. Wen, Z., Liu, H., Li, M., Li, B., Gao, W., Shao, Q., Fan, B., Zhao, F., Wang, Q., Xie, Q., et al. Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumor-associated macrophage infiltration. Oncogene 2014, 34, 1241-1252.
32. Olkhanud, P.B., Damdinsuren, B., Bodogai, M., Gress, R.E., Sen, R., Wejksza, K., Malchinkhuu, E., Wersto, R.P., Biragyn, A. Tumor-evoked regulatory B-cells promote breast cancer metastasis by converting resting CD4+ T-cells to T-regulatory cells. Cancer Res. 2011, 71, 3505-3515.
33. Wejksza, K., Lee-Chang, C., Bodogai, M., Bonzo, J., Gonzalez, F.J., Lehrmann, E., Becker, K., Biragyn, A. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B-cells via peroxisome proliferator-activated receptor alpha. J. Immunol. 2013, 190, 2575-2584.
34. Boger, P.C., Shutt, J.D., Neale, J.R., Wilson, S.J., Bateman, A.C., Holloway, J.W., Patel, P., Sampson, A.P. Increased expression of the 5-lipoxygenase pathway and its cellular localization in Barrett’s adenocarcinoma. Histopathology 2012, 61, 509-517.
35. Balkwill, F.R., Capasso, M., Hagemann, T. The tumor microenvironment at a glance. J. Cell Sci. 2012, 125 Pt 23, 5591-5596.
36. Neels, J.G. A role for 5-lipoxygenase products in obesity-associated inflammation and insulin resistance. Adipocyte 2013, 2, 262-265.
37. Steinhilber, D., Fischer, A.S., Metzner, J., Steinbrink, S.D., Roos, J., Ruthardt, M., Maier, T.J. 5-Lipoxygenase: Underappreciated role of a pro-inflammatory enzyme in tumorigenesis. Front. Pharmacol. 2010, 1, 143.
38. Kubavat, A.H., Khippal, N., Tak, S., Rijhwani, P., Bhargava, S., Patel, T., Shah, N., Kshatriya, R.R., Mittal, R. A randomized, comparative, multicentric clinical trial to assess the efficacy and safety of zileuton extended-release tablets with montelukast sodium tablets in patients suffering from chronic persistent asthma. Am. J. Ther. 2013, 20, 154-162.
39. Harris, R.R., Carter, G.W., Bell, R.L., Moore, J.L., Brooks, D.W. Clinical activity of leukotriene inhibitors. Int. J. Immunopharmacol. 1995, 17, 147-156.
40. Knorr, B., Matz, J., Bernstein, J.A., Nguyen, H., Seidenberg, B.C., Reiss, T.F., Becker, A. Montelukast for chronic asthma in 6-to 14-year-old children: A randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 1998, 279, 1181-1186.
41. Suissa, S., Dennis, R., Ernst, P., Sheehy, O., Wood-Dauphinee, S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 1997, 126, 177-183.
42. Woods, J.W., Coffey, M.J., Brock, T.G., Singer, I.I., Peters-Golden, M. 5-Lipoxygenase is located in the euchromatin of the nucleus in resting human alveolar macrophages and translocates to the nuclear envelope upon cell activation. J. Clin. Investig. 1995, 95, 2035-2046.
43. Radmark, O., Samuelsson, B. Regulation of the activity of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Biochem. Biophys. Res. Commun. 2010, 396, 105-110.
44. Werz, O., Klemm, J., Samuelsson, B., Radmark, O. 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc. Natl. Acad. Sci. USA 2000, 97, 5261-5266.
45. Flamand, N., Ming, L., Peters-Golden, M., Brock, T.G. Phsophorylation of serine 271 on 5-lipoxygenase and its role in nuclear export. J. Biol. Chem. 2009, 284, 306-313.
46. Mancini, J.A., Abramovitz, M., Cox, M.E., Wong, E., Charleson, S., Perrier, H., Wang, Z., Prasit, P., Vickers, P.J. 5-lipoxygenase-activating protein is an arachidonate binding protein. FEBS Lett. 1993, 318, 277-281.
47. Abramovitz, M., Wong, E., Cox, M.E., Richardson, C.D., Li, C., Vickers, P.J. 5-lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase. Eur. J. Biochem. 1993, 215, 105-111.
48. Samuelsson, B., Funk, C.D. Enzymes involved in the biosynthesis of leukotriene B4. J. Biol. Chem. 1989, 264, 19469-19472.
49. Schwenk, U., Schroder, J.M. 5-Oxo-eicosanoids are potent eosinophil chemotactic factors. Functional characterization and structural requirements. J. Biol. Chem. 1995, 270, 15029-15036.
50. Rokach, J., Powell, W.S. Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE. Prog. Lipid Res. 2005, 44, 154-183.
51. Penrose, J.F., Gagnon, L., Goppelt-Struebe, M., Myers, P., Lam, B.K., Jack, R.M., Austen, K.F., Soberman, R.J. Purification of human leukotriene C4 synthase. Proc. Natl. Acad. Sci. USA 1992, 89, 11603-11606.
52. Dennis, E.A., Norris, P.C. Eicosanoid storm in infection and inflammation. Nat. Rev. Immunol. 2015, 15, 511-523.
53. Peters-Golden, M., Gleason, M.M., Togias, A. Cysteinyl leukotrienes: Multi-functional mediators in allergic rhinitis. Clin. Exp. Allergy 2006, 36, 689-703.
54. Chandrasekharan, J.A., Sharma-Walia, N. Lipoxins: Nature’s way to resolve inflammation. J. Inflamm. Res. 2015, 8, 181-192.
55. Lehmann, C., Homann, J., Ball, A.K., Blöcher, R., Kleinschmidt, T.K., Basavarajappa, D., Angioni, C., Ferreirós, N., Häfner, A.K., Rådmark, O., et al. Lipoxin and resolvin biosynthesis is dependent on 5-lipoxygenase activating protein. FASEB J. 2015, 29, 5029-5043.
56. Shutt, J.D., Boger, P., Neale, J.R., Patel, P., Sampson, A.P. Activity of the leukotriene pathway in Barrett’s metaplasia and oesophageal adenocarcinoma. Inflamm. Res. 2012, 61, 1379-1384.
57. Gupta, S., Srivastava, M., Ahmad, N., Sakamoto, K., Bostwick, D.G., Mukhtar, H. Lipoxygenase-5 is overexpressed in prostate adenocarcinoma. Cancer 2001, 91, 737-743.
58. Wasilewicz, M.P., Kolodziej, B., Bojulko, T., Kaczmarczyk, M., Sulzyc-Bielicka, V., Bielicki, D., Ciepiela, K. Overexpression of 5-lipoxygenase in sporadic colonic adenomas and a possible new aspect of colon carcinogenesis. Int. J. Colorectal. Dis. 2010, 25, 1079-1085.
59. Hennig, R., Grippo, P., Ding, X.Z., Rao, S.M., Buchler, M.W., Friess, H., Talamonti, M.S., Bell, R.H., Adrian, T.E. 5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. Cancer Res. 2005, 65, 6011-6016.
60. Tager, A.M., Luster, A.D. BLT1 and BLT2: The leukotriene B(4) receptors. Prostaglandins Leukot. Essent. Fatty Acids 2003, 69, 123-134.
61. Kanaoka, Y., Boyce, J.A. Cysteinyl leukotrienes and their receptors: Cellular distribution and function in immune and inflammatory responses. J. Immunol. 2004, 173, 1503-1510.
62. Spinozzi, F., Russano, A.M., Piattoni, S., Agea, E., Bistoni, O., de Benedictis, D., de Benedictis, F.M. Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes. Clin. Exp. Allergy 2004, 34, 1876-1882.
63. Seo, J.M., Cho, K.J., Kim, E.Y., Choi, M.H., Chung, B.C., Kim, J.H. Up-regulation of BLT2 is critical for the survival of bladder cancer cells. Exp. Mol. Med. 2011, 43, 129-137.
64. Magnusson, C., Mezhybovska, M., Lorinc, E., Fernebro, E., Nilbert, M., Sjolander, A. Low expression of CysLT1R and high expression of CysLT2R mediate good prognosis in colorectal cancer. Eur. J. Cancer 2010, 46, 826-835.
65. Magnusson, C., Liu, J., Ehrnstrom, R., Manjer, J., Jirstrom, K., Andersson, T., Sjolander, A. Cysteinyl leukotriene receptor expression pattern affects migration of breast cancer cells and survival of breast cancer patients. Int. J. Cancer 2011, 129, 9-22.
66. Venerito, M., Kuester, D., Harms, C., Schubert, D., Wex, T., Malfertheiner, P. Upregulation of Leukotriene Receptors in Gastric Cancer. Cancers 2011, 3, 3156-3168.
67. Hennig, R., Osman, T., Esposito, I., Giese, N., Rao, S.M., Ding, X.Z., Tong, W.G., Buchler, M.W., Yokomizo, T., Friess, H., et al. BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation. Br. J. Cancer 2008, 99, 1064-1073.
68. Kim, G.Y., Lee, J.W., Cho, S.H., Seo, J.M., Kim, J.H. Role of the low-affinity leukotriene B4 receptor BLT2 in VEGF-induced angiogenesis. Arterioscler Thromb. Vasc. Biol. 2009, 29, 915-920.
69. Yoo, M.H., Song, H., Woo, C.H., Kim, H., Kim, J.H. Role of the BLT2, a leukotriene B4 receptor, in Ras transformation. Oncogene 2004, 23, 9259-9268.
70. Kim, E.Y., Seo, J.M., Cho, K.J., Kim, J.H. Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway. Oncogene 2010, 29, 1167-1178.
71. Ghosh, J., Myers, C.E. Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc. Natl. Acad. Sci. USA 1998, 95, 13182-13187.
72. Meng, Z., Cao, R., Yang, Z., Liu, T., Wang, Y., Wang, X. Inhibitor of 5-lipoxygenase, zileuton, suppresses prostate cancer metastasis by upregulating E-cadherin and paxillin. Urology 2013, 82, 1452.e7-1452.e14.
73. Sarveswaran, S., Thamilselvan, V., Brodie, C., Ghosh, J. Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon. Biochim. Biophys. Acta 2011, 1813, 2108-2117.
74. Sarveswaran, S., Chakraborty, D., Chitale, D., Sears, R., Ghosh, J. Inhibition of 5-lipoxygenase selectively triggers disruption of c-myc signaling in prostate cancer cells. J. Biol. Chem. 2015, 290, 4994-5006.
75. Saraveswaran, S., Varma, N., Morisetty, S., Ghosh, J. Inhibition of 5-lipoxygenase downregulates stemness and kills prostate cancer stem cells by triggering apoptosis via activation of c-Jun N-terminal kinase. Oncotarget 2016.
76. Matsuyama, M., Yoshimura, R., Mitsuhashi, M., Tsuchida, K., Takemoto, Y., Kawahito, Y., Sano, H., Nakatani, T. 5-Lipoxygenase inhibitors attenuate growth of human renal cell carcinoma and induce apoptosis through arachidonic acid pathway. Oncol. Rep. 2005, 14, 73-79.
77. Ding, X.Z., Tong, W.G., Adrian, T.E. Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer. Oncology 2003, 65, 285-294.
78. Tong, W.G., Ding, X.Z., Witt, R.C., Adrian, T.E. Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol. Cancer Ther. 2002, 1, 929-935.
79. Fischer, A.S., Metzner, J., Steinbrink, S.D., Ulrich, S., Angioni, C., Geisslinger, G., Steinhilber, D., Maier, T.J. 5-Lipoxygenase inhibitors induce potent anti-proliferative and cytotoxic effects in human tumour cells independently of suppression of 5-lipoxygenase activity. Br. J. Pharmacol. 2010, 161, 936-949.
80. Roos, J., Oancea, C., Heinssmann, M., Khan, D., Held, H., Kahnt, A.S., Capelo, R., la Buscato, E., Proschak, E., Puccetti, E., et al. 5-Lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia. Cancer Res. 2014, 74, 5244-5255.
81. Chen, Y., Hu, Y., Zhang, H., Peng, C., Li, S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat. Genet. 2009, 41, 783-792.
82. Gajewski, T.F., Schreiber, H., Fu, Y.X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 2013, 14, 1014-1022.
83. De Visser, K.E., Eichten, A., Coussens, L.M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 2006, 6, 24-37.
84. Zamarron, B.F., Chen, W. Dual roles of immune cells and their factors in cancer development and progression. Int. J. Biol. Sci. 2011, 7, 651-658.
85. Hoque, A., Lippman, S.M., Wu, T.T., Xu, Y., Liang, Z.D., Swisher, S., Zhang, H., Cao, L., Ajani, J.A., Xu, X.C. Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: A potential target for prevention. Carcinogenesis 2005, 26, 785-791.
86. Melstrom, L.G., Bentrem, D.J., Salabat, M.R., Kennedy, T.J., Ding, X.Z., Strouch, M., Rao, S.M., Witt, R.C., Ternent, C.A., Talamonti, M.S., et al. Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin. Cancer Res. 2008, 14, 6525-6530.
87. Cheon, E.C., Khazaie, K., Khan, M.W., Strouch, M.J., Krantz, S.B., Phillips, J., Blatner, N.R., Hix, L.M., Zhang, M., Dennis, K.L., et al. Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APCDelta468 mice. Cancer Res. 2011, 71, 1627-1636.
88. Brock, T.G. Regulating leukotriene synthesis: The role of nuclear 5-lipoxygenase. J. Cell. Biochem. 2005, 96, 1203-1211.
89. Majumdar, R., Tavakoli Tameh, A., Parent, C.A. Exosomes Mediate LTB4 Release during Neutrophil Chemotaxis. PLoS Biol. 2016, 14, e1002336.
90. Peters-Golden, M., Henderson, W.R., Jr. Leukotrienes. N. Engl. J. Med. 2007, 357, 1841-1854.
91. Pace, E., Profita, M., Melis, M., Bonanno, A., Paterno, A., Mody, C.H., Spatafora, M., Ferraro, M., Siena, L., Vignola, A.M., et al. LTB4 is present in exudative pleural effusions and contributes actively to neutrophil recruitment in the inflamed pleural space. Clin. Exp. Immunol. 2004, 135, 519-527.
92. Cheon, E.C., Strouch, M.J., Krantz, S.B., Heiferman, M.J., Bentrem, D.J. Genetic deletion of 5-lipoxygenase increases tumor-infiltrating macrophages in Apc(Delta468) mice. J. Gastrointest. Surg. 2012, 16, 389-393.
93. Qualls, J.E., Murray, P.J. Tumor macrophages protective and pathogenic roles in cancer development. Curr. Top. Dev. Biol. 2011, 94, 309-328.
94. Xing, Z., Zganiacz, A., Santosuosso, M. Role of IL-12 in macrophage activation during intracellular infection: IL-12 and mycobacteria synergistically release TNF-alpha and nitric oxide from macrophages via IFN-gamma induction. J. Leukoc. Biol. 2000, 68, 897-902.
95. Chanmee, T., Ontong, P., Konno, K., Itano, N. Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment. Cancers 2014, 6, 1670-1690.
96. Condeelis, J., Pollard, J.W. Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006, 124, 263-266.
97. Ohta, M., Kitadai, Y., Tanaka, S., Yoshihara, M., Yasui, W., Mukaida, N., Haruma, K., Chayama, K. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int. J. Oncol. 2003, 22, 773-778.
98. Kobayashi, K.S., Flavell, R.A. Shielding the double-edged sword: Negative regulation of the innate immune system. J. Leukoc. Biol. 2004, 75, 428-433.
99. Musa, M. Immune Mechanism: A ‘Double-Edged Sword’. Malays J. Med. Sci. 2013, 20, 61-67.
100. Kilfeather, S. 5-lipoxygenase inhibitors for the treatment of COPD. Chest 2002, 121 (Suppl S5), 197S-200S.
101. Kowal-Bielecka, O., Distler, O., Kowal, K., Siergiejko, Z., Chwiecko, J., Sulik, A., Gay, R.E., Lukaszyk, A.B., Gay, S., Sierakowski, S. Elevated levels of leukotriene B4 and leukotriene E4 in bronchoalveolar lavage fluid from patients with scleroderma lung disease. Arthritis Rheumatol. 2003, 48, 1639-1646.
102. Amat, M., Barcons, M., Mancebo, J., Mateo, J., Oliver, A., Mayoral, J.F., Fontcuberta, J., Vila, L. Evolution of leukotriene B4, peptide leukotrienes, and interleukin-8 plasma concentrations in patients at risk of acute respiratory distress syndrome and with acute respiratory distress syndrome: Mortality prognostic study. Crit. Care Med. 2000, 28, 57-62.
103. Mao, J.T., Tsu, I.H., Dubinett, S.M., Adams, B., Sarafian, T., Baratelli, F., Roth, M.D., Serio, K.J. Modulation of pulmonary leukotriene B4 production by cyclooxygenase-2 inhibitors and lipopolysaccharide. Clin. Cancer Res. 2004, 10, 6872-6878.
104. Mao, J.T., Tashkin, D.P., Tsu, I.H., Serio, K.J. Differential modulation of leukotriene B4 synthesis and degradation in human bronchoalveolar lavage cells by lipopolysaccharide and tobacco smoke. Cancer Prev. Res. 2008, 1, 266-274.
105. Ohd, J.F., Nielsen, C.K., Campbell, J., Landberg, G., Lofberg, H., Sjolander, A. Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas. Gastroenterology 2003, 124, 57-70.
106. Salim, T., Sand-Dejmek, J., Sjolander, A. The inflammatory mediator leukotriene D(4) induces subcellular beta-catenin translocation and migration of colon cancer cells. Exp. Cell Res. 2014, 321, 255-266.
107. Boyce, J.A. Mast cells and eicosanoid mediators: A system of reciprocal paracrine and autocrine regulation. Immunol. Rev. 2007, 217, 168-185.
108. Gounaris, E., Erdman, S.E., Restaino, C., Gurish, M.F., Friend, D.S., Gounari, F., Lee, D.M., Zhang, G., Glickman, J.N., Shin, K., et al. Mast cells are an essential hematopoietic component for polyp development. Proc. Natl. Acad. Sci. USA 2007, 104, 19977-19982.
109. Rodriguez, P.C., Quiceno, D.G., Zabaleta, J., Ortiz, B., Zea, A.H., Piazuelo, M.B., Delgado, A., Correa, P., Brayer, J., Sotomayor, E.M., et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004, 64, 5839-5849.
110. Gounaris, E., Heiferman, M.J., Heiferman, J.R., Shrivastav, M., Vitello, D., Blatner, N.R., Knab, L.M., Phillips, J.D., Cheon, E.C., Grippo, P.J., et al. Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PLoS ONE 2015, 10, e0121402.
111. Knab, L.M., Schultz, M., Principe, D.R., Mascarinas, W.E., Gounaris, E., Munshi, H.G., Grippo, P.J., Bentrem, D.J. Ablation of 5-lipoxygenase mitigates pancreatic lesion development. J. Surg. Res. 2015, 194, 481-487.
112. Mangalath, U., Aslam, S.A., Abdul Khadar, A.H., Francis, P.G., Mikacha, M.S., Kalathingal, J.H. Recent trends in prevention of oral cancer. J. Int. Soc. Prev. Community Dent. 2014, 4 (Suppl S3), S131-S138.
113. Rosenquist, K. Risk factors in oral and oropharyngeal squamous cell carcinoma: A population-based case-control study in southern Sweden. Swed. Dent. J. Suppl. 2005, 179, 1-66.
114. Guo, Y., Wang, X., Zhang, X., Sun, Z., Chen, X. Ethanol promotes chemically induced oral cancer in mice through activation of the 5-lipoxygenase pathway of arachidonic acid metabolism. Cancer Prev. Res. 2011, 4, 1863-1872.
115. Nagashima, T., Ichimiya, S., Kikuchi, T., Saito, Y., Matsumiya, H., Ara, S., Koshiba, S., Zhang, J., Hatate, C., Tonooka, A., et al. Arachidonate 5-lipoxygenase establishes adaptive humoral immunity by controlling primary B-cells and their cognate T-cell help. Am. J. Pathol. 2011, 178, 222-232.
116. Nielsen, J.S., Sahota, R.A., Milne, K., Kost, S.E., Nesslinger, N.J., Watson, P.H., Nelson, B.H. CD20+ tumor-infiltrating lymphocytes have an atypical CD27-memory phenotype and together with CD8+ T-cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 2012, 18, 3281-3292.
117. Erdag, G., Schaefer, J.T., Smolkin, M.E., Deacon, D.H., Shea, S.M., Dengel, L.T., Patterson, J.W., Slingluff, C.L., Jr. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 2012, 72, 1070-1080.
118. He, Y., Qian, H., Liu, Y., Duan, L., Li, Y., Shi, G. The roles of regulatory B-cells in cancer. J. Immunol. Res. 2014, 2014, 215471.
119. Guriec, N., Le Jossic-Corcos, C., Simon, B., Ianotto, J.C., Tempescul, A., Dreano, Y., Salaun, J.P., Berthou, C., Corcos, L. The arachidonic acid-LTB4-BLT2 pathway enhances human B-CLL aggressiveness. Biochim. Biophys. Acta 2014, 1842, 2096-2105.
120. Cook-Moreau, J.M., El-Makhour Hojeij, Y., Barrière, G., Rabinovitch-Chable Héè, C., Faucher, K.S., Sturtz, F.G., Rigaud, M.A. Expression of 5-lipoxygenase (5-LOX) in T lymphocytes. Immunology 2007, 122, 157-166.
121. Prinz, I., Gregoire, C., Mollenkopf, H., Aguado, E., Wang, Y., Malissen, M., Kaufmann, S.H., Malissen, B. The type 1 cysteinyl leukotriene receptor triggers calcium influx and chemotaxis in mouse alpha beta-and gamma delta effector T-cells. J. Immunol. 2005, 175, 713-719.
122. Miyahara, N., Takeda, K., Miyahara, S., Taube, C., Joetham, A., Koya, T., Matsubara, S., Dakhama, A., Tager, A.M., Luster, A.D., et al. Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8+ T-cells and airway hyperresponsiveness. J. Immunol. 2005, 174, 4979-4984.
123. Sharma, R.K., Chheda, Z., Jala, V.R., Haribabu, B. Expression of Leukotriene B(4) receptor-1 on CD8(+) T-cells is required for their migration into tumors to elicit effective antitumor immunity. J. Immunol. 2013.
124. Poczobutt, J.M., Nguyen, T.T., Hanson, D., Li, H., Sippel, T.R., Weiser-Evans, M.C., Gijon, M., Murphy, R.C., Nemenoff, R.A. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment. J. Immunol. 2016, 196, 891-901.
125. Blatner, N.R., Mulcahy, M.F., Dennis, K.L., Scholtens, D., Bentrem, D.J., Phillips, J.D., Ham, S., Sandall, B.P., Khan, M.W., Mahvi, D.M., et al. Expression of RORgammat marks a pathogenic regulatory T-cell subset in human colon cancer. Sci. Transl. Med. 2012, 4, 164ra159.
126. Benard, M., Straat, K., Omarsdottir, S., Leghmari, K., Bertrand, J., Davrinche, C., Duga-Neulat, I., Soderberg-Naucler, C., Rahbar, A., Casper, C. Human cytomegalovirus infection induces leukotriene B4 and 5-lipoxygenase expression in human placentae and umbilical vein endothelial cells. Placenta 2014, 35, 345-350.
127. Walker, J.L., Loscalzo, J., Zhang, Y.Y. 5-Lipoxygenase and human pulmonary artery endothelial cell proliferation. Am. J. Physiol. Heart Circ. Physiol. 2002, 282, H585-H593.
128. Wright, L., Tuder, R.M., Wang, J., Cool, C.D., Lepley, R.A., Voelkel, N.F. 5-Lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 1998, 157, 219-229.
129. Sharma-Walia, N., Chandran, K., Patel, K., Veettil, M.V., Marginean, A. The Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis. J. Virol. 2014, 88, 2131-2156.
130. Delgado, T., Sanchez, E.L., Camarda, R., Lagunoff, M. Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS Pathog. 2012, 8, e1002866.
131. Qiu, H., Johansson, A.S., Sjostrom, M., Wan, M., Schroder, O., Palmblad, J., Haeggstrom, J.Z. Differential induction of BLT receptor expression on human endothelial cells by lipopolysaccharide, cytokines, and leukotriene B4. Proc. Natl. Acad. Sci. USA 2006, 103, 6913-6918.
132. Johansson, A.S., Haeggstrom, J.Z., Palmblad, J. Commonly used leukotriene B4 receptor antagonists possess intrinsic activity as agonists in human endothelial cells: Effects on calcium transients, adhesive events and mediator release. Prostaglandins Leukot. Essent. Fatty Acids 2011, 84, 109-112.
133. Boado, R.J., Pardridge, W.M., Vinters, H.V., Black, K.L. Differential expression of arachidonate 5-lipoxygenase transcripts in human brain tumors: Evidence for the expression of a multitranscript family. Proc. Natl. Acad. Sci. USA 1992, 89, 9044-9048.
134. Bian, X.W., Jiang, X.F., Chen, J.H., Bai, J.S., Dai, C., Wang, Q.L., Lu, J.Y., Zhao, W., Xin, R., Liu, M.Y., et al. Increased angiogenic capabilities of endothelial cells from microvessels of malignant human gliomas. Int. Immunopharmacol. 2006, 6, 90-99.
135. Taylor, K.L., Grant, N.J., Temperley, N.D., Patton, E.E. Small molecule screening in zebrafish: An in vivo approach to identifying new chemical tools and drug leads. Cell Commun. Signal. 2010, 8, 11.
136. Tobia, C., Gariano, G., De Sena, G., Presta, M. Zebrafish embryo as a tool to study tumor/endothelial cell cross-talk. Biochim. Biophys. Acta 2013, 1832, 1371-1377.
137. Zhang, S., Cao, Z., Tian, H., Shen, G., Ma, Y., Xie, H., Liu, Y., Zhao, C., Deng, S., Yang, Y., et al. SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo. Clin. Cancer Res. 2011, 17, 4439-4450.
138. Yang, X., Cui, W., Yu, S., Xu, C., Chen, G., Gu, A., Li, T., Cui, Y., Zhang, X., Bian, X. A synthetic dl-nordihydroguaiaretic acid (Nordy), inhibits angiogenesis, invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model. PLoS ONE 2014, 9, e85759.
139. Sapieha, P., Stahl, A., Chen, J., Seaward, M.R., Willett, K.L., Krah, N.M., Dennison, R.J., Connor, K.M., Aderman, C.M., Liclican, E., et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of omega-3 polyunsaturated fatty acids. Sci. Transl. Med. 2011, 3, 69ra12.
140. Chatterjee, M., Das, S., Roy, K., Chatterjee, M. Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(alpha)anthracene-induced rat mammary carcinogenesis. Mol. Carcinog. 2013, 52, 359-369.
141. Ye, Y.N., Liu, E.S., Shin, V.Y., Wu, W.K., Cho, C.H. Contributory role of 5-lipoxygenase and its association with angiogenesis in the promotion of inflammation-associated colonic tumorigenesis by cigarette smoking. Toxicology 2004, 203, 179-188.
142. Romano, M., Catalano, A., Nutini, M., D’Urbano, E., Crescenzi, C., Claria, J., Libner, R., Davi, G., Procopio, A. 5-lipoxygenase regulates malignant mesothelial cell survival: Involvement of vascular endothelial growth factor. FASEB J. 2001, 15, 2326-2336.
143. Barresi, V., Vitarelli, E., Tuccari, G., Barresi, G. Correlative study of microvessel density and 5-lipoxygenase expression in human sporadic colorectal cancer. Arch. Pathol. Lab. Med. 2008, 132, 1807-1812.
144. Choi, S.P., Kim, S.P., Nam, S.H., Friedman, M. Antitumor effects of dietary black and brown rice brans in tumor-bearing mice: Relationship to composition. Mol. Nutr. Food Res. 2013, 57, 390-400.
145. Feinmark, S.J., Cannon, P.J. Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. J. Biol. Chem. 1986, 261, 16466-16472.
146. Folco, G., Murphy, R.C. Eicosanoid transcellular biosynthesis: From cell-cell interactions to in vivo tissue responses. Pharmacol. Rev. 2006, 58, 375-388.
147. Claesson, H.E., Haeggstrom, J. Human endothelial cells stimulate leukotriene synthesis and convert granulocyte released leukotriene A4 into leukotrienes B4, C4, D4 and E4. Eur. J. Biochem. 1988, 173, 93-100.
148. Palmblad, J., Malmsten, C.L., Uden, A.M., Radmark, O., Engstedt, L., Samuelsson, B. Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence. Blood 1981, 58, 658-661.
149. Tager, A.M., Bromley, S.K., Medoff, B.D., Islam, S.A., Bercury, S.D., Friedrich, E.B., Carafone, A.D., Gerszten, R.E., Luster, A.D. Leukotriene B4 receptor BLT1 mediates early effector T-cell recruitment. Nat. Immunol. 2003, 4, 982-990.
150. Ott, V.L., Cambier, J.C., Kappler, J., Marrack, P., Swanson, B.J. Mast cell-dependent migration of effector CD8+ T-cells through production of leukotriene B4. Nat. Immunol. 2003, 4, 974-981.
151. Lee, E., Robertson, T., Smith, J., Kilfeather, S. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am. J. Respir. Crit. Care Med. 2000, 161, 1881-1886.
152. Bjork, J., Hedqvist, P., Arfors, K.E. Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes. Inflammation 1982, 6, 189-200.
153. Rosengren, S., Olofsson, A.M., von Andrian, U.H., Lundgren-Akerlund, E., Arfors, K.E. Leukotriene B4-induced neutrophil-mediated endothelial leakage in vitro and in vivo. J. Appl. Physiol. (1985) 1991, 71, 1322-1330.
154. Di Gennaro, A., Kenne, E., Wan, M., Soehnlein, O., Lindbom, L., Haeggstrom, J.Z. Leukotriene B4-induced changes in vascular permeability are mediated by neutrophil release of heparin-binding protein (HBP/CAP37/azurocidin). FASEB J. 2009, 23, 1750-1757.
155. Carnini, C., Accomazzo, M.R., Borroni, E., Vitellaro-Zuccarello, L., Durand, T., Folco, G., Rovati, G.E., Capra, V., Sala, A. Synthesis of cysteinyl leukotrienes in human endothelial cells: Subcellular localization and autocrine signaling through the CysLT2 receptor. FASEB J. 2011, 25, 3519-3528.
156. Pedersen, K.E., Bochner, B.S., Undem, B.J. Cysteinyl leukotrienes induce P-selectin expression in human endothelial cells via a non-CysLT1 receptor-mediated mechanism. J. Pharmacol. Exp. Ther. 1997, 281, 655-662.
157. Zhao, L., Moos, M.P., Grabner, R., Pedrono, F., Fan, J., Kaiser, B., John, N., Schmidt, S., Spanbroek, R., Lotzer, K., et al. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat. Med. 2004, 10, 966-973.
158. Uzonyi, B., Lotzer, K., Jahn, S., Kramer, C., Hildner, M., Bretschneider, E., Radke, D., Beer, M., Vollandt, R., Evans, J.F., et al. Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells. Proc. Natl. Acad. Sci. USA 2006, 103, 6326-6331.
159. Duah, E., Adapala, R.K., Al-Azzam, N., Kondeti, V., Gombedza, F., Thodeti, C.K., Paruchuri, S. Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT(2) and CysLT(1) receptors. Sci. Rep. 2013, 3, 3274.
160. Chen, X., Wang, S., Wu, N., Yang, C.S. Leukotriene A4 hydrolase as a target for cancer prevention and therapy. Curr. Cancer Drug Targets 2004, 4, 267-283.
161. Romano, M., Claria, J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: Implications for cancer therapy. FASEB J. 2003, 17, 1986-1995.
162. Park, S.W., Heo, D.S., Sung, M.W. 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. Cell Oncol. 2012, 35, 1-8.
163. Ye, Y.N., Wu, W.K., Shin, V.Y., Bruce, I.C., Wong, B.C., Cho, C.H. Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke. Carcinogenesis 2005, 26, 827-834.
164. De Pergola, G., Silvestris, F. Obesity as a major risk factor for cancer. J. Obes. 2013, 2013, 291546.
165. Nieman, K.M., Romero, I.L., van Houten, B., Lengyel, E. Adipose tissue and adipocytes supports tumorigenesis and metastasis. Biochim. Biophys. Acta 2013, 1831, 1533-1541.
166. Long, E., Beales, I.L.P. The role of obesity in oesophageal cancer development. Ther. Adv. Gastroenterol. 2014, 7, 247-268.
167. Garofalo, C., Surmacz, E. Leptin and cancer. J. Cell. Physiol. 2006, 207, 12-22.
168. Khandekar, M.J., Cohen, P., Spiegelman, B.M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 2011, 11, 886-895.
169. Patterson, E., Wall, R., Fitzgerald, G.F., Ross, R.P., Stanton, C. Health implications of high dietary omega-6 polyunsaturated Fatty acids. J. Nutr. Metab. 2012, 2012, 539426.
170. Horrillo, R., Gonzalez-Periz, A., Martinez-Clemente, M., Lopez-Parra, M., Ferre, N., Titos, E., Moran-Salvador, E., Deulofeu, R., Arroyo, V., Claria, J. 5-lipoxygenase activating protein signals adipose tissue inflammation and lipid dysfunction in experimental obesity. J. Immunol. 2010, 184, 3978-3987.
171. Hirata, K., Wada, K., Murata, Y., Nakajima, A., Yamashiro, T., Kamisaki, Y. Critical role of leukotriene B4 receptor signaling in mouse 3T3-L1 preadipocyte differentiation. Lipids Health Dis. 2013, 12, 122.
172. Li, P., Oh Da, Y., Bandyopadhyay, G., Lagakos, W.S., Talukdar, S., Osborn, O., Johnson, A., Chung, H., Mayoral, R., Maris, M., et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat. Med. 2015, 21, 239-247.
173. Curat, C.A., Miranville, A., Sengenes, C., Diehl, M., Tonus, C., Busse, R., Bouloumie, A. From blood monocytes to adipose tissue-resident macrophages: Induction of diapedesis by human mature adipocytes. Diabetes 2004, 53, 1285-1292.
174. Sartipy, P., Loskutoff, D.J. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 2003, 100, 7265-7270.
175. Kaaman, M., Ryden, M., Axelsson, T., Nordstrom, E., Sicard, A., Bouloumie, A., Langin, D., Arner, P., Dahlman, I. ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance. Int. J. Obes. 2006, 30, 447-452.
176. Matsukawa, A., Hogaboam, C.M., Luckacs, N.W., Lincoln, P.M., Strieter, R.M., Kunkel, S.L. Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: Cross-talk between MCP-1 and leukotriene B4. J. Immunol. 1999, 163, 6148-6154.
177. Lumeng, C.N., Maillard, I., Saltiel, A.R. T-ing up inflammation in fat. Nat. Med. 2009, 15, 846-847.
178. Monteiro, R., Azevedo, I. Chronic inflammation in obesity and the metabolic syndrome. Mediat. Inflamm. 2010, 2010, 289645.
179. Mothe-Satney, I., Filloux, C., Amghar, H., Pons, C., Bourlier, V., Galitzky, J., Grimaldi, P.A., Feral, C.C., Bouloumie, A., van Obberghen, E., et al. Adipocytes secrete leukotrienes: Contribution to obesity-associated inflammation and insulin resistance in mice. Diabetes 2012, 61, 2311-2319.
180. Spite, M., Hellmann, J., Tang, Y., Mathis, S.P., Kosuri, M., Bhatnagar, A., Jala, V.R., Haribabu, B. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. J. Immunol. 2011, 187, 1942-1949.
181. Chakrabarti, S.K., Wen, Y., Dobrian, A.D., Cole, B.K., Ma, Q., Pei, H., Williams, M.D., Bevard, M.H., Vandenhoff, G.E., Keller, S.R., et al. Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats. Am. J. Physiol. Endocrinol. Metab. 2011, 300, E175-E187.
182. Wood, P.A. Connecting the dots: Obesity, fatty acids and cancer. Lab. Investig. 2009, 89, 1192-1194.
183. Somasundar, P., Riggs, D., Jackson, B., Vona-Davis, L., McFadden, D.W. Leptin stimulates esophageal adenocarcinoma growth by nonapoptotic mechanisms. Am. J. Surg. 2003, 186, 575-578.
184. Dirat, B., Bochet, L., Dabek, M., Daviaud, D., Dauvillier, S., Majed, B., Wang, Y.Y., Meulle, A., Salles, B., Le Gonidec, S., et al. Cancer associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011, 71, 2455-2465.
185. Kalluri, R., Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 2006, 6, 392-401.
186. Mensing, H., Czarnetzki, B.M. Leukotriene B4 induces in vitro fibroblast chemotaxis. J. Investig. Dermatol. 1984, 82, 9-12.
187. Chibana, K., Ishii, Y., Asakura, T., Fukuda, T. Up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin. J. Immunol. 2003, 170, 4290-4295.
188. Eap, R., Jacques, E., Semlali, A., Plante, S., Chakir, J. Cysteinyl leukotrienes regulate TGF-beta(1) and collagen production by bronchial fibroblasts obtained from asthmatic subjects. Prostaglandins Leukot. Essent. Fatty Acids 2012, 86, 127-133.
189. Medina, J.F., Barrios, C., Funk, C.D., Larsson, O., Haeggstrom, J., Radmark, O. Human fibroblasts show expression of the leukotriene-A4-hydrolase gene, which is increased after simian-virus-40 transformation. Eur. J. Biochem. 1990, 191, 27-31.
190. Izumo, T., Kondo, M., Nagai, A. Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis. Eur. Respir. J. 2009, 34, 1444-1451.
191. El-Swefy, S., Hassanen, S.I. Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats. Ann. Hepatol. 2009, 8, 41-49.
192. Taylor, P.M., Woodfield, R.J., Hodgkin, M.N., Pettitt, T.R., Martin, A., Kerr, D.J., Wakelam, M.J. Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway. Oncogene 2002, 21, 5765-5772.