title: Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumor-associated macrophage infiltration.
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.
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China.
authors.forename: B
authors.initials: B
authors.lastname: Fan
authors.affiliation: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China.
authors.forename: F
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Qu
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D006893:Hydroxyeicosatetraenoic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase; D020783:Matrix Metalloproteinase 7; C063449:zileuton; D006918:Hydroxyurea