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.

Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

“…The cPLA 2 ␣-dependent extravasation of these other inflammatory cell types may in part be a consequence of generalized compromise of integrity of the airway epithelial barrier resulting from transepithelial PMN migration (27). In addition, other AA metabolites function as inflammatory mediators for a variety of cells (79)(80)(81) such that the release of AA by cPLA 2 ␣ may promote the migration of several inflammatory cell types into airway spaces.…”

The ever-expanding role of HIF in tumour and stromal biology

“…Hypoxia also induces secretion of chemokines, such as endothelial-monocyte-activating peptide II (EMAP II), endothelin-1 and endothelin-2 (ET-1 and ET-2) that recruit macrophages to the tumour 111,112 . In ovarian cancer, hypoxia drives macrophage recruitment by stimulating the production of pro-inflammatory leukotrienes, a process that can be reversed by pharmacologic targeting of leukotriene production 113 .…”

Stress, inflammation, and eicosanoids: an emerging perspective

“…Low affinity LTB4 receptor (BLT2) and LTB4 can also contribute to the chemoresistance; co-treatment with a BLT2 inhibitor substantially reduced resistance to cisplatin in the SKOV-3 cell tumor model [108]. Expression of 5-LOX was much higher in the human ovarian tumor tissues with highly infiltrated tumor-associated macrophages and macrophages treated with 5-LOX metabolites led to increased expression of MMP-7 through the p38 pathway [109]. …”