13-hydroxy-9-11-octadecadienoic-acid and Neoplasms

Cancer initiation and progression are multistep events that require cell proliferation, migration, extravasation to the blood or lymphatic vessels, arrest to the metastatic site, and ultimately secondary growth. Tumor cell functions at both primary or secondary sites are controlled by many different factors, including growth factors and their receptors, chemokines, nuclear receptors, cell-cell interactions, cell-matrix interactions, as well as oxygenated metabolites of arachidonic acid. The observation that cyclooxygenases and lipoxygenases and their arachidonic acid-derived eicosanoid products (prostanoids and HETEs) are expressed and produced by tumor cells, together with the finding that these enzymes can regulate cell growth, survival, migration, and invasion, has prompted investigators to analyze the roles of these enzymes in cancer progression. In this review, we focus on the contribution of cyclooxygenase- and lipoxygenase-derived eicosanoids to tumor cell function in vitro and in vivo and discuss hope and tribulations of targeting these enzymes for cancer prevention and treatment.

Topics: Animals; Antineoplastic Agents; Arachidonate Lipoxygenases; Cell Transformation, Neoplastic; Cyclooxygenase Inhibitors; Eicosanoids; Humans; Linoleic Acids; Neoplasms; Prostaglandin-Endoperoxide Synthases

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Arachidonic Acid; Carcinogenesis; Carcinogens; Dinoprostone; Humans; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Neoplasms; Rats

We hypothesize that the ratio of intracellular 13-hydroxy-octadeca-dienoic acid (13 HODE) and hydroxy-eicosatetraenoic acid (5-, 12- and/or 15-HETE) influences the expression or presentation of adhesive moieties on platelets, leukocytes, malignant cells and endothelial cells, thereby influencing their subsequent adhesive interactions. Thus, we demonstrate that under unstimulated conditions, these cells preferentially synthesize linoleic acid via their lipoxygenase enzymes into 13-HODE, the intracellular level of which is associated with limited or no cell adhesion, while following stimulation, the same cells preferentially metabolize arachidonic acid via the lipoxygenase enzyme into HETEs, the production of which is associated with enhanced adhesion. Which metabolite is synthesized by these cells and the subsequent adhesivity of these cells appear to be dependent upon both the intracellular level of cAMP and the ratio of linoleic and arachidonic acid substrates. This suggests that manipulation of this ratio will have significant effects on the adhesive events involved in the pathogenesis of thrombosis, inflammation and metastasis.

Topics: Animals; Cell Adhesion; Endothelium, Vascular; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukocytes; Linoleic Acids; Lipoxygenase; Models, Biological; Neoplasms; Platelet Adhesiveness; Thrombosis

Some studies report that endothelial cells preferentially take up the lipoxygenase-derived arachidonic acid metabolite, 5-hydroxyeicosatetraenoic acid (5-HETE), released from stimulated leukocytes (polymorphonuclear leukocytes, PMNs), whereas others report that endothelial cells preferentially take up 12-HETE released from platelets. The biological relevance of these observations, however, is unknown. Recently, we and others have found that, under basal conditions, endothelial cells, PMNs and tumor cells metabolize linoleic acid via the lipoxygenase enzyme to 13-hydroxyoctadecadienoic acid (13-HODE). We propose that endogenous levels of these metabolites regulate blood-vessel wall cell adhesion. In this study, we have measured (1) the relative binding of 5-, 12- and 15-HETE, and 13-HODE to endothelial cell monolayers, and (2) their effects on endothelial cell adhesivity with platelets, PMNs and tumor cells. There was a dose-related and specific binding of 5-[3H]HETE to endothelial cells but no binding of 12- or 15-HETE or 13-HODE. Platelet or PMN adhesion to endothelial cells was unaffected by the 5-HETE binding, but tumor cell adhesion was blocked by 40% (P less than 0.01). Interestingly, preincubation of endothelial cells with 13-HODE, 12-HETE or 15-HETE decreased platelet adhesion to endothelial cells (P less than 0.05), even though these metabolites did not bind to the endothelial cells. We conclude that 5-HETE preferentially binds to endothelial cells and interferes with a specific receptor for tumor cells, whereas the other metabolites neither bind to cells nor affect cell adhesion.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Cell Adhesion; Endothelium, Vascular; Humans; Hydroxyeicosatetraenoic Acids; Linoleic Acids; Neoplasms; Neutrophils; Platelet Adhesiveness; Tumor Cells, Cultured