leukotriene-b4 and Neoplasms

Leukotriene B4 (LTB4) is a major type of lipid mediator that is rapidly generated from arachidonic acid through sequential action of 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and LTA4 hydrolase (LTA4H) in response to various stimuli. LTB4 is well known to be a chemoattractant for leukocytes, particularly neutrophils, via interaction with its high-affinity receptor BLT1. Extensive attention has been paid to the role of the LTB4-BLT1 axis in acute and chronic inflammatory diseases, such as infectious diseases, allergy, autoimmune diseases, and metabolic disease via mediating recruitment and/or activation of different types of inflammatory cells depending on different stages or the nature of inflammatory response. Recent studies also demonstrated that LTB4 acts on non-immune cells via BLT1 to initiate and/or amplify pathological inflammation in various tissues. In addition, emerging evidence reveals a complex role of the LTB4-BLT1 axis in cancer, either tumor-inhibitory or tumor-promoting, depending on the different target cells. In this review, we summarize both established understanding and the most recent progress in our knowledge about the LTB4-BLT1 axis in host defense, inflammatory diseases and cancer.

Topics: Animals; Disease; Health; Humans; Inflammation; Leukotriene B4; Neoplasms; Receptors, Leukotriene B4

Leukotriene B

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arthritis; Cardiovascular Diseases; Flap Endonucleases; Humans; Leukotriene B4; Neoplasms; Neutrophils; Pulmonary Disease, Chronic Obstructive; Structure-Activity Relationship

Aberrant arachidonic acid metabolism has recently received intensive attention in the field of cancer research. Recent discoveries regarding the long-term cardiovascular side effects of cyclooxygenase 2 inhibitors have cast doubts on their use for cancer chemoprevention. Although such a problem does not undermine the importance of cyclooxygenase 2 as a cancer chemopreventive target, investigation into other AA-metabolizing pathways that are also important in inflammation and inflammation-associated carcinogenesis is necessary. Here, the important role of the 5-lipoxygenase pathway in carcinogenesis is reviewed. Inhibition of the 5-lipoxygenase pathways clearly has chemopreventive effects on various cancers, and hence further studies on its enzymes, metabolites and receptors for cancer chemoprevention and therapy are warranted.

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Anticarcinogenic Agents; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Carrier Proteins; Enzyme Inhibitors; Humans; Leukotriene B4; Leukotriene C4; Lipoxygenase Inhibitors; Membrane Proteins; Neoplasms; Receptors, Leukotriene; Receptors, Leukotriene B4

Leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme with the activities of epoxide hydrolase and aminopeptidase. As an epoxide hydrolase, LTA4H catalyzes the hydrolysis of the epoxide LTA4 to the diol, leukotriene B4 (LTB4), which mainly functions as a chemoattractant and an activator of inflammatory cells. As an aminopeptidase, LTA4H may process peptides related to inflammation and host defense. In a chronic inflammation-associated animal model of esophageal adenocarcinoma, we have shown that LTA4H was overexpressed in tumor as compared to normal tissues. Bestatin, an LTA4H inhibitor, suppresses tumorigenesis in this animal model. Since LTA4H has long been regarded as an anti-inflammatory target, we propose LTA4H as a target for prevention and therapy of cancers, especially those associated with chronic inflammation. Here we review the gene structure, expression, regulation and functions of LTA4H, as well as its involvement in carcinogenesis. We believe LTA4H/LTB4 may play an important role in chronic inflammation associated carcinogenesis by at least two mechanisms: a) the inflammation-augmenting effect on inflammatory cells through positive feedback mediated by its receptors and downstream signaling molecules; and b) the autocrine growth-stimulatory effect of LTB4 produced by epithelial cells, and the paracrine growth-stimulatory effect of LTB4 produced by inflammatory cells, on precancerous and cancer cells. Based on our present knowledge, inhibitors of LTA4H or antagonists of LTB4 receptors may be used alone or in combination with other agents (e.g., cyclooxygenase 2 inhibitors) in cancer prevention and treatment trials to test their effectiveness.

Topics: Animals; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Leukotriene B4; Neoplasms; Receptors, Leukotriene B4; Signal Transduction

Fibroblast are responsible for the synthesis of the structural proteins of the connective tissue. A further property of these cells, their migratory ability, could be analyzed in the last years. A special form of migration is chemotaxis, which can be quantitatively measured in a modified Boyden chamber in-vitro. Using this method chemoattractive substances could be characterized, which are able to stimulate fibroblasts and tumorcells to chemotactic migration. Furthermore it could be proved, that benign and transformed cell lines react in a different manner towards these chemoattractive substances. The in-vitro results allow some hypotheses about both fibroblast migration in wound healing or chronic inflammation, and the mechanisms of tumor cell evasion in the tumor surrounding tissue or the metastasizing process in other organs.

Topics: Animals; Chemotaxis; Fibroblasts; Fibronectins; Humans; In Vitro Techniques; Leukotriene B4; Lymphokines; Macrophage Activation; Neoplasm Metastasis; Neoplasms; Wound Healing

Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody. The same combination activates human neutrophils in vitro, enabling their lysis of human tumor cells. Mechanistically, this therapy induces rapid mobilization and tumor infiltration of neutrophils along with complement activation in tumors. Complement component C5a activates neutrophils to produce leukotriene B

Topics: Animals; Antineoplastic Agents; Humans; Leukotriene B4; Mice; Neoplasms; Neutrophils; Tumor Necrosis Factor-alpha

Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B(4) receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-kappaB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.

Topics: Animals; Cell Transformation, Neoplastic; Genes, ras; Humans; Leukotriene B4; Matrix Metalloproteinase 9; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; ras Proteins; Rats; Reactive Oxygen Species; Receptors, Leukotriene B4; Tumor Cells, Cultured; Up-Regulation

Topics: Animals; Humans; Infections; Inflammation; Leukotriene B4; Magnetic Resonance Imaging; Neoplasm Metastasis; Neoplasms; Positron-Emission Tomography; Receptor, Adenosine A1

The pleural space is a virtual compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells during a variety of respiratory diseases. Here, we study the potential role of the eicosanoid metabolite leukotriene B4 (LTB4) in disparate diseases leading to acute (pneumonia) or chronic (tuberculosis, cancer) inflammation of the pleural space. LTB4 concentrations were significantly higher in pleural fluid due to pneumonia, tuberculosis and cancer with respect to congestive heart failure and correlated with neutrophil elastase, which is used as an indication of state of activation of neutrophils in the pleural space. Moreover, pleural LTB4 was biologically active, as an anti-LTB4 antibody partially neutralized the chemotactic activity of parapneumonic, tuberculous and cancer effusions. Macrophages, neutrophils, lymphocytes, mesothelial cells and cancer cells all expressed mRNA for 5-lipoxygenase, the enzyme that initiates leukotriene synthesis leading to the production of LTB4, in exudative pleural effusions. Upon stimulation in transudative pleural effusions, pleural macrophages produced, in a time-dependent fashion, a significantly higher concentration of LTB4 than mesothelial cells. These studies demonstrate that different cell types are capable of producing LTB4 in the inflamed pleural space and that this mediator may play a crucial role in the recruitment of neutrophils into the pleural space.

Topics: Adult; Aged; Arachidonate 5-Lipoxygenase; Chemotaxis, Leukocyte; Epithelium; Gene Expression; Hot Temperature; Humans; Leukotriene B4; Lipopolysaccharides; Macrophage Activation; Middle Aged; Neoplasms; Neutrophil Infiltration; Neutrophils; Pancreatic Elastase; Pleural Effusion; Pneumonia; RNA, Messenger; Tuberculosis, Pulmonary

Human esophageal adenocarcinoma (EAC) develops in a sequence from gastroesophageal reflux disease (GERD), columnar-lined esophagus (CLE), dysplasia, and eventually to EAC. We established a rat surgical EAC model with esophagogastroduodenal anastomosis (EGDA) to mimic the staged process of esophageal adenocarcinogenesis. Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 15-hydroeicosatetraenoic acid (HETE), 12-HETE, 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus, with PGE2 as the major metabolite. Consistent with this profile, cyclooxygenase 2 (Cox2) was overexpressed in the basal cell layer of esophageal squamous epithelium, CLE cells and EAC tumor cells of the EGDA rats, as compared with the normal esophageal epithelium. Sulindac (a Cox inhibitor), nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) and alpha-difluoromethylornithine (DFMO, an ornithine decarboxylase inhibitor) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model. In a short-term study (for 4 weeks after surgery), dietary administration of both sulindac (300 and 600 p.p.m.) and NDGA (100 p.p.m.) effectively reduced the EGDA-induced inflammation. In a long-term chemoprevention study (for 40 weeks after surgery), 300 p.p.m. sulindac, alone or in combination with 100 p.p.m. NDGA or 0.5% DFMO, decreased the tumor incidence from 57.7 to 26.9%, or 16.7 or 20%, respectively (P < 0.05). NDGA alone (100 and 200 p.p.m.) slightly decreased the tumor incidence to 52.4 and 37%, respectively, although the difference was not statistically significant. DFMO alone did not show significant effects on tumor incidence. Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2. In conclusion, sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Body Weight; Cyclooxygenase 2; Dinoprostone; Eflornithine; Esophageal Neoplasms; Esophagus; Gas Chromatography-Mass Spectrometry; Hydroxyeicosatetraenoic Acids; Immunoenzyme Techniques; In Situ Hybridization; Inflammation; Isoenzymes; Leukotriene B4; Male; Masoprocol; Mass Spectrometry; Neoplasms; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Sulindac; Time Factors

A single injection of a streptococcal preparation, OK-432, with fresh frozen plasma (FFP) (or fresh human serum) into the peritoneal or pleural cavity for the treatment of malignant ascites or pleurisy resulted in a complete reduction of ascitic fluid or pleural effusion in 5 out of 11 patients. FFP was used a further source of complement for the effective accumulation of antitumor polymorphonuclear leukocytes (PMNs) by complement-derived chemotactic factors in the cavity. C5a increased in the fluids 3-9 h after the injection and preceded a massive increase in PMNs. C1 inhibitor (C1INH) and C3b inactivator (C3bINA) decreased in several cases 6 h after the treatment. Chemotactic arachidonic acid metabolites, thromboxane B2(TXB2) as a characteristics of TXA2, and leukotriene B4(LTB4) also increased at the same time even in cases where C5a changed only minimally, and may play a role in accumulating antitumor PMNs in the cavity.

Topics: Adult; Aged; Aged, 80 and over; Ascites; Biological Products; Complement Activation; Complement C5; Complement C5a; Female; Freezing; Humans; Immunization, Passive; Leukotriene B4; Male; Middle Aged; Neoplasms; Neutrophils; Picibanil; Pleurisy; Thromboxane B2

Whereas leukocytes from patients with early cancer usually show leukocyte adherence inhibition (LAI) to the sensitizing cancer extract, leukocytes from patients with advanced cancer seldom do. The chemoattractant-induced LAI response was studied to determine whether the abnormal response by leukocytes from patients with advanced cancer was related to changes in sensitivity to chemoattractants. Authentic chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine, chemotactic fragment of the fifth component of complement, and leukotriene B4 (LTB4) at optimum concentrations induced about 28-31% of adherent leukocytes to become nonadherent, these leukocytes being from either controls or patients with early breast cancer. However, chemoattractants induced no increased nonadherence of adherent leukocytes from patients with advanced breast cancer. In the control tubes, nonadherent cells for patients with advanced cancer were already increased by about 38% and were slightly greater than the chemoattractant-induced increased of nonadherent cells for control subjects or patients with early cancer. When the intracellular cyclic AMP of the cells were raised transiently, the nonadherent cells in the control tubes for patients with advanced cancer decreased by about 38% compared to 8% for control subjects and 13% for patients with early cancer. When nonadherence was returned to control levels, about 46% of adherent cells from patients with advanced cancer became nonadherent to chemoattractants or to the sensitizing cancer extract. Normal leukocytes, preexposed to chemoattractants, had increased nonadherence and did not respond to the same or other chemoattractants, imitating the state of leukocytes from patients with advanced cancer. However, if the cells were washed and intracellular cyclic AMP raised, nonadherent cells returned to normal levels in the control tubes and showed increased nonadherence with a repeat LTB4 exposure. The increased nonadherence of leukocytes from patients with advanced cancer as well as the refractoriness to chemoattractants was highly suggestive of in vivo activation of leukocytes possibly because of exposure to chemoattractant-like factors, generated by leukocyte-tumor antigen interactions.

Topics: Breast Neoplasms; Cell Adhesion; Chemotactic Factors; Chemotaxis, Leukocyte; Female; Humans; Leukocyte Adherence Inhibition Test; Leukocytes; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neoplasm Staging; Neoplasms; Tissue Extracts