Leukotriene, the dihydroxy leukotriene, LTB, is formed via the  5-LO pathway through the enzyme leukotriene A4 hydrolase. LTB4 is one of the most chemotactic molecules known. It has a preferential action on leukocytes, producing chemotaxis and chemokinesis of neutrophils and mononuclear cells, as well as aggregation, degranulation, and adherence of leukocytes to endothelial cells. The cysteinyl leukotrienes, including LTC, LTD, and LTE, are also known as the slow-reacting substance of anaphylaxis. CysLTs enhance contraction of smooth muscle and increase vascular permeability as well as migration and chemokine production in monocytic cells. CysLTs are produced in high amounts in activated eosinophils, basophils, macrophages, and mast cells.  5-Lipoxygenase (5-LO) catalyzes the biosynthesis of proinflammatory leukotrienes that have both autocrine and paracrine mechanisms and may play an important role in inflammation-induced carcinogenesis. Inflammation is an important component of tumor progression. Many tumors start from the sites of infection and inflammation.

Leukotrienes and  prostaglandins are metabolites of  arachidonic acid that play major roles in various inflammatory conditions (Fig. 1). The release of these mediators, by cells recruited to or present at the site of inflammation, modulates or influences the magnitude of the inflammatory response. An increased understanding of eicosanoids and how their receptors trigger intracellular signaling during inflammatory conditions is helping to elucidate the well-known connection between chronic inflammatory disease and neoplastic transformation. Here, we summarize the role of leukotrienes in cancer. In addition, we delineate how continuous  leukotriene receptor activation and signaling can increase cell survival and proliferation as important early steps toward oncogenicity.

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Today, it is clear that the tumor microenvironment, including inflammatory cells, is an important participant in the neoplastic process, proliferation, survival, and migration. A microenvironment rich in inflammatory cells, generating growth factors, and DNA-damage agents, potentiates the risk of neoplastic formation. Several mutations of key genes also seem to be important for the transformation of the  inflammation–dysplasia–carcinoma sequence.

The leukotrienes potentiate biological activities in the pathogenesis of many diseases. In most chronic inflammatory conditions, such as inflammatory bowel disease, the levels of leukotrienes are increased. The strongest association of chronic inflammation with malignant disease is seen in colon carcinogenesis arising in individuals with inflammatory bowel disease. Indeed, patients suffering from inflammatory bowel disease have a 30–50% increased risk of developing colon cancer. In chronic inflammatory bowel diseases, elevated levels of leukotrienes are found, which increases the risk for development of cancer and thereby a reduced survival of these patients. As expected, it has been established that a cause-and-effect link between chronic inflammation and colon cancer occurs via activation and overexpression of the two enzymes, 5-LO and COX ( Cyclooxygenase, COX-1 and COX-2), responsible for regulating the production of leukotrienes and prostaglandins, respectively (Fig. 1).

The expression of  COX-2 is highly upregulated both during inflammatory conditions and cancer. Elevated prostaglandin production at the site of the tumor is a good indicator of increased COX-2 activity in colon cancer tissue. There are vast amounts of data suggesting that  nonsteroidal anti-inflammatory drugs (NSAIDS),  COX inhibitors, reduce the risk of colon cancer. These inhibitors were shown to suppress the proliferation of intestinal cancer cell lines that express high levels of COX-2.

The production of different leukotrienes from arachidonic acid is dependent on the expression of 5-LO, an enzyme that regulates the first step in the synthesis of leukotrienes. Induction of experimental colitis in mice lacking the 5-LO protein significantly reduced the degree of infiltration of inflammatory cells and colonic injury. A number of other studies have shown that inhibition of 5-LO decreases growth and promotes cell death in several transformed cell lines.

In a recent tissue array study using colorectal cancer and control specimens, elevated levels of 5-LO and COX-2 were found in colorectal carcinomas. In accordance, similar observations were made in different colon carcinoma cell lines when these were compared with nontransformed intestinal epithelial cell lines. Interestingly, activation of CysLT receptor signaling led to an increased COX-2-mediated production of prostaglandin E₂, PGE₂. Mediating COX-2 activation and PGE₂ production has a major impact on intestinal epithelial cell survival.

5-LO metabolites may contribute to the development of several human tumors, including pancreatic, esophageal, prostate, breast, and colon cancer. COX-2 and 5-LO have been reported to be simultaneously upregulated in colorectal cancer. It is possible that blocking one of these enzymatic pathways may activate the other. Therefore, combined treatment of these pathways could be a better treatment option. There is an additive effect of inhibiting proliferation, inducing apoptosis, decreasing Bcl-2 levels, and increasing Bax levels in cancer cells, after combined treatment with inhibitors of COX-2 and 5-LO.

 Leukotriene receptors are upregulated in colon cancer, and their signaling facilitates the survival and proliferation of cancer cells and reduces apoptosis. In agreement with this, an increased expression level of leukotriene receptors in different colon cancer cell lines correlates well with the ability of leukotrienes to increase the survival of these cells.

Apart from Bcl-2, there are a number of other cellular proteins that are closely connected to the regulation of cell proliferation, survival, and apoptosis. One of these is  β-catenin. This protein became of interest in relation to LTD₄-induced survival signaling when a novel LTD₄-triggered association between Bcl-2 and β-catenin in the mitochondria from intestinal epithelial cell lines was identified. It could be hypothesized that LTD4 may enhance cell survival via activation and association of β-catenin with Bcl-2 in the mitochondria. β-catenin activation and signaling execute an antiapoptotic effect through protection of cytochrome c leakage from the mitochondria.

β-catenin is a protein with many roles, one well established as an effector molecule of the  Wnt signaling pathway. The Wnt receptors, Frizzleds, belong to the same GPCR family of receptors as the leukotrienes. The presence of a Wnt signal allows β-catenin to translocate to the nucleus where it activates the transcription factors TCF/LEF. Normally, β-catenin is regulated by the adenomatous polyposis coli ( APC) complex to control the intracellular levels of β-catenin. LTD₄ can inactivate GSK-3β, known to phosphorylate β-catenin and induce its ubiquitination and degradation, and thus has the potential to increase the amount of free β-catenin if inactivated. LTD₄ induces inactivation of GSK-3β via PI3-kinase/Akt pathway allowing free β-catenin to be able to enter the nucleus and activate the transcription factor TCF/LEF, which activates potentially oncogenic genes, such as cyclin D1, c-myc, and COX-2 (see Fig. 2).

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The infection–inflammation–dysplasia–carcinoma sequence is exemplified by Helicobacter pylori (HP) infection, a well-known risk factor for gastric adenocarcinoma. HP infection may also be a possible risk factor for respiratory system disease, which triggers a marked local inflammatory response and a chronic system immune response. Some of the possibly mediators involved in the pathogenesis of these infections include leukotrienes that may have a role in the development of lung cancer in association with HP infection. The risk of lung cancer in patients with gastric ulcers is around three times higher than in individuals without ulcers.

Activation of leukotriene receptor signaling pathways and subsequent effects on proliferation and survival of epithelial cells indicate that the inflammatory mediator, leukotrienes, can contribute to growth of cells during pathological inflammatory conditions. This, in turn, indicates that these receptors have an important role in neoplastic transformation and development of cancer.