However, chronic inflammation can be a major health problem in allergic, cardiovascular, fibrotic, local and systemic inflammatory diseases and several cancers[ 2 - 9 ].
In , Rudolf Virchow was the first to speculate about the role of long-term inflammation in cancer based on his observations that cancerous tissues were frequently infiltrated by leukocytes[ 10 ]. Evidence from observational studies and randomized trials concerning the protective action of non-steroidal anti-inflammatory drugs NSAIDs such as aspirin have indicated not only a reduced long-term risk of esophageal, gastric, biliary, breast, prostate, lung, and CRC but also a lowered risk of metastasis[ 14 - 18 ].
Inflammation present in the tumor microenvironment is characterized by high leukocyte infiltration, ranging in size, distribution and composition, such as tumor-associated macrophages TAMs , mast cells, dendritic cells DCs , natural killer cells NKs , neutrophils, eosinophils and lymphocytes[ 19 - 21 ]. These cells produce a variety of cytotoxic mediators such as reactive oxygen and nitrogen species, serine and cysteine proteases, membrane-perforating agents, matrix metalloproteinases, pro-inflammatory cytokines, interferons IFNs and increased levels of enzymes such as cyclooxygenase-2 COX-2 , 5-lipoxygenase 5-LOX and phospholipase A 2 PLA 2 , hence contributing to carcinogenesis[ 22 - 25 ].
This review addresses the role of cysteinyl leukotrienes in inflammation-induced colorectal carcinogenesis. It serves as a precursor to several lipid pro-inflammatory mediators such as prostaglandins PGs , prostacyclins, thromboxanes TXAs , lipoxins and leukotrienes LTs , which have individual as well as overlapping functions in acute and chronic inflammation[ 26 ].
Aberrant AA metabolism is often linked to production of pro-inflammatory eicosanoids, chronic inflammatory diseases and carcinogenesis. AA, which is stored as diacylglycerol DAG , is released from the phosphatidylinositol 4,5-bisphosphate PIP 2 present in the outer nuclear envelope of cells, from which it is mobilized into the cytoplasm either by activation of calcium-dependent cytosolic PLA 2 or by the combined action of phospholipase C PLC and DAG lipase[ 26 , 28 ]. The role of these eicosanoids in maintaining intestinal epithelial cell homeostasis is well documented[ 29 - 32 ].
Various epidemiological, clinical, and laboratory studies have shown that dysregulation of the COX and LOX pathways results in chronic inflammation and subsequently cancer[ 14 , 29 ]. The term leukotriene is derived from the two words leuko for white blood cells and trienes , meaning three conjugated double bonds, indicating that the ability to generate LTs from AA is largely restricted to leukocytes[ 28 ].
The latter does not exhibit any enzymatic activity but facilitates the interaction between 5-LOX and its substrate AA.
Functionally, CysLTs induce smooth muscle contraction, vascular leakage, eosinophil recruitment in inflammatory diseases, mucus production and chemotaxis[ 43 - 46 ]. LTB 4 also plays a pivotal role in inflammatory processes such as leukocyte chemoattraction, particularly of granulocytes and T cells, induction of rapid invasion and recruitment of these cells to the plasma membrane of endothelial cells, production of reactive oxygen species, and induction of gene expression[ 47 , 48 ].
The tissue distribution of the two receptors is quite different. Whereas BLT 1 expression in both mice and humans has been reported to be predominantly restricted to peripheral leukocytes, BLT 2 expression in humans appears to be fairly ubiquitous, with the highest level observed in the spleen, liver, and lymphocytes[ 51 ]. Inflammation and CRC initiation and dissemination go hand in hand[ 10 , 52 ]. IBDs are characterized by increased leukocyte infiltration into the intestinal wall, where they can induce non-specific inflammation through activation and production of AA-derived pro-inflammatory metabolites such as LTs and PGs and subsequent tissue injury.
Thus, the gastrointestinal tract is richly supplied with these eicosanoids that mediate several gastrointestinal diseases, including cancers. Although UC is fundamentally similar to CD, a few differences exist, primarily the presentation of a cytokine profile with a T helper 2 Th2 antibody-mediated response[ 61 ].
Moreover, recent evidence supports the concept that malignant tumors also recruit a specific subpopulation of myeloid cells called myeloid-derived suppressor cells[ 64 ]. These cells share some characteristics with monocytes, macrophages, neutrophils, and DCs and help suppress any potential anti-tumor immune response and tumor angiogenesis. As in several cancers, including CRC, in which the major inflammatory cellular components are macrophages, TAMs contribute immensely to cancer growth and expansion. TAMs are macrophages that display an M2 type alternatively activated phenotype and secrete high levels of Th2 cytokines, growth factors and inflammatory mediators that promote tumor growth, angiogenesis, and metastasis[ 65 , 66 ].
Apart from its role in inflammation-associated diseases such as asthma, psoriasis, rheumatoid arthritis and IBD[ 68 ], LTB 4 has pro-tumorigenic effects in breast cancer, melanoma, lymphoma, and head and neck carcinoma[ 69 - 72 ]. Using both the 5-LOX inhibitor AA and selective BLT 1 antagonist U in these cell lines, the authors showed induction of apoptosis and reduced proliferation[ 73 ].
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LTB 4 -stimulated extracellular signal-regulated kinase Erk activation in these cancer cells was also abrogated by U A subsequent study investigated the effectiveness of another LTB 4 receptor antagonist LY in combination with gemcitabine, an anti-tumor adjuvant and radiosensitizer, on the proliferation rate of human colon cancer cell lines LoVo and HT in an athymic heterotrophic xenograft mouse model and found a significant reduction in tumor growth due to apoptosis via the mitochondrial pathway[ 74 ].
The findings from these and several other studies emphasize the role of LTB 4 signaling in colon cancer cells and warrant the use of specific LTB 4 receptor antagonists to suppress CRC expansion. Increased expression of the enzymes responsible for production of PGs and LTs - COX-2 and 5-LOX, respectively has been documented in human colorectal adenocarcinomas compared with adjacent normal mucosa[ 79 - 81 ].
Various clinical trials over the past two decades have highlighted the use of eicosanoid-depressing and anti-inflammatory drugs in the prevention and treatment of CRC. Upregulated expression of CysLT 1 R has been observed in several human cancers, including transitional cell carcinoma TCC in the bladder, neuroblastomas, and brain, prostate, breast, and CRCs[ 6 , 80 , 83 - 86 ]. We have also demonstrated high CysLT 1 R expression in established colon cancer cell lines[ 42 , 80 ]. Accordingly, we have shown that these two receptors are co-localized and form hetero- and homodimers in a human intestinal epithelial cell line and that LTC 4 stimulation of CysLT 2 R negatively regulates the plasma membrane expression of CysLT 1 R by inducing internalization of the receptor heterodimer complex[ 88 ].
Moreover, our previous work has shown that LTD 4 -induced CysLT 1 R signaling results in cell proliferation, survival, and migration through distinct signaling pathways. By contrast, decreased expression of CysLT 2 R has been observed in different colon cancer cell lines Caco-2 and SW compared with an epithelial intestinal cell line, and LTC 4 stimulation of CysLT 2 R has been shown to induce differentiation as demonstrated by increased intestinal alkaline phosphatase activity in Caco-2 cells[ 42 ].
CysLT 1 R antagonists have been used in studies of inflammatory diseases such as rheumatoid arthritis and atherosclerosis[ 96 , 97 ]. The CysLT 1 R antagonists pranlukast, zafirlukast and montelukast are commercially available and are currently in clinical use to treat asthmatic patients[ 98 ]. Emerging data suggest that the pro-inflammatory CysLTs might have an important role in solid tumors. CysLT 1 R antagonist treatment has been shown to inhibit tumor growth by inducing apoptosis in a variety of human urological cancer cell lines e.
Montelukast has been shown to induce early apoptosis in a bladder transitional cell carcinoma TCC cell line, as well as in three different prostate cancer cell lines[ 6 , 83 ]. In addition, montelukast has been shown to induce the intrinsic apoptotic pathway, resulting in cleavage of caspases 3 and 9, and cell cycle arrest in neuroblastoma cell lines[ 84 ].
Studies in CysLT 1 R-deficient mice have revealed its role in enhanced vascular permeability during an acute inflammatory response[ ]. Pranlukast and montelukast have been shown to reduce vascular permeability by regulating vascular endothelial growth factor VEGF expression in allergen-induced asthmatic lungs of mice[ ].
Furthermore, the two abovementioned CysLT 1 R antagonists have been shown to inhibit the permeability of peripheral capillaries, thereby preventing tumor metastasis in a Lewis lung carcinoma metastasis model[ ]. Proliferation and migration of endothelial cells are needed to form new vessels, a process required in cancer development. In line with aforementioned data, we have demonstrated in a nude mouse xenograft model of colon cancer that reduction of tumor growth can be accomplished with CysLT 1 R antagonist treatment.
The molecular mechanisms underlying the observed inhibition of tumor growth was attributed to the reduction in proliferation, induction of apoptosis and impairment of angiogenesis[ ]. The combined treatment was also shown to induce apoptosis, whereas none of these compounds had any effect alone. Other approaches are being explored, such as inhibition of 5-LOX activity.
Accordingly, the anti-tumor effects of celecoxib in colon cancer cells were augmented when combined with inhibition of 5-LOX activity using the FLAP inhibitor MK[ ].
Effect of Prostaglandins on the Motility of the Digestive Tract | SpringerLink
The combined inhibition of COX-2 and 5-LOX activity have also shown a more pronounced anti-tumor growth effect in a cigarette smoke-promoting mouse xenograft model of CRC[ ]. However, targeting either the COX or LOX pathway alone resulted in a shunt toward the other pathway, except in the latter study, in which a shunt was observed when COX-2 activity was targeted with celecoxib. The abovementioned studies investigated the effects on CRC growth targeting the eicosanoid production in epithelial cells.
The mast cells were found to utilize 5-LOX to promote proliferation of intestinal epithelial cells and recruit myeloid-derived suppressor cells to the polyp site[ ]. Another possible effective chemopreventive option against CRC could be the modification of AA metabolism. Reduced polyp formation could be observed in both the intestine and the colon of these mice.
Deregulated AA metabolism creates an imbalance in the tissue homeostatic events of proliferation, regeneration and repair, and host defense. Additionally, deregulated AA metabolism contributes to sustained inflammatory processes that could result in CRC development. Among the implicated inflammatory mediators are the eicosanoids, such as CysLTs.
Thus, the modification of CysLT signaling could pave the way for the development of new personalized medicine for patients with CRC[ ]. Advanced Search. This Article.
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Citation of this article. Cysteinyl leukotrienes and their receptors: Bridging inflammation and colorectal cancer. Corresponding Author of This Article. Publishing Process of This Article. Research Domain of This Article. Gastroenterology and Hepatology.
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Total Article Views All Articles published online. Times Cited of This Article. Journal Information of This Article. All rights reserved. World J Gastroenterol. Author contributions : Savari S and Vinnakota K contributed equally to this work; all authors discussed, read and approved the manuscript.
Arachidonic acid AA is a polyunsaturated fatty acid found in the phospholipids of cell membranes. AA is mobilized into the cytoplasm mostly by the activation of calcium-dependent cytosolic phospholipase A 2 cPLA 2. Eicosanoids and colorectal cancer. Cysteinyl leukotrienes, their receptors and colorectal cancer.