Long-standing inflammation has emerged as a hallmark of neoplastic transformation of epithelial cells and may be a limiting factor of successful conventional tumor therapies. A complex milieu composed of distinct stromal and immune cells, soluble factors and inflammatory mediators plays a crucial role in supporting and promoting various types of cancers. An augmented inflammatory response can predispose a patient to colorectal cancer (CRC). Common risk factors associated with CRC development include diet and lifestyle, altered intestinal microbiota and commensals, and chronic inflammatory bowel diseases. Cysteinyl leukotrienes are potent inflammatory metabolites synthesized from arachidonic acid and have a broad range of functions involved in the etiology of various pathologies. This review discusses the important role of cysteinyl leukotriene signaling in linking inflammation and CRC.

Background: Inflammatory cells and inflammatory mediators play an important role in colorectal cancer (CRC). Previous studies have shown that CRC patients with increased expression of cysteinyl leukotriene receptor 1 (CysLTR1) have a poorer prognosis, and Cysltr1^−/− mice display fewer intestinal polyps. However, the role of mast cells (MCs) in colon cancer progression remains unclear. The aim of the present study was to explore the relevance of MCs in CRC. Material and methods: A tissue microarray from 72 CRC patients was stained with MC anti-tryptase and -chymase antibodies. Mouse colon tissue was stained with MC anti-tryptase antibody. Immunohistochemistry was used to identify MCs in patients and mice. Results: Patient colon cancer tissue had in comparison with normal colon tissue a reduced number of MCs, predominantly of chymase-positive cells. Further analysis revealed that patients with a relative high MCD in their cancer tissues showed significantly longer overall survival compared to those with a low MCD [hazard ratio (HR) 0.539; 95% confidence interval (CI), 0.302–0.961]. Similar results were observed in subgroups of patients with either no distant metastasis (p = 0.004), or <75 years (p = 0.015) at time of diagnosis. Multivariate Cox analysis showed that MCD independently correlated with reduced risk of death in colon cancer patients (HR 0.380; 95% CI 0.202–0.713). Additionally, a negative correlation was found between cytoplasmic CysLTR1 expression and number of MCs. In agreement, in the CAC mouse model, Cysltr1^−/− mice showed significantly higher MCs in their polyp/tumor areas compared with wild-type mice. Conclusion: A high MCD in cancer tissue correlated with longer patient survival independently from other risk factors for CRC. The concept that MCs have an anti-tumor effect in CRC is further supported by the findings of a negative correlation with CysLTR1 expression in patients and a high MCD in colon polyps/tumors from CysLTR1^−/− mice.

The expression of the inflammatory G-protein coupled receptor CysLT₁R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT₁R and colon cancer development in vivo using CysLT₁R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT₁R in tumor initiation. Nude mice were inoculated with 50 µM CysLT₁R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT₁R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT₁R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21^WAF/Cip1 (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT₁R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT₁R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

Leukotrienes (LTs) and prostaglandins (PGs) are metabolites of arachidonic acid that play major roles in various inflammatory conditions. The release of these mediators, by cells recruited to or present at the site of inflammation, modulate/influence the magnitude of the inflammatory response. A better 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. In the current review, we summarize the role of LTs and PGs in chronic inflammation and, in particular, we focus on recent insights into the role of CysLT₁receptor signaling pathway. In addition, we delineate how continuous CysLT₁receptor activation and signaling can increase cell survival and proliferation as important early steps toward oncogenicity.

The fact that breast cancer patients with local or distal dissemination exhibit decreased survival, promotes a search for novel mechanisms to suppress such tumor progression. Here, we have determined the expression of proinflammatory cysteinyl leukotriene receptors (CysLTRs) in breast tumor tissue and their signaling effect on breast cancer cell functions related to tumor progression. Patients with breast tumors characterized by high CysLT₁R and low CysLT₂R expression levels exhibited increased risk of cancer‐induced death in univariate analysis for both the total patient group (hazard ratio [HR] = 2.88, 95% confidence interval [CI] = 1.11–7.41), as well as patients with large (>20 mm) tumors (HR = 5.08, 95% CI = 1.39–18.5). Multivariate analysis revealed that patients with large tumors exhibiting high CysLT₁R and low CysLT₂R expression levels had a significantly reduced survival, also when adjusted for established prognostic parameters (HR = 7.51, 95% CI = 1.83–30.8). In patients with large (>20 mm) tumors, elevated CysLT₂R expression predicted an improved 5‐year survival (log‐rank test p = 0.04). Surprisingly, for longer time periods, this prognostic value was lost. This disappearance coincided with the termination of hormonal treatment. Tamoxifen preserved and even induced transcription of CysLT₂R, but not CysLT₁R, in estrogene receptor‐positive MCF‐7 breast cancer cells. This elevated CysLT₂R expression decreased, even below the level of untreated cells, when tamoxifen was withdrawn. CysLT₂R signaling reduced MCF‐7 cell migration, but had no effect on either proliferation or apoptosis. Our data indicate that low CysLT₁R together with high CysLT₂R expression levels might be useful parameters in prognostication and treatment stratification of breast cancer patients.