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1
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García de Alba Graue P, Abdouh M, Goyeneche A, Burnier JV, Burnier MN. CYSLTR1 antagonism displays potent anti-tumor effects in uveal melanoma. Exp Eye Res 2024; 248:110120. [PMID: 39389443 DOI: 10.1016/j.exer.2024.110120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024]
Abstract
Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults. Although rare, it is a deadly tumor, with a long-term prognosis of death occurring in more than 50% of the cases. It is characterized by frequent (∼80%) driver mutations in GNAQ and GNA11 genes, both of which are activated by cysteinyl leukotriene receptors (CYSLTRs). CYSLTR1 is upregulated and participated in the progression of several cancers. In the present study, we sought to determine the expression levels of CYSLTR1 in 31 human UM specimens and cell lines (3 primary and 1 metastatic), and its role in the proliferation and viability of these cells by analyzing cell metabolic activity, cell confluence and apoptosis levels. We show that all analyzed UM specimens and cells expressed CYSLTR1 at high levels. Notably, the pharmacological blockage of this receptor, using the inverse agonist MK571, reduced the growth and metabolic activity, and increased the apoptotic cell death of all analyzed UM cell lines. We provide evidence that CYSLTR1 is expressed in human UM and plays a significant role in UM progression behavior. Our data highlight the potential beneficial effects of targeting CYSLTR1 in the control of UM progression.
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Affiliation(s)
- Paulina García de Alba Graue
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; The MUHC - McGill University Ocular Pathology & Translational Research Laboratory, Montreal, QC, Canada
| | - Mohamed Abdouh
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; The MUHC - McGill University Ocular Pathology & Translational Research Laboratory, Montreal, QC, Canada.
| | - Alicia Goyeneche
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; The MUHC - McGill University Ocular Pathology & Translational Research Laboratory, Montreal, QC, Canada
| | - Julia Valdemarin Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
| | - Miguel N Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; The MUHC - McGill University Ocular Pathology & Translational Research Laboratory, Montreal, QC, Canada
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2
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Kahnt AS, Häfner AK, Steinhilber D. The role of human 5-Lipoxygenase (5-LO) in carcinogenesis - a question of canonical and non-canonical functions. Oncogene 2024; 43:1319-1327. [PMID: 38575760 PMCID: PMC11065698 DOI: 10.1038/s41388-024-03016-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 04/06/2024]
Abstract
5-Lipoxygenase (5-LO), a fatty acid oxygenase, is the central enzyme in leukotriene (LT) biosynthesis, potent arachidonic acid-derived lipid mediators released by innate immune cells, that control inflammatory and allergic responses. In addition, through interaction with 12- and 15-lipoxgenases, the enzyme is involved in the formation of omega-3 fatty acid-based oxylipins, which are thought to be involved in the resolution of inflammation. The expression of 5-LO is frequently deregulated in solid and liquid tumors, and there is strong evidence that the enzyme plays an important role in carcinogenesis. However, global inhibition of LT formation and signaling has not yet shown the desired success in clinical trials. Curiously, the release of 5-LO-derived lipid mediators from tumor cells is often low, and the exact mechanism by which 5-LO influences tumor cell function is poorly understood. Recent data now show that in addition to releasing oxylipins, 5-LO can also influence gene expression in a lipid mediator-independent manner. These non-canonical functions, including modulation of miRNA processing and transcription factor shuttling, most likely influence cancer cell function and the tumor microenvironment and might explain the low clinical efficacy of pharmacological strategies that previously only targeted oxylipin formation and signaling by 5-LO. This review summarizes the canonical and non-canonical functions of 5-LO with a particular focus on tumorigenesis, highlights unresolved issues, and suggests future research directions.
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Affiliation(s)
- Astrid S Kahnt
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438, Frankfurt/Main, Germany.
| | - Ann-Kathrin Häfner
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438, Frankfurt/Main, Germany
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438, Frankfurt/Main, Germany
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3
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Kaya-Yasar Y, Engin S, Barut EN, Inan C, Saygin I, Erkoseoglu I, Sezen SF. The contribution of the WNT pathway to the therapeutic effects of montelukast in experimental murine airway inflammation induced by ovalbumin and lipopolysaccharide. Drug Dev Res 2024; 85:e22178. [PMID: 38528652 DOI: 10.1002/ddr.22178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 02/15/2024] [Accepted: 03/11/2024] [Indexed: 03/27/2024]
Abstract
The wingless/integrase-1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic-acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA-Al(OH)3 administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK-974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5-HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5-HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5-HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK-3β and WNT5A levels, which had been induced by airway inflammation, in a dose-dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad-2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin-17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK-3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model.
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Affiliation(s)
- Yesim Kaya-Yasar
- Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye
| | - Seckin Engin
- Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye
| | - Elif Nur Barut
- Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye
| | - Cihan Inan
- Department of Molecular Biology and Genetics, Faculty of Sciences, Karadeniz Technical University, Trabzon, Turkey
| | - Ismail Saygin
- Department of Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Ilknur Erkoseoglu
- Department of Medical Pharmacology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Sena F Sezen
- Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye
- Drug and Pharmaceutical Technology Application and Research Center, Karadeniz Technical University, Trabzon, Turkey
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4
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Meng YW, Liu JY. Pathological and pharmacological functions of the metabolites of polyunsaturated fatty acids mediated by cyclooxygenases, lipoxygenases, and cytochrome P450s in cancers. Pharmacol Ther 2024; 256:108612. [PMID: 38369063 DOI: 10.1016/j.pharmthera.2024.108612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/19/2024] [Accepted: 02/05/2024] [Indexed: 02/20/2024]
Abstract
Oxylipins have garnered increasing attention because they were consistently shown to play pathological and/or pharmacological roles in the development of multiple cancers. Oxylipins are the metabolites of polyunsaturated fatty acids via both enzymatic and nonenzymatic pathways. The enzymes mediating the metabolism of PUFAs include but not limited to lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P450s (CYPs) pathways, as well as the down-stream enzymes. Here, we systematically summarized the pleiotropic effects of oxylipins in different cancers through pathological and pharmacological aspects, with specific reference to the enzyme-mediated oxylipins. We discussed the specific roles of oxylipins on cancer onset, growth, invasion, and metastasis, as well as the expression changes in the associated metabolic enzymes and the associated underlying mechanisms. In addition, we also discussed the clinical application and potential of oxylipins and related metabolic enzymes as the targets for cancer prevention and treatment. We found the specific function of most oxylipins in cancers, especially the underlying mechanisms and clinic applications, deserves and needs further investigation. We believe that research on oxylipins will provide not only more therapeutic targets for various cancers but also dietary guidance for both cancer patients and healthy humans.
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Affiliation(s)
- Yi-Wen Meng
- CNTTI of the Institute of Life Sciences & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China
| | - Jun-Yan Liu
- CNTTI of the Institute of Life Sciences & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
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Topi G, Satapathy SR, Ghatak S, Hellman K, Ek F, Olsson R, Ehrnström R, Lydrup ML, Sjölander A. High Oestrogen receptor alpha expression correlates with adverse prognosis and promotes metastasis in colorectal cancer. Cell Commun Signal 2024; 22:198. [PMID: 38549115 PMCID: PMC10979551 DOI: 10.1186/s12964-024-01582-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/23/2024] [Indexed: 04/01/2024] Open
Abstract
In normal colon tissue, oestrogen receptor alpha (ERα) is expressed at low levels, while oestrogen receptor beta (ERβ) is considered the dominant subtype. However, in colon carcinomas, the ERα/β ratio is often increased, an observation that prompted us to further investigate ERα's role in colorectal cancer (CRC). Here, we assessed ERα nuclear expression in 351 CRC patients. Among them, 119 exhibited positive ERα nuclear expression, which was significantly higher in cancer tissues than in matched normal tissues. Importantly, patients with positive nuclear ERα expression had a poor prognosis. Furthermore, positive ERα expression correlated with increased levels of the G-protein coupled cysteinyl leukotriene receptor 1 (CysLT1R) and nuclear β-catenin, both known tumour promoters. In mouse models, ERα expression was decreased in Cysltr1-/- CAC (colitis-associated colon cancer) mice but increased in ApcMin/+ mice with wild-type Cysltr1. In cell experiments, an ERα-specific agonist (PPT) increased cell survival via WNT/β-catenin signalling. ERα activation also promoted metastasis in a zebrafish xenograft model by affecting the tight junction proteins ZO-1 and Occludin. Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis.
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Affiliation(s)
- Geriolda Topi
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
| | - Shakti Ranjan Satapathy
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden.
| | - Souvik Ghatak
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Karin Hellman
- Chemical Biology & Therapeutics Group, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Fredrik Ek
- Chemical Biology & Therapeutics Group, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Roger Olsson
- Chemical Biology & Therapeutics Group, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Roy Ehrnström
- Department of Pathology, Skåne University Hospital, Malmö, Sweden
| | | | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden.
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6
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Satapathy SR, Ghatak S, Sjölander A. The tumor promoter cysteinyl leukotriene receptor 1 regulates PD-L1 expression in colon cancer cells via the Wnt/β-catenin signaling axis. Cell Commun Signal 2023; 21:138. [PMID: 37316937 DOI: 10.1186/s12964-023-01157-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 05/01/2023] [Indexed: 06/16/2023] Open
Abstract
Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a subset of patients benefit from PD-1/PD-L1 treatment. Previously, we showed that high cysteinyl leukotriene receptor 1 (CysLT1R) levels are associated with poor prognosis in CRC patients. Recently, we have revealed the role of the tumor promoter CysLT1R in drug resistance and stemness in colon cancer (CC) cells. Here, we show the role of the CysLT1R/Wnt/β-catenin signaling axis in the regulation of PD-L1 using both in vitro and in vivo preclinical model systems. Interestingly, we found that both endogenous and IFNγ-induced PD-L1 expression in CC cells is mediated through upregulation of CysLT1R, which enhances Wnt/β-catenin signaling. Therapeutic targeting of CysLT1R with its antagonist montelukast (Mo), as well as CRISPR/Cas9-mediated or doxycycline-inducible functional absence of CysLT1R, negatively regulated PD-L1 expression in CC cells. Interestingly, an anti-PD-L1 neutralizing antibody exhibited stronger effects together with the CysLT1R antagonist in cells (Apcmut or CTNNB1mut) with either endogenous or IFNγ-induced PD-L1 expression. Additionally, mice treated with Mo showed depletion of PD-L1 mRNA and protein. Moreover, in CC cells with combined treatment of a Wnt inhibitor and an anti-PD-L1 antibody was effective only in β-catenin-dependent (APCmut) context. Finally, analysis of public dataset showed positive correlations between the PD-L1 and CysLT1R mRNA levels. These results elucidate a previously underappreciated CysLT1R/Wnt/β-catenin signaling pathway in the context of PD-L1 inhibition in CC, which might be considered for improving the efficacy of anti-PD-L1 therapy in CC patients. Video Abstract.
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Affiliation(s)
- Shakti Ranjan Satapathy
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Center, Lund University, Skåne University Hospital, Jan Waldenströms Gata 35, 205 02, Malmö, Sweden.
| | - Souvik Ghatak
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Center, Lund University, Skåne University Hospital, Jan Waldenströms Gata 35, 205 02, Malmö, Sweden
| | - Anita Sjölander
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Center, Lund University, Skåne University Hospital, Jan Waldenströms Gata 35, 205 02, Malmö, Sweden.
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7
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Ghatak S, Satapathy SR, Sjölander A. DNA Methylation and Gene Expression of the Cysteinyl Leukotriene Receptors as a Prognostic and Metastatic Factor for Colorectal Cancer Patients. Int J Mol Sci 2023; 24:ijms24043409. [PMID: 36834820 PMCID: PMC9963074 DOI: 10.3390/ijms24043409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 01/19/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
Colorectal cancer (CRC), one of the leading causes of cancer-related deaths in the western world, is the third most common cancer for both men and women. As a heterogeneous disease, colon cancer (CC) is caused by both genetic and epigenetic changes. The prognosis for CRC is affected by a variety of features, including late diagnosis, lymph node and distant metastasis. The cysteinyl leukotrienes (CysLT), as leukotriene D4 and C4 (LTD4 and LTC4), are synthesized from arachidonic acid via the 5-lipoxygenase pathway, and play an important role in several types of diseases such as inflammation and cancer. Their effects are mediated via the two main G-protein-coupled receptors, CysLT1R and CysLT2R. Multiple studies from our group observed a significant increase in CysLT1R expression in the poor prognosis group, whereas CysLT2R expression was higher in the good prognosis group of CRC patients. Here, we systematically explored and established the role of the CysLTRs, cysteinyl leukotriene receptor 1(CYSLTR1) and cysteinyl leukotriene receptor 2 (CYSLTR2) gene expression and methylation in the progression and metastasis of CRC using three unique in silico cohorts and one clinical CRC cohort. Primary tumor tissues showed significant CYSLTR1 upregulation compared with matched normal tissues, whereas it was the opposite for the CYSLTR2. Univariate Cox proportional-hazards (CoxPH) analysis yielded a high expression of CYSLTR1 and accurately predicted high-risk patients in terms of overall survival (OS; hazard ratio (HR) = 1.87, p = 0.03) and disease-free survival [DFS] Hazard ratio [HR] = 1.54, p = 0.05). Hypomethylation of the CYSLTR1 gene and hypermethylation of the CYSLTR2 gene were found in CRC patients. The M values of the CpG probes for CYSLTR1 are significantly lower in primary tumor and metastasis samples than in matched normal samples, but those for CYSLTR2 are significantly higher. The differentially upregulated genes between tumor and metastatic samples were uniformly expressed in the high-CYSLTR1 group. Two epithelial-mesenchymal transition (EMT) markers, E-cadherin (CDH1) and vimentin (VIM) were significantly downregulated and upregulated in the high-CYSLTR1 group, respectively, but the result was opposite to that of CYSLTR2 expression in CRC. CDH1 expression was high in patients with less methylated CYSLTR1 but low in those with more methylated CYSLTR2. The EMT-associated observations were also validated in CC SW620 cell-derived colonospheres, which showed decreased E-cadherin expression in the LTD4 stimulated cells, but not in the CysLT1R knockdown SW620 cells. The methylation profiles of the CpG probes for CysLTRs significantly predicted lymph node (area under the curve [AUC] = 0.76, p < 0.0001) and distant (AUC = 0.83, p < 0.0001) metastasis. Intriguingly, the CpG probes cg26848126 (HR = 1.51, p = 0.03) for CYSLTR1, and cg16299590 (HR = 2.14, p = 0.03) for CYSLTR2 significantly predicted poor prognosis in terms of OS, whereas the CpG probe cg16886259 for CYSLTR2 significantly predicts a poor prognosis group in terms of DFS (HR = 2.88, p = 0.03). The CYSLTR1 and CYSLTR2 gene expression and methylation results were successfully validated in a CC patient cohort. In this study, we have demonstrated that CysLTRs' methylation and gene expression profile are associated with the progression, prognosis, and metastasis of CRC, which might be used for the assessment of high-risk CRC patients after validating the result in a larger CRC cohort.
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Tsai MJ, Chang WA, Chuang CH, Wu KL, Cheng CH, Sheu CC, Hsu YL, Hung JY. Cysteinyl Leukotriene Pathway and Cancer. Int J Mol Sci 2021; 23:ijms23010120. [PMID: 35008546 PMCID: PMC8745400 DOI: 10.3390/ijms23010120] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated immunity, may contribute to carcinogenesis and cancer progression. The cysteinyl leukotriene (CysLT) pathway is involved in several signal pathways, having various functions in different tissues. We summarized major findings of studies about the roles of the CysLT pathway in cancer. Many in vitro studies suggested the roles of CysLTs in cell survival/proliferation via CysLT1 receptor (CysLT1R). CysLT1R antagonism decreased cell vitality and induced cell death in several types of cancer cells, such as colorectal, urological, breast, lung and neurological malignancies. CysLTs were also associated with multidrug resistance of cancer, and CysLT1R antagonism might reverse chemoresistance. Some animal studies demonstrated the beneficial effects of CysLT1R antagonist in inhibiting tumorigenesis and progression of some cancer types, particularly colorectal cancer and lung cancer. The expression of CysLT1R was shown in various cancer tissues, particularly colorectal cancer and urological malignancies, and higher expression was associated with a poorer prognosis. The chemo-preventive effects of CysLT1R antagonists were demonstrated in two large retrospective cohort studies. In summary, the roles of the CysLT pathway in cancer have been delineated, whereas further studies are still warranted.
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Affiliation(s)
- Ming-Ju Tsai
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Wei-An Chang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Cheng-Hao Chuang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Kuan-Li Wu
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Chih-Hung Cheng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Chau-Chyun Sheu
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ya-Ling Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Jen-Yu Hung
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (M.-J.T.); (W.-A.C.); (C.-H.C.); (K.-L.W.); (C.-H.C.); (C.-C.S.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 5651)
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Saier L, Peyruchaud O. Emerging role of cysteinyl LTs in cancer. Br J Pharmacol 2021; 179:5036-5055. [PMID: 33527344 DOI: 10.1111/bph.15402] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/28/2020] [Accepted: 01/23/2021] [Indexed: 01/31/2023] Open
Abstract
Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumour development and metastasis through promoting a pro-tumour micro-environment. Up-regulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signalling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.
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Affiliation(s)
- Lou Saier
- INSERM, Unit 1033, LYOS, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Peyruchaud
- INSERM, Unit 1033, LYOS, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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10
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Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding. Cancer Immunol Immunother 2020; 70:203-213. [PMID: 32683508 PMCID: PMC7838147 DOI: 10.1007/s00262-020-02660-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 07/03/2020] [Indexed: 02/06/2023]
Abstract
In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment.
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11
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Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells. Cancer Lett 2020; 488:50-62. [PMID: 32474153 DOI: 10.1016/j.canlet.2020.05.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/22/2020] [Accepted: 05/20/2020] [Indexed: 12/15/2022]
Abstract
Colon cancer is a therapy-resistant cancer with a low 5-year survival frequency. The drug 5-fluorouracil (5-FU) has been used as a first-line therapy in metastatic colon cancer in combination with leucovorin or oxaliplatin with a >40% resistance rate. High CysLT1R expression in tumors is associated with poor survival of colon cancer patients. We sought to examine the role of CysLT1R in 5-FU resistance and established 5-FU-resistant (5-FU-R) colon cancer cells. These 5-FU-R-cells expressed increased levels of CysLT1R and showed increased survival and migration compared to nonresistant cells. Increases in thymidylate synthase and active β-catenin were also observed in the 5-FU-R-cells. LTD4/CysLT1R signaling was further increased and abolished after CYSLTR1 CRISPR-Cas9-knockdown and reduced in CysLT1R-doxycycline-knockdown experiments and CysLT1R-antagonist montelukast/5-FU-treated cells. Montelukast and 5-FU resulted in synergistic effects by reducing HT-29 cell and 5-FU-R-HT-29 cell migration and zebrafish xenograft metastasis. An increase in the stem cell markers in 5-FU-R-cells and 5-FU-R-cell-derived colonospheres and in CysLT1R-Dox-knockdown cells increased colonosphere formation and stem cell markers was noticed after 5-FU treatment. IL-4-mediated stemness in both HT-29-colonospheres and 5-FU-R-cell derived colonospheres was abolished by montelukast or montelukast + 5-FU-treatment. Targeting CysLT1R signaling by montelukast might reverse drug resistance and decrease resistance-derived stemness in colon cancer patients.
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12
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Voelkel NF, Peters-Golden M. A new treatment for severe pulmonary arterial hypertension based on an old idea: inhibition of 5-lipoxygenase. Pulm Circ 2020; 10:2045894019882635. [PMID: 32257113 PMCID: PMC7103594 DOI: 10.1177/2045894019882635] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/24/2019] [Indexed: 12/17/2022] Open
Abstract
It has been generally accepted that severe forms of pulmonary arterial hypertension are associated with inflammation. Plasma levels in patients with severe pulmonary arterial hypertension show elevated levels of interleukins and mediators of inflammation and histologically the diseased small pulmonary arterioles show infiltrates of inflammatory and immune cells. Here, we review the literature that connects pulmonary hypertension with the arachidonic acid/5-lipoxygenase-derived leukotriens. This mostly preclinical background data together with the availability of 5-lipoxygenase inhibitors and leukotriene receptor blockers provide the rationale for testing the hypothesis that 5-lipoxygenase products contribute to the pathobiology of severe pulmonary arterial hypertension in a subgroup of patients.
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Affiliation(s)
- Norbert F. Voelkel
- Department of Pulmonary Medicine,
University of Amsterdam Medical Centers, Amsterdam, the Netherlands
| | - Marc Peters-Golden
- Pulmonary and Critical Care Medicine
Division,
University
of Michigan Medical School, Ann Arbor, MI,
USA
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13
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Wu K, Yu X, Huang Z, Zhu D, Yi X, Wu YL, Hao Q, Kemp KT, Elshimali Y, Iyer R, Nguyen KT, Zheng S, Chen G, Chen QH, Wang G, Vadgama JV, Wu Y. Targeting of PP2Cδ By a Small Molecule C23 Inhibits High Glucose-Induced Breast Cancer Progression In Vivo. Antioxid Redox Signal 2019; 30:1983-1998. [PMID: 29808718 PMCID: PMC6486665 DOI: 10.1089/ars.2017.7486] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 05/24/2018] [Accepted: 05/28/2018] [Indexed: 12/14/2022]
Abstract
Aims: Epidemiologic evidence indicates that diabetes may increase risk of breast cancer (BC) and mortality in patients with cancer. The pathophysiological relationships between diabetes and cancer are not fully understood, and personalized treatments for diabetes-associated BC are urgently needed. Results: We observed that high glucose (HG), via activation of nuclear phosphatase PP2Cδ, suppresses p53 function, and consequently promotes BC cell proliferation, migration, and invasion. PP2Cδ expression is higher in tumor tissues from BC patients with hyperglycemia than those with normoglycemia. The mechanisms underlying HG stimulation of PP2Cδ involve classical/novel protein kinase-C (PKC) activation and GSK3β phosphorylation. Reactive oxygen species (ROS)/NF-κB pathway also mediates HG induction of PP2Cδ. Furthermore, we identified a 1,5-diheteroarylpenta-1,4-dien-3-one (Compound 23, or C23) as a novel potent PP2Cδ inhibitor with a striking cytotoxicity on MCF-7 cells through cell-based screening assay for growth inhibition and activity of a group of curcumin mimics. Beside directly inhibiting PP2Cδ activity, C23 blocks HG induction of PP2Cδ expression via heat shock protein 27 (HSP27) induction and subsequent ablation of ROS/NF-κB activation. C23 can thus significantly block HG-triggered inhibition of p53 activity, leading to the inhibition of cancer cell proliferation, migration, and invasion. In addition, hyperglycemia promotes BC development in diabetic nude mice, and C23 inhibits the xenografted BC tumor growth. Conclusions and Innovation: Our findings elucidate mechanisms that may have contributed to diabetes-associated BC progression, and provide the first evidence to support the possible alternative therapeutic approach to BC patients with diabetes. Antioxid. Redox Signal. 30, 1983-1998.
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Affiliation(s)
- Ke Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
- School of Health Sciences, Wuhan University, Wuhan, China
| | - Xiaoting Yu
- Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhimin Huang
- Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Donghui Zhu
- Department of Biomedical Engineering, University of North Texas, Denton, Texas
| | - Xianghua Yi
- Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ying-Li Wu
- Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiongyu Hao
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
| | - Kevin T. Kemp
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
| | - Yahya Elshimali
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
| | - Roshni Iyer
- Department of Biomedical Engineering, University of Texas at Arlington, Arlington, Texas
| | - Kytai Truong Nguyen
- Department of Biomedical Engineering, University of Texas at Arlington, Arlington, Texas
| | - Shilong Zheng
- RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, Louisiana
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana
| | - Guanglin Chen
- Department of Chemistry, California State University, Fresno, Fresno, California
| | - Qiao-Hong Chen
- Department of Chemistry, California State University, Fresno, Fresno, California
| | - Guangdi Wang
- RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, Louisiana
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
- David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California
| | - Yong Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
- David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California
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14
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Deng Z, Chai J, Zeng Q, Zhang B, Ye T, Chen X, Xu X. The anticancer properties and mechanism of action of tablysin-15, the RGD-containing disintegrin, in breast cancer cells. Int J Biol Macromol 2019; 129:1155-1167. [PMID: 30660566 DOI: 10.1016/j.ijbiomac.2019.01.073] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/10/2019] [Accepted: 01/16/2019] [Indexed: 01/24/2023]
Abstract
αvβ3 integrin expressed on cancer cell surfaces is associated with important cancer hallmarks including survival and metastasis and is thus a potential anticancer drug target. Tablysin-15 contains the RGD motif and is a high-affinity αvβ3 integrin antagonist. The aim of this study was to investigate the antitumor effect and mechanism of action of tablysin-15 against αvβ3 integrin high-expressing breast cancer cell lines in vitro and in vivo. Tablysin-15 dose-dependently inhibited the proliferation, migration, and invasion of two breast cancer cell lines via the αvβ3 integrin in vitro. Proliferation inhibition was attributable to G0/G1 phase cell cycle arrest rather than apoptosis or necrosis. Furthermore, tablysin-15 downregulated the activity and mRNA expression of MMP-2/-9, VEGF, and COX-2 but upregulated TIMP-1/-2 mRNA in both cell lines. Further, tablysin-15 suppressed the expression of CDK2, CDK6, cyclin D1, and cyclin E, the phosphorylation of FAK, Akt, GSK-3β, and ERK, and the nuclear translocation of NF-κB while increasing the expression of the CDK inhibitor p21waf1/C1. Lastly, tablysin-15 provided effective antitumor protection in vivo. Thus, tablysin-15 inhibits the metastasis and proliferation of breast cancer cells through binding αvβ3 integrin and blocking FAK-associated signaling pathways as well as nuclear translocation of NF-κB.
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Affiliation(s)
- Zhenhui Deng
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jinwei Chai
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qingye Zeng
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Bei Zhang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Tiaofei Ye
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xin Chen
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
| | - Xueqing Xu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
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15
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Lee CH. Epithelial-mesenchymal transition: Initiation by cues from chronic inflammatory tumor microenvironment and termination by anti-inflammatory compounds and specialized pro-resolving lipids. Biochem Pharmacol 2018; 158:261-273. [DOI: 10.1016/j.bcp.2018.10.031] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023]
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Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the USA. It is of practical importance to identify novel therapeutic targets of CRC to develop new anti-cancer drugs and to discover novel biomarkers of CRC to develop new detection methods. Eicosanoids, which are metabolites of polyunsaturated fatty acids produced by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, are important lipid-signaling molecules involved in the regulation of inflammation and tumorigenesis. Substantial studies have shown that the profiles of eicosanoids are deregulated in CRC, and the enzymes, metabolites, and receptors in the eicosanoid signaling cascade play critical roles in regulating colonic inflammation and colon tumorigenesis. In this review, we discuss the roles of the COX, LOX, and CYP pathways in the carcinogenesis of CRC.
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Affiliation(s)
- Yuxin Wang
- College of Life Science, Northwest University, Xi'an, Shaanxi, China
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Weicang Wang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Katherine Z Sanidad
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, USA
| | - Pei-An Shih
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Xinfeng Zhao
- College of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Guodong Zhang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, USA.
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17
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Osman J, Savari S, Chandrashekar NK, Bellamkonda K, Douglas D, Sjölander A. Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitis-associated colon cancer. Oncotarget 2018; 8:34773-34786. [PMID: 28410235 PMCID: PMC5471010 DOI: 10.18632/oncotarget.16718] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/20/2017] [Indexed: 12/19/2022] Open
Abstract
Cysteinyl leukotriene receptor 1 (CysLT1R) has been shown to be up-regulated in the adenocarcinomas of colorectal cancer patients, which is associated with a poor prognosis. In a spontaneous model of colon cancer, CysLT1R disruption was associated with a reduced tumor burden in double-mutant female mice (ApcMin/+/Cysltr1-/-) compared to ApcMin/+ littermates. In the current study, we utilized a genetic approach to investigate the effect of CysLT1R in the induced azoxymethane/dextran sulfate sodium (AOM/DSS) model of colitis-associated colon cancer. We found that AOM/DSS female mice with a global disruption of the Cysltr1 gene (Cysltr1-/-) had a higher relative body weight, a more normal weight/length colon ratio and smaller-sized colonic polyps compared to AOM/DSS wild-type counterparts. The Cysltr1-/- colonic polyps exhibited low-grade dysplasia, while wild-type polyps had an adenoma-like phenotype. The Cysltr1-/- colonic polyps exhibited significant decreases in nuclear β-catenin and COX-2 protein expression, while the normal crypts surrounding the polyps exhibited increased Mucin 2 expression. Furthermore, Cysltr1-/- mice exhibited an overall reduction in inflammation, with a significant decrease in proinflammatory cytokines, polyp 5-LOX expression and infiltration of CD45 leukocytes and F4/80 macrophages. In conclusion, the present genetic approach in an AOM/DSS model further supports an important role for CysLT1R in colon tumorigenesis.
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Affiliation(s)
- Janina Osman
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Sayeh Savari
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Naveen Kumar Chandrashekar
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Kishan Bellamkonda
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Desiree Douglas
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
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18
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Koopmans T, Gosens R. Revisiting asthma therapeutics: focus on WNT signal transduction. Drug Discov Today 2017; 23:49-62. [PMID: 28890197 DOI: 10.1016/j.drudis.2017.09.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 07/20/2017] [Accepted: 09/01/2017] [Indexed: 12/16/2022]
Abstract
Asthma is a complex disease of the airways that develops as a consequence of both genetic and environmental factors. This interaction has highlighted genes important in early life, particularly those that control lung development, such as the Wingless/Integrase-1 (WNT) signalling pathway. Although aberrant WNT signalling is involved with an array of human conditions, it has received little attention within the context of asthma. Yet it is highly relevant, driving events involved with inflammation, airway remodelling, and airway hyper-responsiveness (AHR). In this review, we revisit asthma therapeutics by examining whether WNT signalling is a valid therapeutic target for asthma.
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Affiliation(s)
- Tim Koopmans
- Department of Molecular Pharmacology, University of Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, The Netherlands
| | - Reinoud Gosens
- Department of Molecular Pharmacology, University of Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, The Netherlands.
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19
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Prognostic Impact of Intra-abdominal/Pelvic Inflammation After Radical Surgery for Locally Recurrent Rectal Cancer. Dis Colon Rectum 2017; 60:827-836. [PMID: 28682968 DOI: 10.1097/dcr.0000000000000853] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The influence of postoperative infectious complications, such as anastomotic leakage, on survival has been reported for various cancers, including colorectal cancer. However, it remains unclear whether intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is relevant to its prognosis. OBJECTIVE The purpose of this study was to evaluate factors associated with survival after radical surgery for locally recurrent rectal cancer. DESIGN The prospectively collected data of patients were retrospectively evaluated. SETTINGS This study was conducted at a single-institution tertiary care cancer center. PATIENTS Between 1983 and 2012, patients who underwent radical surgery for locally recurrent rectal cancer with curative intent at the National Cancer Center Hospital were reviewed. MAIN OUTCOME MEASURES Factors associated with overall and relapse-free survival were evaluated. RESULTS During the study period, a total of 180 patients were eligible for analyses. Median blood loss and operation time for locally recurrent rectal cancer were 2022 mL and 634 minutes. Five-year overall and 3-year relapse-free survival rates were 38.6% and 26.7%. Age (p = 0.002), initial tumor stage (p = 0.03), pain associated with locally recurrent rectal cancer (p = 0.03), CEA level (p = 0.004), resection margin (p < 0.001), intra-abdominal/pelvic inflammation (p < 0.001), and surgery period (p = 0.045) were independent prognostic factors associated with overall survival, whereas CEA level (p = 0.01), resection margin (p = 0.002), and intra-abdominal/pelvic inflammation (p = 0.001) were associated with relapse-free survival. Intra-abdominal/pelvic inflammation was observed in 45 patients (25.0%). A large amount of perioperative blood loss was the only factor associated with the occurrence of intra-abdominal/pelvic inflammation (p = 0.007). LIMITATIONS This study was limited by its retrospective nature and heterogeneous population. CONCLUSIONS Intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is associated with poor prognosis. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.
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20
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Chu YM, Peng HX, Xu Y, Yang DM, Zhou FL, Li J, Kuai R, Lin Y. MicroRNA-1254 inhibits the migration of colon adenocarcinoma cells by targeting PSMD10. J Dig Dis 2017; 18:169-178. [PMID: 28296190 DOI: 10.1111/1751-2980.12463] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 02/28/2017] [Accepted: 03/05/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE MicroRNA-1254 (miR-1254) has not been studied in colorectal cancer (CRC) to date. This study aimed to investigate the inhibitory mechanism of miR-1254 in CRC tumorigenesis. METHODS MiR-1254 expression was examined using real-time polymerase chain reaction in CRC and adjacent non-tumorous tissues. The correlation between miR-1254 expressions and proliferation and migration of cancer cells was determined using the CCK-8 and transwell assays. RNA sequencing was used to identify differentially expressed genes downstream from miR-1254. A luciferase reporter assay was used to confirm the direct interaction between miR-1254 and its predicted target gene, PSMD10. Moreover, PSMD10 was either overexpressed or silenced in colon carcinoma cells overexpressing miR-1254 to determine whether their interaction contributed to CRC migration and epithelial-mesenchymal transition (EMT). RESULTS Significantly lower miR-1254 expressions were observed in CRC tissues than in adjacent non-tumorous tissues. Exogenous miR-1254 expression suppressed the migration of colon carcinoma cell lines SW1116 and HCT116. RNA sequencing and luciferase assays revealed that miR-1254 directly binded to the 3'-untranslated region of PSMD10, an important regulator of EMT and cell migration. PSMD10 knockdown inhibited EMT and colon cancer cell migration, whereas PSMD10 overexpression reversed the inhibition of EMT and cell migration caused by miR-1254. CONCLUSION MiR-1254 may act as a tumor suppressor in CRC and may inhibit CRC migration by directly targeting PSMD10 to suppress the EMT process.
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Affiliation(s)
- Yi Min Chu
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hai Xia Peng
- Department of Endoscopy, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ying Xu
- Department of Endoscopy, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Da Ming Yang
- Department of Endoscopy, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Feng Li Zhou
- Department of Endoscopy, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ji Li
- Department of Endoscopy, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rong Kuai
- Department of Endoscopy, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yong Lin
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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21
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Vinnakota K, Zhang Y, Selvanesan BC, Topi G, Salim T, Sand-Dejmek J, Jönsson G, Sjölander A. M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases. J Cell Physiol 2017; 232:3468-3480. [PMID: 28098359 DOI: 10.1002/jcp.25808] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 01/13/2017] [Accepted: 01/17/2017] [Indexed: 12/19/2022]
Abstract
The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-α (TNFα) and leukotriene D4 (LTD4 ). MMP-9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD4 ) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFα and LTD4 induced stabilization/nuclear translocation of β-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD4 . The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2-medium enriched in TNFα and LTD4 promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT.
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Affiliation(s)
- Katyayni Vinnakota
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Yuan Zhang
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Benson Chellakkan Selvanesan
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Geriolda Topi
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Tavga Salim
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Janna Sand-Dejmek
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Gunilla Jönsson
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden
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22
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Moore GY, Pidgeon GP. Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway. Int J Mol Sci 2017; 18:E236. [PMID: 28125014 PMCID: PMC5343774 DOI: 10.3390/ijms18020236] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/03/2017] [Accepted: 01/13/2017] [Indexed: 12/15/2022] Open
Abstract
5-lipoxygenase is an enzyme responsible for the synthesis of a range of bioactive lipids signalling molecules known collectively as eicosanoids. 5-lipoxygenase metabolites such as 5-hydroxyeicosatetraenoic acid (5-HETE) and a number of leukotrienes are mostly derived from arachidonic acid and have been shown to be lipid mediators of inflammation in different pathological states including cancer. Upregulated 5-lipoxygenase expression and metabolite production is found in a number of cancer types and has been shown to be associated with increased tumorigenesis. 5-lipoxygenase activity is present in a number of diverse cell types of the immune system and connective tissue. In this review, we discuss potential routes through which cancer cells may utilise the 5-lipoxygenase pathway to interact with the tumour microenvironment during the development and progression of a tumour. Furthermore, immune-derived 5-lipoxygenase signalling can drive both pro- and anti-tumour effects depending on the immune cell subtype and an overview of evidence for these opposing effects is presented.
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Affiliation(s)
- Gillian Y Moore
- Department of Surgery, Trinity College Dublin, Dublin 8, Ireland.
| | - Graham P Pidgeon
- Department of Surgery, Trinity College Dublin, Dublin 8, Ireland.
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Dehydropeptidase 1 promotes metastasis through regulation of E-cadherin expression in colon cancer. Oncotarget 2017; 7:9501-12. [PMID: 26824987 PMCID: PMC4891055 DOI: 10.18632/oncotarget.7033] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 01/19/2016] [Indexed: 01/05/2023] Open
Abstract
Dehydropeptidase 1 (DPEP1) is a zinc-dependent metalloproteinase that is expressed aberrantly in several cancers. The role of DPEP1 in cancer remain controversial. In this study, we demonstrate that DPEP1 functions as a positive regulator for colon cancer cell metastasis. The expression of DPEP1 mRNA and proteins were upregulated in colon cancer tissues compared to normal mucosa. Gain-of-function and loss-of-function approaches were used to examine the malignant phenotype of DPEP1-expressing or DPEP1-depleted cells. DPEP1 expression caused a significant increase in colon cancer cell adhesion and invasion in vitro, and metastasis in vivo. In contrast, DPEP1 depletion induced opposite effects. Furthermore, cilastatin, a DPEP1 inhibitor, suppressed the invasion and metastasis of DPEP1-expressing cells. DPEP1 inhibited the leukotriene D4 signaling pathway and increased the expression of E-cadherin. We also show that DPEP1 mediates TGF-β-induced EMT. TGF-β transcriptionally repressed DPEP1 expression. TGF-β treatment decreased E-cadherin expression and promoted cell invasion in DPEP1-expressing colon cancer cell lines, whereas it did not affect these parameters in DPEP1-depleted cell lines. These results suggest that DPEP1 promotes cancer metastasis by regulating E-cadherin plasticity and that it might be a potential therapeutic target for preventing the progression of colon cancer.
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Yektaei-Karin E, Zovko A, Nilsson A, Näsman-Glaser B, Kanter L, Rådmark O, Wallvik J, Ekblom M, Dolinska M, Qian H, Stenke L. Modulation of leukotriene signaling inhibiting cell growth in chronic myeloid leukemia. Leuk Lymphoma 2016; 58:1903-1913. [DOI: 10.1080/10428194.2016.1262029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
| | - Ana Zovko
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Anders Nilsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | | | - Lena Kanter
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Olof Rådmark
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jonas Wallvik
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Marja Ekblom
- Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Monika Dolinska
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hong Qian
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Leif Stenke
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, Division of Hematology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
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Burke L, Butler CT, Murphy A, Moran B, Gallagher WM, O'Sullivan J, Kennedy BN. Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer. Front Cell Dev Biol 2016; 4:103. [PMID: 27709113 PMCID: PMC5030284 DOI: 10.3389/fcell.2016.00103] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 08/30/2016] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF, and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore, CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target.
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Affiliation(s)
- Lorraine Burke
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College DublinDublin, Ireland; Translational Oncology, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's HospitalDublin, Ireland
| | - Clare T Butler
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin Dublin, Ireland
| | - Adrian Murphy
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital Baltimore, MD, USA
| | - Bruce Moran
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin Dublin, Ireland
| | - William M Gallagher
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital Dublin, Ireland
| | - Breandán N Kennedy
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin Dublin, Ireland
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26
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Venerito M, Helmke C, Jechorek D, Wex T, Rosania R, Antweiler K, Weigt J, Malfertheiner P. Leukotriene receptor expression in esophageal squamous cell cancer and non-transformed esophageal epithelium: a matched case control study. BMC Gastroenterol 2016; 16:85. [PMID: 27475906 PMCID: PMC4967508 DOI: 10.1186/s12876-016-0499-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 07/21/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Leukotriene B4 (LTB4R and LTB4R2) and cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2) contribute to malignant cell transformation. We aimed to investigate the expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 in esophageal squamous cell carcinoma and adjacent non-transformed squamous epithelium of the esophagus, as well as in control biopsy samples from esophageal squamous epithelium of patients with functional dyspepsia. METHODS Expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 was analyzed by immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in biopsy samples of 19 patients with esophageal squamous cell cancer and 9 sex- and age-matched patients with functional dyspepsia. RESULTS LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 were expressed in all biopsy samples. Major findings were: 1) protein levels of all leukotriene receptors were significantly increased in esophageal squamous cell cancer compared to control mucosa (p < 0.05); 2) CYSLTR1 and CYSLTR2 gene expression was decreased in cancer tissue compared to control at 0.26-fold and 0.23-fold respectively; 3) an up-regulation of LTB4R (mRNA and protein expression) and a down-regulation of CYSLTR2 (mRNA expression) in non-transformed epithelium of cancer patients compared to control (p < 0.05) was observed. CONCLUSIONS The expression of leukotriene receptors was deregulated in esophageal squamous cell cancer. Up-regulation of LTB4R and down-regulation of CYSLTR2 gene expression may occur already in normal squamous esophageal epithelium of patients with esophageal cancer suggesting a potential role of these receptors in early steps of esophageal carcinogenesis. Larger studies are warranted to confirm these observations.
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Affiliation(s)
- M Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - C Helmke
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - D Jechorek
- Institute of Pathology, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - T Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - R Rosania
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - K Antweiler
- Department of Biometrics and Medical Informatics, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - J Weigt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - P Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany.
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Bellamkonda K, Chandrashekar NK, Osman J, Selvanesan BC, Savari S, Sjölander A. The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model. BMC Cancer 2016; 16:425. [PMID: 27388564 PMCID: PMC4937611 DOI: 10.1186/s12885-016-2466-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/29/2016] [Indexed: 12/11/2022] Open
Abstract
Background Colorectal cancer is one of the most common types of cancers worldwide. Recent studies have identified cancer-initiating cells (CICs) as a subgroup of replication-competent cells in the development of colorectal cancer. Although it is understood that an inflammation-rich tumor microenvironment presumably supports CIC functions, the contributory factors are not very well defined. The present study advances our understanding of the role of the eicosanoids leukotriene D4 (LTD4) and prostaglandin E2 (PGE2) in the tumorigenic ability of CICs and investigates the consequential changes occurring in the tumor environment that might support tumor growth. Methods In this study we used human HCT-116 colon cancer ALDH+ cells in a nude mouse xenograft model. Protein expression and immune cell was determined in tumor-dispersed cells by flow cytometry and in tumor sections by immunohistochemistry. mRNA expressions were quantified using RT-q-PCR and plasma cytokine levels by Multiplex ELISA. Results We observed that LTD4 and PGE2 treatment augmented CIC-induced tumor growth. LTD4-and PGE2-treated xenograft tumors revealed a robust increase in ALDH and Dclk1 protein expression, coupled with activated β-catenin signaling and COX-2 up-regulation. Furthermore, LTD4 or PGE2 accentuated the accumulation of CD45 expressing cells within xenograft tumors. Further analysis revealed that these infiltrating immune cells consisted of neutrophils (LY6G) and M2 type macrophages (CD206+). In addition, LTD4 and PGE2 treatment significantly elevated the plasma levels of cysteinyl leukotrienes and PGE2, as well as levels of IL-1β, IL-2, IL-6, TNF-α and CXCL1/KC/GRO. In addition, increased mRNA expression of IL-1β, IL-6 and IL-10 were detected in tumors from mice that had been treated with LTD4 or PGE2. Conclusion Our data suggest that both LTD4 and PGE2 promote CICs in initiating tumor growth by allowing modifications in the tumor environment. Our data indicate that new therapeutic strategies targeting eicosanoids, specifically LTD4 and PGE2, could be tested for better therapeutic management of colon cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2466-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kishan Bellamkonda
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Naveen Kumar Chandrashekar
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Janina Osman
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Benson Chellakkan Selvanesan
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Sayeh Savari
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
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Zhang L, Geng WR, Hu J, Chen XM, Shen YL, Wang LL, Jiang JP, Chen YY. Lipopolysaccharide pretreatment promotes cardiac stem cell migration through heat shock protein 90-dependent β-catenin activation. Life Sci 2016; 153:132-40. [DOI: 10.1016/j.lfs.2016.04.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 04/06/2016] [Accepted: 04/14/2016] [Indexed: 12/14/2022]
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Savari S, Chandrashekar NK, Osman J, Douglas D, Bellamkonda K, Jönsson G, Juhas M, Greicius G, Pettersson S, Sjölander A. Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+mouse model. Carcinogenesis 2016; 37:491-9. [DOI: 10.1093/carcin/bgw031] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 02/25/2016] [Indexed: 12/24/2022] Open
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30
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Galvão AF, Petta T, Flamand N, Bollela VR, Silva CL, Jarduli LR, Malmegrim KCR, Simões BP, de Moraes LAB, Faccioli LH. Plasma eicosanoid profiles determined by high-performance liquid chromatography coupled with tandem mass spectrometry in stimulated peripheral blood from healthy individuals and sickle cell anemia patients in treatment. Anal Bioanal Chem 2016; 408:3613-23. [PMID: 26968567 DOI: 10.1007/s00216-016-9445-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/17/2016] [Accepted: 02/23/2016] [Indexed: 01/19/2023]
Abstract
Eicosanoids play an important role in homeostasis and in the pathogenesis of various human diseases. Pharmacological agents such as Ca(2+) ionophores and Ca(2+)-ATPase inhibitors, as well as natural agonists such as formylmethionine-leucyl-phenylalanine (fMLP), can stimulate eicosanoid biosynthesis. The aims of this work were to develop a method to determine the eicosanoid profile of human plasma samples after whole blood stimulation and to assess differences between healthy and sick individuals. For this purpose, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was partially validated for the quantification of 22 eicosanoids using human plasma from healthy volunteers. In addition, we optimized a method for the stimulation of eicosanoids in human whole blood. LC-MS/MS analyses were performed by negative electrospray ionization and multiple reaction monitoring. An assumption of linearity resulted in a regression coefficient ≥0.98 for all eicosanoids tested. The mean intra-assay and inter-assay accuracy and precision values had relative standard deviations and relative errors of ≤15%, except for the lower limit of quantification, where these values were ≤20%. For whole blood stimulation, four stimuli (fMLP, ionomycin, A23187, and thapsigargin) were tested. Results of the statistical analysis showed that A23187 and thapsigargin were potent stimuli for the production or liberation of eicosanoids. We next compared the eicosanoid profiles of stimulated whole blood samples of healthy volunteers to those of patients with sickle cell anemia (SCA) under treatment with hydroxyurea (HU) or after chronic red blood cell (RBC) transfusion. The results indicate that the method was sufficient to find a difference between lipid mediators released in whole blood of SCA patients and those of healthy subjects, mainly for 5-HETE, 12-HETE, LTB4, LTE4, TXB2, and PGE2. In conclusion, our analytical method can detect significant changes in eicosanoid profiles in stimulated whole blood, which will contribute to establishing the eicosanoid profiles associated with different inflammatory and infectious diseases.
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Affiliation(s)
- Alyne Fávero Galvão
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil
| | - Tânia Petta
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil
| | - Nicolas Flamand
- Département de Médecine, Faculté de Médecine Université Laval, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725, chemin Sainte-Foy, Québec, G1V 4G5, Canada
| | - Valdes Roberto Bollela
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Célio Lopes Silva
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Luciana Ribeiro Jarduli
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil
| | - Kelen Cristina Ribeiro Malmegrim
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil.,Centro de Terapia Celular, Centro Regional de Hemoterapia do Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Rua Tenente Catão Roxo 2501, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Belinda Pinto Simões
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Luiz Alberto Beraldo de Moraes
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-901, Brazil
| | - Lúcia Helena Faccioli
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil.
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Reynolds AL, Alvarez Y, Sasore T, Waghorne N, Butler CT, Kilty C, Smith AJ, McVicar C, Wong VHY, Galvin O, Merrigan S, Osman J, Grebnev G, Sjölander A, Stitt AW, Kennedy BN. Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis. J Biol Chem 2016; 291:7242-55. [PMID: 26846851 DOI: 10.1074/jbc.m115.710665] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Indexed: 12/21/2022] Open
Abstract
Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge Diverset(TM)library and inhibition of hyaloid vessel angiogenesis in Tg(fli1:EGFP) zebrafish. 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol, (quininib) robustly inhibits developmental angiogenesis at 4-10 μmin zebrafish and significantly inhibits angiogenic tubule formation in HMEC-1 cells, angiogenic sprouting in aortic ring explants, and retinal revascularization in oxygen-induced retinopathy mice. Quininib is well tolerated in zebrafish, human cell lines, and murine eyes. Profiling screens of 153 angiogenic and inflammatory targets revealed that quininib does not directly target VEGF receptors but antagonizes cysteinyl leukotriene receptors 1 and 2 (CysLT1-2) at micromolar IC50values. In summary, quininib is a novel anti-angiogenic small-molecule CysLT receptor antagonist. Quininib inhibits angiogenesis in a range of cell and tissue systems, revealing novel physiological roles for CysLT signaling. Quininib has potential as a novel therapeutic agent to treat ocular neovascular pathologies and may complement current anti-VEGF biological agents.
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Affiliation(s)
- Alison L Reynolds
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Yolanda Alvarez
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Temitope Sasore
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Nora Waghorne
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Clare T Butler
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Claire Kilty
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Andrew J Smith
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Carmel McVicar
- the Centre for Experimental Medicine, Queen's University Belfast, Wellcome-Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom, and
| | - Vickie H Y Wong
- the Centre for Experimental Medicine, Queen's University Belfast, Wellcome-Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom, and
| | - Orla Galvin
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Stephanie Merrigan
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Janina Osman
- the Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, 20502 Malmö, Sweden
| | - Gleb Grebnev
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Anita Sjölander
- the Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, 20502 Malmö, Sweden
| | - Alan W Stitt
- the Centre for Experimental Medicine, Queen's University Belfast, Wellcome-Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom, and
| | - Breandán N Kennedy
- From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland,
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32
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Molecular mechanisms of target recognition by lipid GPCRs: relevance for cancer. Oncogene 2015; 35:4021-35. [PMID: 26640151 DOI: 10.1038/onc.2015.467] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 11/02/2015] [Accepted: 11/02/2015] [Indexed: 12/18/2022]
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33
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Jiang WG, Sanders AJ, Katoh M, Ungefroren H, Gieseler F, Prince M, Thompson SK, Zollo M, Spano D, Dhawan P, Sliva D, Subbarayan PR, Sarkar M, Honoki K, Fujii H, Georgakilas AG, Amedei A, Niccolai E, Amin A, Ashraf SS, Ye L, Helferich WG, Yang X, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Azmi AS, Keith WN, Bilsland A, Bhakta D, Halicka D, Nowsheen S, Pantano F, Santini D. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin Cancer Biol 2015; 35 Suppl:S244-S275. [PMID: 25865774 DOI: 10.1016/j.semcancer.2015.03.008] [Citation(s) in RCA: 351] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 03/17/2015] [Accepted: 03/18/2015] [Indexed: 12/12/2022]
Abstract
Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.
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Affiliation(s)
- W G Jiang
- Cardiff University, Cardiff, United Kingdom.
| | | | - M Katoh
- National Cancer Center, Tokyo, Japan
| | - H Ungefroren
- University Hospital Schleswig-Holstein, Lübeck, Germany
| | - F Gieseler
- University Hospital Schleswig-Holstein, Lübeck, Germany
| | - M Prince
- University of Michigan, Ann Arbor, MI, USA
| | | | - M Zollo
- Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples Federico II, Naples, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy
| | - D Spano
- CEINGE Biotecnologie Avanzate, Naples, Italy
| | - P Dhawan
- University of Nebraska Medical Center, Omaha, USA
| | - D Sliva
- Purdue Research Park, Indianapolis, IN, USA
| | | | - M Sarkar
- University of Miami, Miami, FL, USA
| | - K Honoki
- Nara Medical University, Kashihara, Japan
| | - H Fujii
- Nara Medical University, Kashihara, Japan
| | - A G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Athens, Greece
| | - A Amedei
- University of Florence, Florence, Italy
| | | | - A Amin
- United Arab Emirates University, Al Ain, United Arab Emirates and Faculty of Science, Cairo University, Egypt
| | - S S Ashraf
- United Arab Emirates University, Al Ain, United Arab Emirates and Faculty of Science, Cairo University, Egypt
| | - L Ye
- Cardiff University, Cardiff, United Kingdom
| | - W G Helferich
- University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - X Yang
- University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | | | - G Guha
- SASTRA University, Thanjavur, India
| | | | - K Aquilano
- University of Rome Tor Vergata, Rome, Italy
| | - S Chen
- Ovarian and Prostate Cancer Research Trust Laboratory, Surrey, United Kingdom
| | - A S Azmi
- Wayne State University, Detroit, MI, USA
| | - W N Keith
- University of Glasgow, Glasgow, United Kingdom
| | - A Bilsland
- University of Glasgow, Glasgow, United Kingdom
| | - D Bhakta
- SASTRA University, Thanjavur, India
| | - D Halicka
- New York Medical College, Valhalla, NY, USA
| | - S Nowsheen
- Mayo Clinic College of Medicine, Rochester, MN, USA
| | - F Pantano
- University Campus Bio-Medico, Rome, Italy
| | - D Santini
- University Campus Bio-Medico, Rome, Italy
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Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 2015; 35 Suppl:S25-S54. [PMID: 25892662 PMCID: PMC4898971 DOI: 10.1016/j.semcancer.2015.02.006] [Citation(s) in RCA: 482] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 02/08/2023]
Abstract
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, Temple University, Philadelphia, PA, United States.
| | - Alla Arzumanyan
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Rob J Kulathinal
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Stacy W Blain
- Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
| | - Randall F Holcombe
- Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, United States
| | - Jamal Mahajna
- MIGAL-Galilee Technology Center, Cancer Drug Discovery Program, Kiryat Shmona, Israel
| | - Maria Marino
- Department of Science, University Roma Tre, V.le G. Marconi, 446, 00146 Rome, Italy
| | - Maria L Martinez-Chantar
- Metabolomic Unit, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain
| | - Roman Nawroth
- Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Isidro Sanchez-Garcia
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Dipali Sharma
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Neeraj K Saxena
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
| | - Neetu Singh
- Tissue and Cell Culture Unit, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India
| | | | - Shanchun Guo
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - S Salman Ashraf
- Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - Chandra S Boosani
- Department of BioMedical Sciences, Creighton University, Omaha, NE, United States
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Sophie Chen
- Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey GU2 7YG, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Asfar S Azmi
- Department of Pathology, Karmonas Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States
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35
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de Hoog VC, Bovens SM, de Jager SC, van Middelaar BJ, van Duijvenvoorde A, Doevendans PA, Pasterkamp G, de Kleijn DP, Timmers L. BLT1 antagonist LSN2792613 reduces infarct size in a mouse model of myocardial ischaemia–reperfusion injury. Cardiovasc Res 2015; 108:367-76. [DOI: 10.1093/cvr/cvv224] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 08/12/2015] [Indexed: 01/23/2023] Open
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Dhall S, Wijesinghe DS, Karim ZA, Castro A, Vemana HP, Khasawneh FT, Chalfant CE, Martins-Green M. Arachidonic acid-derived signaling lipids and functions in impaired healing. Wound Repair Regen 2015; 23:644-56. [PMID: 26135854 DOI: 10.1111/wrr.12337] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 05/26/2015] [Indexed: 12/30/2022]
Abstract
Very little is known about lipid function during wound healing, and much less during impaired healing. Such understanding will help identify what roles lipid signaling plays in the development of impaired/chronic wounds. We took a lipidomics approach to study the alterations in lipid profile in the LIGHT(-/-) mouse model of impaired healing which has characteristics that resemble those of impaired/chronic wounds in humans, including high levels of oxidative stress, excess inflammation, increased extracellular matrix degradation and blood vessels with fibrin cuffs. The latter suggests excess coagulation and potentially increased platelet aggregation. We show here that in these impaired wounds there is an imbalance in the arachidonic acid (AA) derived eicosonoids that mediate or modulate inflammatory reactions and platelet aggregation. In the LIGHT(-/-) impaired wounds there is a significant increase in enzymatically derived breakdown products of AA. We found that early after injury there was a significant increase in the eicosanoids 11-, 12-, and 15-hydroxyeicosa-tetranoic acid, and the proinflammatory leukotrienes (LTD4 and LTE) and prostaglandins (PGE2 and PGF2α ). Some of these eicosanoids also promote platelet aggregation. This led us to examine the levels of other eicosanoids known to be involved in the latter process. We found that thromboxane (TXA2 /B2 ), and prostacyclins 6kPGF1α are elevated shortly after wounding and in some cases during healing. To determine whether they have an impact in platelet aggregation and hemostasis, we tested LIGHT(-/-) mouse wounds for these two parameters and found that, indeed, platelet aggregation and hemostasis are enhanced in these mice when compared with the control C57BL/6 mice. Understanding lipid signaling in impaired wounds can potentially lead to development of new therapeutics or in using existing nonsteroidal anti-inflammatory agents to help correct the course of healing.
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Affiliation(s)
- Sandeep Dhall
- Department of Cell Biology and Neuroscience, University of California, Riverside, California.,Department of Bioengineering Interdepartmental Graduate Program, University of California, Riverside, California
| | - Dayanjan Shanaka Wijesinghe
- Department of Surgery, Virginia Commonwealth University, Richmond, Virginia.,Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia.,The Massey Cancer Center, Richmond, VA, Virginia Commonwealth University, Richmond, Virginia.,Virginia Commonwealth University Reanimation Engineering Science Center (VCURES)
| | - Zubair A Karim
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Anthony Castro
- Department of Cell Biology and Neuroscience, University of California, Riverside, California
| | - Hari Priya Vemana
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California
| | - Fadi T Khasawneh
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Charles E Chalfant
- Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia.,The Massey Cancer Center, Richmond, VA, Virginia Commonwealth University, Richmond, Virginia.,Virginia Commonwealth University Reanimation Engineering Science Center (VCURES).,Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Manuela Martins-Green
- Department of Cell Biology and Neuroscience, University of California, Riverside, California.,Department of Bioengineering Interdepartmental Graduate Program, University of California, Riverside, California
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Zhang ZZ, Li Y, Wang M, Xu F. Significance of β-catenin and vitamin D receptor expression in colorectal carcinoma. Shijie Huaren Xiaohua Zazhi 2015; 23:3700-3705. [DOI: 10.11569/wcjd.v23.i23.3700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of β-catenin and vitamin D receptor (VDR) in colorectal carcinoma to explore their roles in colorectal carcinoma pathogenesis.
METHODS: The expression of β-catenin and VDR was detected by immunohistochemistry in 65 colorectal carcinoma specimens and 65 normal colorectal mucosa specimens.
RESULTS: The missing expression of β-catenin on the cell membrane and ectopic expression in colorectal carcinoma specimens and normal colorectal mucosa specimens had a significant difference (P < 0.01). The strongly positive expression of VDR in colorectal carcinoma specimens and normal colorectal mucosa specimens had a significant difference (P < 0.01). The abnormal expression of β-catenin was positively correlated with that of VDR in colorectal carcinoma (r = 0.98, P < 0.01), and both were found to be associated with lymph node metastasis and tumor invasion.
CONCLUSION: Lower expression of VDR may influence β-catenin and activate the Wnt signaling pathway in human colorectal carcinoma. Detecting the abnormal expression of β-catenin and VDR may be helpful for the diagnosis and evaluation of the prognosis of colorectal carcinoma.
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Cabral M, Martín-Venegas R, Moreno JJ. Leukotriene D4-induced Caco-2 cell proliferation is mediated by prostaglandin E2 synthesis. Physiol Rep 2015. [PMID: 26216432 PMCID: PMC4552517 DOI: 10.14814/phy2.12417] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Leukotriene D4 (LTD4) is a pro-inflammatory mediator formed from arachidonic acid through the action of 5-lipoxygenase (5-LOX). Its biological effects are mediated by at least two G-coupled plasmatic cysteinyl LT receptors (CysLT1-2R). It has been reported an upregulation of the 5-LOX pathway in tumor tissue unlike in normal colon mucosa. Colon tumors generally have an increased expression of CysLT1R and colon cancer patients with high expression levels of CysLT1R have poor prognosis. We previously observed that the cyclooxygenase pathway is involved in the control of intestinal epithelial cancer cell growth through PGE2 production. The aim of this study was therefore to assess the effect of LTD4 binding with CysLT1R on Caco-2 cell growth. We note a number of key findings from this research. We observed that at a concentration similar to that found under inflammatory conditions, LTD4 was able to induce Caco-2 cell proliferation and DNA synthesis. Moreover, with the use of a specific receptor antagonist this study has demonstrated that the effect of LTD4 is a result of its interaction with CystLT1R. We also note the possible participation of the PLC-IP3-Ca2+/DAG-PKC signaling pathways in cytosolic PLA2 and [3H]AA release induced by LTD4-CystLT1R interaction. Finally, we found that the resulting activation of the AA cascade and the production of PGE2 eicosanoid could be related to the activation of cell signaling pathways such as ERK and CREB. These findings will help facilitate our understanding of how inflammatory mediators can affect the survival and dissemination of intestinal carcinoma cells.
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Affiliation(s)
- Marisol Cabral
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Raquel Martín-Venegas
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Juan J Moreno
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
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Kofoed SC, Calatayud D, Jensen LS, Helgstrand F, Achiam MP, De Heer P, Svendsen LB. Intrathoracic anastomotic leakage after gastroesophageal cancer resection is associated with increased risk of recurrence. J Thorac Cardiovasc Surg 2015; 150:42-8. [PMID: 25986493 DOI: 10.1016/j.jtcvs.2015.04.030] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 04/07/2015] [Accepted: 04/11/2015] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Intrathoracic anastomotic leakage after intended curative resection for cancer in the esophagus or gastroesophageal junction has a negative impact on long-term survival. The aim of this study was to investigate whether an anastomotic leakage was associated with an increased recurrence rate. METHODS This nationwide study included consecutively collected data on patients undergoing curative surgical resection with intrathoracic anastomosis, alive 8 weeks postoperatively, between 2003 and 2011. Patients with incomplete resection, or metastatic disease intraoperatively, were excluded. Only biopsy-proven recurrences were accepted. RESULTS In total, 1085 patients were included. The frequency of anastomotic leakage was 8.6%. The median follow-up time was 29 months (interquartile range [IQR]: 13-58 months). Overall, 369 (34%) patients had disease recurrence, of which 346 patients died of recurrent gastroesophageal carcinoma. Twenty-three patients were alive with recurrence at the censoring date. In the study period, 333 patients died without signs of recurrent disease. The overall median time to recurrence was 66 weeks (IQR: 38-109 weeks). Distant metastases were found in 267 (25%), and local disease recurrence in 102 (9%) patients. Overall, 5-year disease-free survival in patients with leakage was 27%, versus 39% in those without leakage (P = .017). Anastomotic leakage was independently associated with higher risk of recurrence (hazard ratio [HR] = 1.63; 95% confidence interval [CI]: 1.17-2.29, P = .004) and all-cause mortality (HR = 1.57; 95% CI: 1.23-2.05, P < .0001). CONCLUSIONS Intrathoracic anastomotic leakage increased the risk of recurrence in patients who underwent curative gastroesophageal cancer resection.
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Affiliation(s)
- Steen C Kofoed
- Department of Surgery & Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Dan Calatayud
- Department of Surgery & Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lone S Jensen
- Department of Surgery, Aarhus Hospital, University of Aarhus, Aarhus, Denmark
| | - Frederik Helgstrand
- Department of Surgery & Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Michael P Achiam
- Department of Surgery & Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Pieter De Heer
- Department of Surgery & Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lars B Svendsen
- Department of Surgery & Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Postoperative peritoneal infection enhances migration and invasion capacities of tumor cells in vitro: an insight into the association between anastomotic leak and recurrence after surgery for colorectal cancer. Ann Surg 2015; 260:939-43; discussion 943-4. [PMID: 25243554 DOI: 10.1097/sla.0000000000000958] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE The aim of this study was to investigate the effect of postoperative peritoneal infection on proliferation, migration, and invasion capacities of cancer cells lines in vitro after surgery for colorectal cancer. BACKGROUND Anastomotic leakage is associated with higher rates of recurrence after surgery for colorectal cancer. However, the mechanisms responsible are unknown. We hypothesized that the infection-induced inflammatory response may enhance tumor progression features of residual cancer cells. METHODS Prospective matched cohort study. Patients undergoing surgery for colorectal cancer with curative intent (January 2008-March 2012) were included. Patients who had an anastomotic leak or intra-abdominal abscess were included in the infection group (n=47). For each case patient, another patient with an uncomplicated postoperative course was selected for the control group (n=47).In vitro treatments on cancer cell lines (MDA-MB-231 and SW620) were performed using baseline and postoperative serum and peritoneal fluid samples to determine cell proliferation and cell migration/invasion activities. RESULTS Postoperative peritoneal fluid from infected patients enhanced both cell migration (infection: 140±85 vs control: 94±30; P=0.016) and cell invasion (infection: 117±31 vs control: 103±16; P=0.024) capacities of cancer cell lines. With serum samples, these effects were only observed in cell migration assays (infection: 98±28 vs control: 87±17; P=0.005). Some minor activation of cell proliferation was observed by treatment with serum from infection group. Two-year cumulative disease-free survival was significantly lower in patients with postoperative peritoneal infection (infection: 77.6% vs control: 90.6%; P=0.032). CONCLUSIONS Our results suggest that postoperative peritoneal infection enhances the invasive capacity of residual tumor cells after surgery, thus facilitating their growth to recurrent tumors.
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Vinpocetine and pyritinol: a new model for blood rheological modulation in cerebrovascular disorders—a randomized controlled clinical study. BIOMED RESEARCH INTERNATIONAL 2014; 2014:324307. [PMID: 25548768 PMCID: PMC4274818 DOI: 10.1155/2014/324307] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Revised: 08/21/2014] [Accepted: 09/16/2014] [Indexed: 01/29/2023]
Abstract
Blood and plasma viscosity are the major factors affecting blood flow and normal circulation. Whole blood viscosity is mainly affected by plasma viscosity, red blood cell deformability/aggregation and hematocrit, and other physiological factors. Thirty patients (twenty males + ten females) with age range 50-65 years, normotensive with history of cerebrovascular disorders, were selected according to the American Heart Stroke Association. Blood viscosity and other rheological parameters were measured after two-day abstinence from any medications. Dual effects of vinpocetine and pyritinol exhibit significant effects on all hemorheological parameters (P < 0.05), especially on low shear whole blood viscosity (P < 0.01), but they produced insignificant effects on total serum protein and high shear whole blood viscosity (P > 0.05). Therefore, joint effects of vinpocetine and pyritinol improve blood and plasma viscosity in patients with cerebrovascular disorders.
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42
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Klampfer L. Vitamin D and colon cancer. World J Gastrointest Oncol 2014; 6:430-7. [PMID: 25400874 PMCID: PMC4229786 DOI: 10.4251/wjgo.v6.i11.430] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/31/2014] [Accepted: 09/23/2014] [Indexed: 02/05/2023] Open
Abstract
Calcitriol, 1α, 25-dihydroxyvitamin D3 (1,25 (OH)2D3), the most active form of vitamin D, is a pleotropic hormone with a wide range of biological activities. Due to its ability to regulate calcium and phosphate metabolism, 1,25D3 plays a major role in bone health. In addition, 1,25D3 binds to the vitamin D receptor and thereby regulates the expression of a number of genes which control growth, differentiation and survival of cancer cells. In agreement, the levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models. Vitamin D3 has been estimated to lower the incidence of colorectal cancer by 50%, which is consistent with the inverse correlation between dietary vitamin D3 intake or sunlight exposure and human colorectal cancer. Several studies confirmed that increasing vitamin D3 lowers colon cancer incidence, reduces polyp recurrence, and that sufficient levels of vitamin D3 are associated with better overall survival of colon cancer patients. Vitamin D regulates the homeostasis of intestinal epithelium by modulating the oncogenic Wnt signaling pathway and by inhibiting tumor-promoting inflammation. Both activities contribute to the ability of 1,25D3 to prevent the development and progression of colon cancer.
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Affiliation(s)
- Lidija Klampfer
- Lidija Klampfer, Southern Research Institute, Birmingham, AL 35205, United States
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43
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Bellamkonda K, Sime W, Sjölander A. The impact of inflammatory lipid mediators on colon cancer-initiating cells. Mol Carcinog 2014; 54:1315-27. [PMID: 25154976 DOI: 10.1002/mc.22207] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 06/19/2014] [Accepted: 06/24/2014] [Indexed: 01/16/2023]
Abstract
The role of inflammatory lipid-mediators in tumor progression is well recognized in colorectal cancer; however, if this includes promotion of cancer-initiating cells remains unclear. We show that the inflammatory lipid-mediators leukotriene D4 and prostaglandin E2 increased the Aldehyde dehydrogenase (ALDH(+) ) population, the colony formation capacity, and tumor growth in a xenograft model of colon cancer. The ALDH(+) cells showed significant resistance to irradiation and 5-fluorouracil treatment that could be further augmented by these lipid-mediators, occurring in parallel with increased target gene expression. Our data emphasize a role for tumor microenvironment derived inflammatory lipid-mediators to favor cancer stem cells-like characteristics and thus promote tumor progression.
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Affiliation(s)
- Kishan Bellamkonda
- Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmö, Sweden
| | - Wondossen Sime
- Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmö, Sweden.
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Savari S, Vinnakota K, Zhang Y, Sjölander A. Cysteinyl leukotrienes and their receptors: Bridging inflammation and colorectal cancer. World J Gastroenterol 2014; 20:968-977. [PMID: 24574769 PMCID: PMC3921548 DOI: 10.3748/wjg.v20.i4.968] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 11/16/2013] [Accepted: 12/06/2013] [Indexed: 02/06/2023] Open
Abstract
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.
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