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Umar N, Alleyne L, Cheung D, Rees J, Trudgill C, Zanetto U, Muzaffar S, Trudgill N. Variation in proliferative and cell cycle markers in Barrett's esophagus in relation to circumferential and axial location in the esophagus. Eur J Gastroenterol Hepatol 2024; 36:306-312. [PMID: 38251437 DOI: 10.1097/meg.0000000000002700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
BACKGROUND Adenocarcinoma in Barrett's esophagus (BE) occurs more frequently between 12 and 3 o'clock at the gastroesophageal junction (GEJ). METHODS BE patients were prospectively recruited from December 2013 to July 2016. Expression of p53, Ki-67, cyclin-D1, COX-2 and p21 was assessed in quadrantic biopsies from the proximal and distal margins of the BE segments. Cell cycle marker association with current or subsequent dysplasia or adenocarcinoma was examined. RESULTS 110 patients: median age 64 (IQR, 56-71) years; median BE segment length C4M6; and a median follow-up of 4.7 (IQR, 3.6-5.7) years. In total 13 (11.8%) had evidence of dysplasia or neoplasia (2.7% indefinite for dysplasia, 5.5% low grade, 1.8% high grade and 1.8% adenocarcinoma) at index endoscopy. Six (7%) developed dysplasia or neoplasia (1 low grade, 2 high grade and 3 adenocarcinoma) during follow-up. Ki-67 expression was highest at 3 o'clock, and overall was 49.6% higher in the 12-6 o'clock position compared to 6-12 o'clock [odds ratio (OR), 1.42 (95% confidence interval (CI), 1.00-2.12)]. A similar pattern was found with p21 [1.82 (1.00-3.47)]. There was increased expression of several markers in distal BE biopsies; cyclin-D1 [1.74 (1.29-2.34)]; Cyclo-oxygenase 2 [2.03 (1.48-2.78]) and p21 [2.06 (1.16-3.68)]. Expression of Ki-67 was lower in distal compared to proximal biopsies [0.58 (0.43-0.78)]. P53 expression had high specificity (93.8%) for subsequent low-grade dysplasia, high-grade dysplasia or adenocarcinoma. CONCLUSION Increased cellular proliferation was seen at 12-6 o'clock at the GEJ. Cell-cycle marker expression was increased at the GEJ compared to the proximal BE segment. These findings mirror reflux esophagitis and suggest ongoing reflux contributes to the progression of dysplasia and malignancy in BE.
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Affiliation(s)
- Nosheen Umar
- Sandwell and West Birmingham NHS Trust, West Bromwich, UK
| | - Lance Alleyne
- Sandwell and West Birmingham NHS Trust, West Bromwich, UK
| | - Danny Cheung
- Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | - James Rees
- Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | | | | | | | - Nigel Trudgill
- Sandwell and West Birmingham NHS Trust, West Bromwich, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, UK
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Al-Nattah S, Matkovic E, Schwalbe M, Matkowskyj KA. Pathologic Features of Esophageal and Gastric Malignancies. Cancer Treat Res 2024; 192:19-48. [PMID: 39212914 DOI: 10.1007/978-3-031-61238-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Esophageal cancer is the eighth most common cancer globally, affecting approximately 570,000 people worldwide and currently ranking sixth among cancer-related mortality (Uhlenhopp et al. in, Clin J Gastroenterol 13:1010-1021, 2020). The prognosis is poor as many patients present with locally incurable or metastatic disease. In spite of advancements in treatment, the overall 5-year survival rates are in the realm of 10% whereas the 5-year post-esophagectomy survival rates are in the realm of 15-40% [2]. The incidence rates vary dramatically worldwide, which can be attributed to demographic and socioeconomic factors. Although the vast majority of esophageal neoplasms arise from the epithelial layer and include squamous cell carcinoma (SCC) and adenocarcinoma (AC), a subset of neuroendocrine and soft tissue tumors can also occur in the esophagus. Several tasks are presented to the surgical pathologist when dealing with esophageal carcinoma that include rendering a diagnosis, classifying the histological type, and assessing prognostic factors. This narrative review aims to evaluate current literature on various esophageal neoplasms and highlight pathological factors that impact clinical decision making and prognosis.
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Affiliation(s)
- Sanaa Al-Nattah
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Quest Diagnostics, Las Vegas, NV, USA
| | - Eduard Matkovic
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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Ganduri V, Rajasekaran K, Duraiyarasan S, Adefuye MA, Manjunatha N. Colorectal Carcinoma, Cyclooxygenases, and COX Inhibitors. Cureus 2022; 14:e28579. [PMID: 36185863 PMCID: PMC9521169 DOI: 10.7759/cureus.28579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal carcinoma (CRC) is the most common of gastrointestinal cancers, the majority presenting with sporadic occurrence compared to the less frequently inherited syndromes. The increasing incidence, decreasing gender and age disparities, and the prevalent risk factors are concerning. The malignancy arising from benign precursor polyps transforms slowly over time. The adenoma variant polyps reported a marked upregulation of cyclooxygenases (COX), significantly COX-2 isoform, influenced by various determinants such as genetics, pathology, histology, and site of the carcinoma. These COX enzymes are responsible for prostaglandin synthesis and the consequent cascade of cell inflammation and proliferation. Therefore, COX inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) targeted against both the isoforms COX-1 and COX-2 have been studied for decades in anticipation of preventing the occurrence of colorectal carcinoma in high-risk populations. This article has collated and highlighted the overexpression of COX enzymes by the adenomatous polyps and provides corroborating evidence from multiple studies in favor of COX inhibition by NSAIDs. Aspirin and Sulindac were two drugs to be initially proven to halt the progression and cause regression of the polyps. Celecoxib, a selective COX-2 inhibitor besides NSAIDs, was also used in experimental studies.
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Procerolides A-B from Microcionidae marine sponge Clathria procera: Anti-inflammatory macrocylic lactones with selective cyclooxygenase-2 attenuation properties. Bioorg Chem 2021; 109:104663. [PMID: 33581508 DOI: 10.1016/j.bioorg.2021.104663] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 10/22/2022]
Abstract
Cyclooxygenase-2 has been recognized to catalyze the formation of inflammatory prostaglandins from arachidonic acid. Attenuation potential against cyclooxygenase-2 coupled with greater anti-inflammatory selectivity index were contemplated to be vital indicators to assess anti-inflammatory activities of bioactive compounds. In the present study, two undescribed fourteen-membered macrocyclic lactones, procerolide A and B were isolated to homogeneity from the organic extract of the marine sponge Clathria procera (family: Microcionidae). Procerolide B exhibited greater attenuation potential against cyclooxygenase-2 (IC50 0.89 mM) than that displayed by procerolide A, whereas 5-lipoxygenase inhibitory activity of procerolide B (IC50 1.08 mM) was significantly greater than that displayed by procerolide A (IC50 0.95 mM) and anti-inflammatory agent ibuprofen (IC50 4.50 mM). Additionally, greater anti-inflammatory selectivity index of the procerolides (~1.3) than the synthetic agent (0.43) was accounted for the selective inhibition of the compounds towards cyclooxygenase-2. Higher electronic properties (topological polar surface area of > 100) along with lesser steric properties (molar volume < 300 cm3) of the compounds compared to the standard supported their significant anti-inflammatory potential. Additionally, procerolide B exhibited comparatively lesser binding energy with aminoacyl residues of cyclooxygenase-2 (-9.82 kcal/mol) thereby recognizing its prospective therapeutic use against inflammatory pathogenesis.
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Lipid droplet biogenesis and COX-2 pathway activation are triggered by Barrett's esophagus and adenocarcinoma, but not esophageal squamous cell carcinoma risk factors. Sci Rep 2021; 11:981. [PMID: 33441691 PMCID: PMC7807011 DOI: 10.1038/s41598-020-80035-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 11/24/2020] [Indexed: 12/09/2022] Open
Abstract
Esophageal cancer (EC) is an aggressive disease, presenting two main histological subtypes: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). The two EC subtypes widely differ concerning virtually all factors. ESCC development is mainly associated with tobacco and alcohol abuse, whereas obesity and chronic gastroesophageal reflux disease (GERD) are important risk factors not only for EAC, but also for for Barrett’s esophagus (BE), an intestinal metaplasia that precedes EAC. Obesity triggers ectopic lipid droplets (LD) accumulation in non-adipose tissues. LD are organelles involved in cell metabolism, signaling, proliferation and production of inflammatory mediators. Therefore, the aim of this work was to investigate LD occurrence and role in EC. This study shows progressive LD levels increase along EAC development, in esophageal samples from non-obese through obese individuals, as well as BE, and EAC patients, whereas no significant changes were observed in ESCC samples, when compared to non-tumor samples. Additionally, in order to mimic BE and EAC risk factors exposure, a non-tumor esophageal cell line was incubated with oleic acid (OA) and acidified medium and/or deoxycholic acid (DCA), revealing a significant increment in LD amount as well as in COX-2 and CXCL-8 expression, and in IL-8 secretion. Further, COX-2 expression and LD amount presented a significant positive correlation and were detected co-localized in EAC, but not in ESCC, suggesting that LD may be the site for eicosanoid production in EAC. In conclusion, this study shows that obesity, and BE- and EAC-associated inflammatory stimuli result in a gradual increase of LD, that may be responsible for orchestrating inflammatory mediators’ production and/or action, thus contributing to BE and EAC genesis and progression.
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Stomopneulactone D from long-spined sea urchin Stomopneustes variolaris: Anti-inflammatory macrocylic lactone attenuates cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages. Bioorg Chem 2020; 103:104140. [DOI: 10.1016/j.bioorg.2020.104140] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/17/2020] [Accepted: 07/21/2020] [Indexed: 12/13/2022]
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Majka J, Wierdak M, Szlachcic A, Magierowski M, Targosz A, Urbanczyk K, Krzysiek-Maczka G, Ptak-Belowska A, Bakalarz D, Magierowska K, Chmura A, Brzozowski T. Interaction of epidermal growth factor with COX-2 products and peroxisome proliferator-activated receptor-γ system in experimental rat Barrett's esophagus. Am J Physiol Gastrointest Liver Physiol 2020; 318:G375-G389. [PMID: 31928220 DOI: 10.1152/ajpgi.00410.2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1) vehicle, 2) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3) ranitidine or pantoprazole, and 4) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1β, TNFα, and mucosal PGE2 content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE.NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.
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Affiliation(s)
- Jolanta Majka
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Mateusz Wierdak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Aleksandra Szlachcic
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Aneta Targosz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Urbanczyk
- Department of Pathomorphology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Gracjana Krzysiek-Maczka
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Dominik Bakalarz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Anna Chmura
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
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Jiménez-Martínez M, Ostalé CM, van der Burg LR, Galán-Martínez J, Hardwick JCH, López-Pérez R, Hawinkels LJAC, Stamatakis K, Fresno M. DUSP10 Is a Regulator of YAP1 Activity Promoting Cell Proliferation and Colorectal Cancer Progression. Cancers (Basel) 2019; 11:cancers11111767. [PMID: 31717606 PMCID: PMC6896144 DOI: 10.3390/cancers11111767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 10/31/2019] [Accepted: 11/05/2019] [Indexed: 12/24/2022] Open
Abstract
Cell contact inhibition (CCI) is deregulated in cancer. Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. We found that dual-specificity phosphatase 10 (DUSP10) is involved in CRC. DUSP10 overexpression increased the growth of CRC cell lines and mouse xenografts, while the opposite phenotype was observed by DUSP10 silencing. High cell density (HD) induced DUSP10 expression in CRC cell lines, particularly within the nucleus. Yes-associated protein 1 (YAP1) is activated by dephosphorylation, controlling organ growth and CCI, both processes being deregulated in CRC. Expression levels and localization of DUSP10 matched with YAP1 levels in CRC cell lines. DUSP10 and YAP1 co-immunoprecipitated and their interaction was dependent on YAP1 Ser397. The existence of DUSP10 and YAP1 pathway in vivo was confirmed by using a transgenic Drosophila model. Finally, in CRC patients’ samples, high levels of nuclear DUSP10 correlated with nuclear YAP1 in epithelial tumor tissue. Strong nuclear DUSP10 staining also correlated with high tumor stage and poor survival. Overall, these findings describe a DUSP10–YAP1 molecular link in CRC cell lines promoting cell growth in HD. We present evidence suggesting a pro-tumorigenic role of nuclear DUSP10 expression in CRC patients.
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Affiliation(s)
- Marta Jiménez-Martínez
- Department of Cell Biology and Immunology, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain; (M.J.-M.); (J.G.-M.); (R.L.-P.); (K.S.)
- Department of Molecular Biology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
- Instituto de Investigación Sanitaria de La Princesa (IIS-P), 28006 Madrid, Spain
| | - Cristina M. Ostalé
- Department of Development and Regeneration, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain;
| | - Lennart R. van der Burg
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; (L.R.v.d.B.); (J.C.H.H.); (L.J.A.C.H.)
| | - Javier Galán-Martínez
- Department of Cell Biology and Immunology, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain; (M.J.-M.); (J.G.-M.); (R.L.-P.); (K.S.)
- Department of Molecular Biology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
- Instituto de Investigación Sanitaria de La Princesa (IIS-P), 28006 Madrid, Spain
| | - James C. H. Hardwick
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; (L.R.v.d.B.); (J.C.H.H.); (L.J.A.C.H.)
| | - Ricardo López-Pérez
- Department of Cell Biology and Immunology, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain; (M.J.-M.); (J.G.-M.); (R.L.-P.); (K.S.)
| | - Lukas J. A. C. Hawinkels
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; (L.R.v.d.B.); (J.C.H.H.); (L.J.A.C.H.)
| | - Konstantinos Stamatakis
- Department of Cell Biology and Immunology, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain; (M.J.-M.); (J.G.-M.); (R.L.-P.); (K.S.)
- Department of Molecular Biology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
- Instituto de Investigación Sanitaria de La Princesa (IIS-P), 28006 Madrid, Spain
| | - Manuel Fresno
- Department of Cell Biology and Immunology, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain; (M.J.-M.); (J.G.-M.); (R.L.-P.); (K.S.)
- Department of Molecular Biology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
- Instituto de Investigación Sanitaria de La Princesa (IIS-P), 28006 Madrid, Spain
- Correspondence: ; Tel.: +34-911-964-565
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Negi RR, Rana SV, Gupta V, Gupta R, Chadha VD, Prasad KK, Dhawan DK. Over-Expression of Cyclooxygenase-2 in Colorectal Cancer Patients. Asian Pac J Cancer Prev 2019; 20:1675-1681. [PMID: 31244287 PMCID: PMC7021602 DOI: 10.31557/apjcp.2019.20.6.1675] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Indexed: 12/28/2022] Open
Abstract
Background: Colorectal carcinoma (CRC) is the most common neoplasm of the gastrointestinal tract. COX-2 plays an important role in CRC development and is a key target for the regression of colorectal tumorigenesis by non-steroidal anti-inflammatory drugs. The present study was conducted to examine the relationship of the levels of COX-2 in CRC patients with the clinico-pathological parameters and also to assess its usefulness as a potential biomarker for diagnosis of CRC. Methods: Prior to surgery, 30 CRC patients were enrolled and the samples from colon tumors and surrounding tissues were taken after they underwent surgical intervention at PGIMER, Chandigarh. mRNA expression levels of COX-2 were examined in 30 CRC and adjacent normal colonic mucosa by quantitative polymerase chain reaction (qPCR). The expression of COX-2 was assessed by immunohistochemical method using rabbit polyclonal antibodies against human COX-2 protein. Results: The quantitative relative expression of COX-2 mRNA was observed to be significantly higher (p<0.05) in colorectal cancer tissues as compared to adjacent normal colon tissues. Also, female CRC patients showed significantly higher (p<0.009) expression of COX-2 mRNA vis-a-vis male colorectal cancer patients. This is the first study which has reported a direct relationship between COX-2 mRNA expressions in male colorectal cancer patients versus females. Further, immunohistochemistry of COX-2 confirmed the quantitative real time-PCR findings. Conclusion: Our study shows that COX-2 over expression in colorectal carcinoma patients is closely associated with clinico-pathological parameters and is more pronounced in males versus females. Further, COX-2 mRNA expression can serve as a potential biomarker for the diagnosis of CRC.
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Affiliation(s)
- Ram Rattan Negi
- Department of Biophysics, Panjab University, Chandigarh, India.
| | - Satya Vati Rana
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Vikas Gupta
- Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Rajesh Gupta
- Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Kaushal Kishor Prasad
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Spence AD, Trainor J, McMenamin Ú, Turkington RC, McQuaid S, Bingham V, James J, Salto-Tellez M, McManus DT, Johnston BT, Cardwell CR, Coleman HG. High PTGS2 expression in post-neoadjuvant chemotherapy-treated oesophageal adenocarcinoma is associated with improved survival: a population-based cohort study. Histopathology 2019; 74:587-596. [PMID: 30408225 DOI: 10.1111/his.13786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 11/05/2018] [Indexed: 12/13/2022]
Abstract
AIMS High prostaglandin endoperoxide synthase-2 (PTGS2) enzyme expression in oesophageal adenocarcinoma has been shown to independently predict poor prognosis; however, the evidence is inconsistent. The aim of this study was to investigated the association between PTGS2 expression and prognosis in patients with oesophageal adenocarcinoma. METHODS AND RESULTS A cohort of 135 patients with oesophageal adenocarcinoma who received neoadjuvant chemotherapy and surgery from 2004 to 2012 was identified in the Northern Ireland Cancer Centre. Tissue microarrays were created in the Northern Ireland Biobank, with triplicate cores being sampled from each tumour. Immunohistochemical PTGS2 expression was scored by two independent assessors, with intensity and proportion of tumour staining being used to calculate H-scores for each patient. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cancer-specific survival, and recurrence-free survival by PTGS2 expression, with adjustment for potential confounders. Patients were followed up for a mean of 3.0 years (standard deviation 1.8 years). The PTGS2 expression cut-off value was determined from the median H-score of the cohort (270/300). High (n = 79), as compared with low (n = 56), PTGS2 expression was associated with improved cancer-specific survival (adjusted HR 0.56, 95% CI 0.33-0.94; P = 0.03). PTGS2 expression was not significantly associated with recurrence-free survival (adjusted HR 0.85, 95% CI 0.52-1.38; P = 0.51). CONCLUSIONS High PTGS2 expression in oesophageal adenocarcinoma tissue was associated with improved overall and cancer-specific survival, in contrast to previous evidence. As this is the first study of its kind to include patients who had undergone neoadjuvant chemotherapy, further studies are needed to clarify these associations.
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Affiliation(s)
- Andrew D Spence
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - James Trainor
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK
| | - Úna McMenamin
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Richard C Turkington
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Stephen McQuaid
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Victoria Bingham
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Jacqueline James
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Manuel Salto-Tellez
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Damian T McManus
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK
| | - Brian T Johnston
- Department of Gastroenterology, Belfast Health and Social Care Trust, Belfast, UK
| | - Chris R Cardwell
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Helen G Coleman
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
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Shrestha P, Penninkilampi R, Eslick GD. The Esophageal Microbiome. GASTROINTESTINAL DISEASES AND THEIR ASSOCIATED INFECTIONS 2019:1-16. [DOI: 10.1016/b978-0-323-54843-4.00001-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Pennel KAF, Park JH, McMillan DC, Roseweir AK, Edwards J. Signal interaction between the tumour and inflammatory cells in patients with gastrointestinal cancer: Implications for treatment. Cell Signal 2018; 54:81-90. [PMID: 30453014 DOI: 10.1016/j.cellsig.2018.11.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/15/2018] [Accepted: 11/15/2018] [Indexed: 12/12/2022]
Abstract
Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention.
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Affiliation(s)
- Kathryn A F Pennel
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, United Kingdom.
| | - James H Park
- Academic Unit of Surgery, School of Medicine - University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
| | - Donald C McMillan
- Academic Unit of Surgery, School of Medicine - University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
| | - Antonia K Roseweir
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine - University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
| | - Joanne Edwards
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, United Kingdom
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13
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Takaoka RTC, Sertório ND, Magalini LPJ, Dos Santos LM, Souza HR, Iyomasa-Pilon MM, Possebon L, Costa SS, Girol AP. Expression profiles of Annexin A1, formylated peptide receptors and cyclooxigenase-2 in gastroesophageal inflammations and neoplasias. Pathol Res Pract 2017; 214:181-186. [PMID: 29254791 DOI: 10.1016/j.prp.2017.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 11/25/2017] [Accepted: 12/04/2017] [Indexed: 01/14/2023]
Abstract
The anti-inflammatory protein Annexin-A1 (ANXA1) is associated to tumor invasion process and its actions can be mediated by formylated peptides receptors (FPRs). Therefore, we evaluated the expression and correlation of ANXA1, FPR and cyclooxygenase-2 (COX-2) enzyme in esophageal and stomach inflammations and neoplasias. The study of proteins was performed by immunohistochemistry in biopsies of esophagitis, Barrett's esophagus, squamous cell carcinoma and adenocarcinoma of the esophagus, as well as gastritis, stomach polypus and gastric adenocarcinoma. The intensity of the expressions was evaluated by densitometry. The immunohistochemical and densitometric analyzes showed specificity for the FPR1 receptor and modulation of the ANXA1, COX-2 and FPR1 expressions in the epithelial cells in the different studied conditions. Increased immunoreactivity of these proteins was observed in cases of inflammation and stomach polypus. Interestingly, moderate immunoreactivity for ANXA1 and FPR1 but increased immunolabeling for COX-2 were observed in Barrett́s esophagus and esophageal adenocarcinomas. Also, there was reduced expression of ANXA1 and FPR1 in esophageal carcinoma but COX-2 overexpression in this tumor. There was no expression of FPR2 but ANXA1 and FPR1 expressions were positively correlated in all clinical conditions studied. Positive correlation between ANXA1 and COX-2 were also observed in inflammation conditions while negative correlation between ANXA1 and COX-2 was observed in esophageal carcinoma. Our results demonstrate the unregulated expression of ANXA1 and COX-2 in precursor lesions of esophageal and stomach cancers, reinforcing their involvement in gastroesophageal carcinogenesis. In addition, the data show that the actions of ANXA1 in the inflammatory and neoplastic processes of the esophagus and stomach are specifically mediated by the FPR1 receptor.
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Affiliation(s)
- Rodolfo T C Takaoka
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Nathália D Sertório
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Lara P J Magalini
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Leandro M Dos Santos
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Helena R Souza
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Melina M Iyomasa-Pilon
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Lucas Possebon
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil; São Paulo State University, (UNESP), Department of Biology, Laboratory of Immunomorphology, São José do Rio Preto, São Paulo, Brazil
| | - Sara S Costa
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil
| | - Ana P Girol
- Padre Albino Integrated College (FIPA), Department of Physical and Biological Sciences, Catanduva, São Paulo, Brazil; São Paulo State University, (UNESP), Department of Biology, Laboratory of Immunomorphology, São José do Rio Preto, São Paulo, Brazil.
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14
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Hu Z, Yang Y, Zhao Y, Huang Y. The prognostic value of cyclooxygenase-2 expression in patients with esophageal cancer: evidence from a meta-analysis. Onco Targets Ther 2017; 10:2893-2901. [PMID: 28652771 PMCID: PMC5476766 DOI: 10.2147/ott.s134599] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Published studies have investigated the prognostic role of cyclooxygenase-2 (COX-2) expression in patients with esophageal cancer (EC), but the result remains controversial. Thus, this meta-analysis was conducted to comprehensively evaluate the impact of COX-2 expression on the prognostic value in patients with EC. Relevant studies were identified from PubMed, EMBASE, and Web of Science databases. Studies that detected the COX-2 expression by immunohistochemistry and evaluated the relationship between COX-2 expression and overall survival (OS) or clinicopathological parameters were used in our analysis. The summary hazard ratios (HRs) or odds ratios were calculated to assess the risk or hazard association. A total of 25 studies, which included 2,465 patients, were included in our meta-analysis. Our analysis suggested that overexpression of COX-2 was associated with poor OS (HR =1.60, 95% CI =1.32–1.94, P<0.001). Subgroup analyses by race, percentage of high/positive COX-2 expression, histology type, treatment, and sample size all suggested significant association. Moreover, overexpression of COX-2 was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and TNM stage. This meta-analysis suggested that overexpression of COX-2 might serve as a prognostic biomarker for EC. Large well-designed prospective studies are needed to confirm our conclusion.
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Affiliation(s)
| | - Yanlong Yang
- Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital)
| | - Yonghe Zhao
- Department of Pathology, The Forensic School of Kunming Medical University
| | - Yunchao Huang
- Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital).,Cancer Research Institute of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan Province, People's Republic of China
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15
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Jacalin Has Chemopreventive Effects on Colon Cancer Development. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4614357. [PMID: 28676858 PMCID: PMC5476885 DOI: 10.1155/2017/4614357] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 05/03/2017] [Indexed: 01/03/2023]
Abstract
Colorectal cancer, which is one of the most common causes of cancer-related deaths worldwide, has a slow natural history that provides a great opportunity for prevention strategies. Plant-derived natural products have received considerable attention because of their inherent colorectal cancer chemopreventive effects. The plant lectin jacalin specifically recognizes the tumor-associated Thomsen-Friedenreich antigen and has antiproliferative effects on human colon cancer cells, highlighting its potential antitumor activity. To evaluate jacalin's potential application in colorectal cancer chemoprevention, we studied its effects on the early stages of carcinogenesis. Balb/c mice were given 4 intrarectal deposits of 0.1 ml solution of Methyl-N'-Nitro-N-Nitroso-Guanidine (5 mg/ml) twice a week (with a 3-day interval) for 2 weeks. Starting 2 weeks before carcinogen administration, animals were treated orally with jacalin (0.5 and 25 μg) three times a week (on alternate weekdays) for 10 weeks. We show that jacalin treatment reduced the number of preneoplastic lesions in carcinogen-exposed mice. This anticarcinogenic activity was associated with decreased colonic epithelial cell proliferation and stromal COX-2 expression and with increased intestinal production of TNF-α. Our results demonstrate that jacalin is able to modulate the early stages of colon carcinogenesis and emphasize its promising chemopreventive activity in colorectal cancer.
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16
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Araujo JL, Altorki NK, Sonett JR, Rodriguez A, Sungur-Stasik K, Spinelli CF, Neugut AI, Abrams JA. Prediagnosis aspirin use and outcomes in a prospective cohort of esophageal cancer patients. Therap Adv Gastroenterol 2016; 9:806-814. [PMID: 27803735 PMCID: PMC5076766 DOI: 10.1177/1756283x16657985] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Esophageal cancer remains associated with poor outcomes, yet little is known regarding factors that influence survival. Aspirin use prior to cancer diagnosis may influence outcomes. We aimed to assess the effects of prediagnosis aspirin use in patients with esophageal cancer. METHODS We conducted a prospective cohort study of newly-diagnosed esophageal cancer patients at two tertiary care centers. We assessed history of prediagnosis aspirin use, and prospectively followed patients and assessed mortality, cause of death, and development of metastases. RESULTS We enrolled 130 patients, the majority of whom were male (81.5%) and had adenocarcinoma (80.8%). Overall, 57 patients (43.9%) were regular aspirin users. In unadjusted analyses, we found no difference in all-cause mortality between aspirin users and nonusers. In multivariate analyses, prediagnosis aspirin use was not associated with all-cause mortality [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.48-1.57] or esophageal cancer-specific mortality (HR 1.07, 95% CI 0.52-2.21). Prediagnosis aspirin use was associated with a significantly increased risk of interval metastasis (HR 3.59, 95% CI 1.08-11.96). CONCLUSIONS In our cohort of esophageal cancer patients, prediagnosis aspirin use was not associated with all-cause or cancer-specific mortality. However, risk of interval metastatic disease was increased among those who took aspirin regularly prediagnosis. Future studies are warranted to assess whether aspirin influences the molecular characteristics of esophageal tumors, with potential prognostic and therapeutic implications.
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Affiliation(s)
- James L. Araujo
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Nasser K. Altorki
- Department of Thoracic Surgery, Weill Cornell Medical Center, New York, NY, USA
| | - Joshua R. Sonett
- Department of Thoracic Surgery, Columbia University Medical Center, New York, NY, USA
| | - Adriana Rodriguez
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | | | - Cathy F. Spinelli
- Department of Thoracic Surgery, Weill Cornell Medical Center, New York, NY, USA
| | - Alfred I. Neugut
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
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17
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Fisher OM, Levert-Mignon AJ, Lehane CW, Botelho NK, Maag JLV, Thomas ML, Edwards M, Lord SJ, Bobryshev YV, Whiteman DC, Lord RV. CD151 Gene and Protein Expression Provides Independent Prognostic Information for Patients with Adenocarcinoma of the Esophagus and Gastroesophageal Junction Treated by Esophagectomy. Ann Surg Oncol 2016; 23:746-754. [PMID: 27577713 DOI: 10.1245/s10434-016-5504-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient's tumor biology and prognosis. METHODS Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx)-naïve patients with external validation in a separate cohort of 62 CRTx-naïve patients and 169 patients with advanced-stage disease treated with CRTx. RESULTS As a novel prognostic biomarker after external validation, CD151 showed promise. Patients exhibiting high levels of CD151 (≥median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9 months; p = 0.01). This effect persisted in a multivariable Cox-regression model with adjustment for tumor stage [adjusted hazard ratio (aHR), 0.33; 95 % confidence interval (CI), 0.14-0.78; p = 0.01] and was further corroborated through immunohistochemical analysis (aHR, 0.22; 95 % CI, 0.08-0.59; p = 0.003). This effect was not found in the separate cohort of CRTx-exposed patients. CONCLUSION Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.
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Affiliation(s)
- Oliver M Fisher
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia.,School of Medical Sciences, UNSW Australia, Sydney, Australia.,Department of Surgery, School of Medicine, University of Notre Dame, Sydney, Australia
| | - Angelique J Levert-Mignon
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia
| | - Christopher W Lehane
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia
| | - Natalia K Botelho
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia
| | - Jesper L V Maag
- School of Medical Sciences, UNSW Australia, Sydney, Australia.,Genomics & Epigenetics Division, Garvan Institute of Medical Research, Sydney, Australia
| | - Melissa L Thomas
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia
| | | | - Sarah J Lord
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia.,NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.,Department of Surgery, School of Medicine, University of Notre Dame, Sydney, Australia
| | - Yuri V Bobryshev
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia
| | | | - Reginald V Lord
- Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia. .,Department of Surgery, School of Medicine, University of Notre Dame, Sydney, Australia.
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18
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The effect of aspirin and nonsteroidal anti-inflammatory drug use after diagnosis on survival of oesophageal cancer patients. Br J Cancer 2016; 114:1053-9. [PMID: 27115570 PMCID: PMC4984910 DOI: 10.1038/bjc.2016.65] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 01/31/2016] [Accepted: 02/14/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Aspirin use has been shown to lower incidence and mortality in cancer patients. The aim of this population-based study was to determine the effect of postdiagnosis low-dose aspirin use on survival of patients with oesophageal cancer. METHODS Patients with oesophageal cancer (1998-2010) were selected from the Eindhoven Cancer Registry and linked with outpatient pharmacy data regarding aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Users were subdivided into both prediagnosis and postdiagnosis or only postdiagnosis users. Parametric survival models with an exponential (Poisson) distribution were used with non-specific death as endpoint. RESULTS In this study 560 patients were included. Overall, 157 patients (28.0%) were non-users, 293 patients (52.3%) pre- and postdiagnosis (89 aspirin and 204 NSAID users) and 110 patients (19.6%) only postdiagnosis users (16 aspirin and 94 NSAID users). Postdiagnosis aspirin use was associated with overall survival (RR 0.45 (95% CI 0.34-0.60; P<0.001); adjusted rate ratio was 0.42 (95% CI: 0.30-0.57; P<0.001). Postdiagnosis use of NSAIDs was associated with overall survival (RR 0.61 (95% CI 0.49-0.76; <0.001); however, adjusted analyses did not show a significant association with a rate ratio of 0.84 (95% CI 0.66-1.07; P=0.2). CONCLUSIONS Our study shows that postdiagnosis aspirin use might be associated with a higher survival rate in oesophageal cancer patients. A randomised clinical trial is needed to verify our observations of possible postdiagnosis aspirin use benefit.
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19
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Yoon AR, Stasinopoulos I, Kim JH, Yong HM, Kilic O, Wirtz D, Bhujwalla ZM, An SS. COX-2 dependent regulation of mechanotransduction in human breast cancer cells. Cancer Biol Ther 2016; 16:430-7. [PMID: 25701047 DOI: 10.1080/15384047.2014.1003004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
The ability of living cells to exert physical forces upon their surrounding is a necessary prerequisite for diverse biological processes, such as local cellular migrations in wound healing to metastatic-invasion of cancer. How forces are coopted in metastasis has remained unclear, however, because the mechanical interplay between cancer cells and the various stromal components has not been experimentally accessible. Current dogma implicates inflammation in these mechanical processes. Using Fourier transform traction microscopy, we measured the force-generating capacity of human breast cancer cells occupying a spectrum of invasiveness as well as basal and inducible COX-2 expression (MCF-7<SUM-149<MDA-MB-231). Compared with non-invasive MCF-7 and moderately-invasive SUM-149, poorly-differentiated MDA-MB-231 cells showed increased cellular dispersion on collagen matrix that was accompanied by emergent distribution of contractile stresses at the interface between the adherent cell and its substrate, defined herein as the traction field. In metastatic MDA-MB-231 cells, the local tractions were precisely tuned to the surrounding matrix rigidity in a physiologic range with the concomitant expression of mechanosensitive integrin β1. These discrete responses at the single-cell resolution were correlated with PGE2 secretion and were ablated by shRNA-mediated knockdown of COX-2. Both COX-2-silenced and COX-2-expressing cells expressed EP2 and EP4 receptors, but not EP1 and EP3. Exogenous addition of PGE2 increased cell tractions and stiffened the underlying cytoskeletal network. To our knowledge this is the first report linking the expression of COX-2 with mechanotransduction of human breast cancer cells, and the regulation of COX-2-PGE2-EP signaling with physical properties of the tumor microenvironment. Drug treatments aimed at reducing this mechanical interplay may have therapeutic potential in the treatment of breast cancer.
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Affiliation(s)
- A-Rum Yoon
- a Environmental Health Science ; Johns Hopkins Bloomberg School of Public Health ; Baltimore , MD USA
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20
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Abstract
Esophageal cancer is one of the deadliest cancers, with a dismal prognosis. It is increasingly recognized that esophageal cancer is a heterogeneous disease. It can be subdivided into two distinct groups: squamous cell carcinoma and adenocarcinoma, based on histological appearance. In the Western world, the incidence of squamous cell carcinoma was considerably higher than esophageal adenocarcinoma (EA) until the 1990s when, due to a dramatic increase, the incidence of EA surpassed that of squamous cell carcinoma. EA typically follows a well-established stepwise evolution from chronic inflammation due to reflux esophagitis (RE) that progresses to metaplasia (Barrett's esophagus [BE]) to dysplasia, which often culminates in EA. The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. The current understanding of the etiology of EA is mainly derived from epidemiological studies of risk factors such as cigarette smoking, obesity, gastroesophageal reflux disorders (GERD), and low fruit and vegetable consumption. Numerous studies have been done, but the factors that drive the dynamic increase in the incidence of EA remain elusive. The advent of widespread antibiotic use occurred in the 1950s, preceding the surge of EA. Based on this temporal sequence, it has been hypothesized that antibiotics alter the microbiome to which the esophagus is exposed in patients who have GERD and that chronic exposure to this abnormal microbiome (ie, changes in species diversity or abundance) accounts for the increase in EA. If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia-EA), they may represent potential targets for chemoprevention. New discoveries will help improve our understanding of the biology and pathogenesis of these cancers, and aid in finding novel therapeutic targets.
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Affiliation(s)
- Antonio Galvao Neto
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - April Whitaker
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Zhiheng Pei
- Department of Veterans Affairs New York Harbor Healthcare System, New York, NY, USA; Departments of Medicine and Pathology, New York University School of Medicine, New York, NY, USA.
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21
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Yamada T, Osawa S, Ikuma M, Kajimura M, Sugimoto M, Furuta T, Iwaizumi M, Sugimoto K. Guggulsterone, a plant-derived inhibitor of NF-TB, suppresses CDX2 and COX-2 expression and reduces the viability of esophageal adenocarcinoma cells. Digestion 2015; 90:208-17. [PMID: 25427631 DOI: 10.1159/000365750] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 07/07/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Induction by bile acid of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression via nuclear factor-κB (NF-κB) activation is a critical event in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Guggulsterone (GS) is a plant sterol that inhibits NF-κB activity. Here, we evaluated whether GS has either or both chemopreventive or therapeutic effects against EAC. METHODS Two EAC cells lines were treated with deoxycholic acid (DCA) in the presence of GS or vehicle. The levels of transcription and translation of IκBα, CDX2, and COX-2 were determined. Prostaglandin E2 (PGE2) levels, cell viability, and cell cycle distribution were assessed as well. RESULTS GS inhibited DCA-induced IκBα phosphorylation. GS and the NF-κB inhibitor BAY11-7085 suppressed DCA-induced CDX2 and COX-2 expression in EAC cells. GS also suppressed basal transcription levels of CDX2 and COX-2 and reduced constitutive synthesis of COX-2 and PGE2. Further, GS reduced the viability of EAC cells, increased their numbers in the apoptotic sub-G1 fraction. CONCLUSION GS suppressed DCA-induced and NF-κB-dependent activation of CDX2 and COX-2 expression. Further, GS also reduced the viability of EAC cells. GS may serve as candidate for preventing and treating EAC and BE.
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Affiliation(s)
- Takanori Yamada
- Department of Gastroenterology, Iwata City Hospital, Iwata, Japan
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22
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McCormick Matthews LH, Noble F, Tod J, Jaynes E, Harris S, Primrose JN, Ottensmeier C, Thomas GJ, Underwood TJ. Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma. Br J Cancer 2015; 113:107-18. [PMID: 26110972 PMCID: PMC4647536 DOI: 10.1038/bjc.2015.179] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 02/22/2015] [Accepted: 04/29/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identify potential biomarkers. METHODS Relevant articles were identified via Ovid medline 1946-2013. For inclusion, studies had to conform to REporting recommendations for tumor MARKer (REMARK) prognostic study criteria. The primary end-point was a pooled hazard ratio (HR) and variance, summarising the effect of marker expression on prognosis. RESULTS A total of 3059 articles were identified. After exclusion of irrelevant titles and abstracts, 214 articles were reviewed in full. Nine molecules had been examined in more than one study (CD3, CD8, COX-2, EGFR, HER2, Ki67, LgR5, p53 and VEGF) and were meta-analysed. Markers with largest survival effects were COX-2 (HR=2.47, confidence interval (CI)=1.15-3.79), CD3 (HR=0.51, 95% CI=0.32-0.70), CD8 (HR=0.55, CI=0.31-0.80) and EGFR (HR=1.65, 95% CI=1.14-2.16). DISCUSSION Current methods have not delivered clinically useful molecular prognostic biomarkers in OAC. We have highlighted the paucity of good-quality robust studies in this field. A genome-to-protein approach would be better suited for the development and subsequent validation of biomarkers. Large collaborative projects with standardised methodology will be required to generate clinically useful biomarkers.
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Affiliation(s)
- L H McCormick Matthews
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
| | - F Noble
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
- Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - J Tod
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
| | - E Jaynes
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - S Harris
- Public Health Sciences and Medical Statistics, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - J N Primrose
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
- Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - C Ottensmeier
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
- National Institute for Health Research, Experimental Cancer Medicine Centre, Southampton SO16 6YD, UK
| | - G J Thomas
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - T J Underwood
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building, MP824, Southampton SO16 6YD, UK
- Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
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23
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Fisher OM, Levert-Mignon AJ, Lord SJ, Lee-Ng KKM, Botelho NK, Falkenback D, Thomas ML, Bobryshev YV, Whiteman DC, Brown DA, Breit SN, Lord RV. MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma. Br J Cancer 2015; 112:1384-91. [PMID: 25867265 PMCID: PMC4402450 DOI: 10.1038/bjc.2015.100] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/05/2015] [Accepted: 02/16/2015] [Indexed: 12/22/2022] Open
Abstract
Background: Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC. Methods: One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC. Results: Median tissue expression of MIC-1/GDF15 mRNA was ⩾25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73–0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015). High MIC-1/GDF15 plasma levels (⩾1140 pg ml−1) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01–14.75; P=0.047). Conclusions: Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett's disease.
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Affiliation(s)
- O M Fisher
- St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia
| | - A J Levert-Mignon
- St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia
| | - S J Lord
- 1] St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia [2] NHMRC Clinical Trials Centre University of Sydney, Sydney, NSW 2050, Australia [3] Department of Epidemiology and Medical Statistics, School of Medicine, University of Notre Dame, Sydney, NSW 2010 Australia
| | - K K M Lee-Ng
- St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia
| | - N K Botelho
- St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia
| | - D Falkenback
- 1] St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia [2] Department of Surgery, Lund University Hospital (Skåne University Hospital) and Lund University, Lund 221 85, Sweden
| | - M L Thomas
- St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia
| | - Y V Bobryshev
- 1] St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia [2] Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - D C Whiteman
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - D A Brown
- 1] St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia [2] Peter Duncan Neuroscience Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, NSW 2010 Australia
| | - S N Breit
- St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia
| | - R V Lord
- 1] St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW 2010 Australia [2] Department of Surgery, School of Medicine, University of Notre Dame, Sydney, NSW 2010 Australia
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Fouad YM, Mostafa I, Yehia R, El-Khayat H. Biomarkers of Barrett's esophagus. World J Gastrointest Pathophysiol 2014; 5:450-456. [PMID: 25400988 PMCID: PMC4231509 DOI: 10.4291/wjgp.v5.i4.450] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 07/02/2014] [Accepted: 07/17/2014] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus is the strongest risk for esophageal adenocarcinoma (EAC). Metaplasia in patients with BE may progress to dysplasia and then invasive carcinoma. Well-defined diagnostic, progressive, predictive, and prognostic biomarkers are needed to identify the presence of the disease, estimate the risk of malignant transformation, and predict the therapeutic outcome and survival of EAC patients. There are many predictive and prognostic markers that lack substantial validation, and do not allow stratification of patients with gastroesophageal reflux disease in clinical practice for outcome and effectiveness of therapy. In this short review we summarize the current knowledge regarding possible biomarkers, focusing on the pathophysiologic mechanisms to improve prognostic and therapeutic approaches.
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Fisher OM, Levert-Mignon AJ, Lord SJ, Botelho NK, Freeman AK, Thomas ML, Falkenback D, Wettstein A, Whiteman DC, Bobryshev YV, Lord RV. High Expression of Cathepsin E in Tissues but Not Blood of Patients with Barrett's Esophagus and Adenocarcinoma. Ann Surg Oncol 2014; 22:2431-8. [PMID: 25348778 PMCID: PMC4458267 DOI: 10.1245/s10434-014-4155-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Indexed: 12/13/2022]
Abstract
Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues. Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4155-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Oliver M Fisher
- St. Vincent's Centre for Applied Medical Research, Sydney, Australia
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LIU NINGNING, WU QIONG, WANG YAN, SUI HUA, LIU XUAN, ZHOU NING, ZHOU LIHONG, WANG YIFEI, YE NAIJING, FU XIAOLING, YU NIKITINALEXANDER, LI QI. Helicobacter pylori promotes VEGF expression via the p38 MAPK-mediated COX-2-PGE2 pathway in MKN45 cells. Mol Med Rep 2014; 10:2123-9. [DOI: 10.3892/mmr.2014.2458] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 03/12/2014] [Indexed: 11/06/2022] Open
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Roelofs HMJ, Te Morsche RHM, van Heumen BWH, Nagengast FM, Peters WHM. Over-expression of COX-2 mRNA in colorectal cancer. BMC Gastroenterol 2014; 14:1. [PMID: 24383454 PMCID: PMC3880419 DOI: 10.1186/1471-230x-14-1] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 12/20/2013] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2, PTGS2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of biologic processes such as inflammation, cell proliferation and angiogenesis. COX-2 over-expression was reported in many (pre) malignant tissues, but data strongly vary and seem to depend on the methodology used. METHODS Normal colorectal mucosa and paired cancerous tissue from 60 patients with colorectal cancer was investigated for the levels of COX-2 mRNA by real-time quantitative Polymerase Chain Reaction (qPCR). COX-2 levels were expressed relative to either: tissue weight or levels of the housekeeping genes beta-2 microglobulin (B2M) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS COX-2 mRNA levels, normalized with respect to tissue weight or mRNA levels of the housekeeping genes B2M or GAPDH, were over-expressed in 80%, 70% and 40% of the colorectal tumor tissues, as compared to the paired adjacent normal colorectal mucosa samples, respectively. Highest mRNA COX-2 ratios tumor/normal were measured when expressed per mg tissue (mean ratio 21.6). When normalized with respect to the housekeeping genes B2M or GAPDH, mean tumor/normal ratios were 16.1 and 7.5, respectively. CONCLUSION Expression of COX-2 mRNA levels per mg tissue is most simple in comparison to normalization with respect to the housekeeping genes B2M or GAPDH. Levels of COX-2 mRNA are found over-expressed in almost 80% of the colorectal tumors, compared to paired adjacent normal colorectal mucosa, suggesting a role of COX-2 as a potential biomarker for cancer risk, whereas inhibitors of COX-2 could be of value in chemoprevention of colon cancer.
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Affiliation(s)
| | | | | | | | - Wilbert H M Peters
- Department of Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
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Zhang R, Yin X, Shi H, Wu J, Shakya P, Liu D, Zhang J. Adiponectin modulates DCA-induced inflammation via the ROS/NF-κ B signaling pathway in esophageal adenocarcinoma cells. Dig Dis Sci 2014; 59:89-97. [PMID: 24096876 DOI: 10.1007/s10620-013-2877-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 09/04/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Deoxycholic acid (DCA) promotes the development and progression of esophageal adenocarcinoma (EAC) by inducing inflammation. Adiponectin is reported to have anti-inflammatory and anti-tumor effects. PURPOSE This study investigated the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on DCA-induced inflammation, and investigated the involvement of the reactive oxygen species (ROS)/NF-κB signaling pathway in inflammation in EAC. METHODS OE19 cells were treated with DCA (50-300 μM) and/or f-Ad/g-Ad (10.0 μg/ml) or N-acetylcysteine (NAC). The viability of cells exposed to DCA was measured by use of the MTT assay. mRNA and protein levels of the inflammatory factors were examined by real-time PCR and ELISA. Intra-cellular ROS levels were determined by use of flow cytometry. Protein levels of total and p-NF-κB p65 were measured by western blot. RESULTS DCA induced dose and time-dependent cytotoxicity. mRNA and protein expression of TNF-α, IL-8, and IL-6 in cells treated with DCA alone were up-regulated, and intra-cellular ROS and p-NF-κB p65 protein levels were also increased. g-Ad promoted inflammatory factor production, ROS levels, and p-NF-κB p65 protein expression whereas f-Ad had a suppressive effect. When combined with DCA, g-Ad enhanced the pro-inflammatory effect of DCA whereas f-Ad, similar to NAC, suppressed the effect. CONCLUSION DCA has a pro-inflammatory effect in EAC. f-Ad has an anti-inflammatory effect whereas g-Ad seems to have a pro-inflammatory effect in an ROS/NF-κB p65-dependent manner. This indicates that f-Ad could be a potential anti-inflammatory reagent for cancer therapy.
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Affiliation(s)
- Rong Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, No. 157, Xi Wu Road, Xi'an, 710004, Shaanxi Province, China
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Chen M, Huang J, Zhu Z, Zhang J, Li K. Systematic review and meta-analysis of tumor biomarkers in predicting prognosis in esophageal cancer. BMC Cancer 2013; 13:539. [PMID: 24206575 PMCID: PMC3828582 DOI: 10.1186/1471-2407-13-539] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 09/20/2013] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Esophageal cancer (EC) is a frequently occurring cancer with poor prognosis despite combined therapeutic strategies. Many biomarkers have been proposed as predictors of adverse events. We sought to assess the prognostic value of biomarkers in predicting the overall survival of esophageal cancer and to help guide personalized cancer treatment to give patients the best chance at remission. METHODS We conducted a systematic review and meta-analysis of the published literature to summarize evidence for the discriminatory ability of prognostic biomarkers for esophageal cancer. Relevant literature was identified using the PubMed database on April 11, 2012, and conformed to the REMARK criteria. The primary endpoint was overall survival and data were synthesized with hazard ratios (HRs). RESULTS We included 109 studies, exploring 13 different biomarkers, which were subjected to quantitative meta-analysis. Promising markers that emerged for the prediction of overall survival in esophageal squamous cell cancer included VEGF (18 eligible studies, n=1476, HR=1.85, 95% CI, 1.55-2.21), cyclin D1 (12 eligible studies, n=1476, HR=1.82, 95% CI, 1.50-2.20), Ki-67 (3 eligible studies, n=308, HR=1.11, 95% CI, 0.70-1.78) and squamous cell carcinoma antigen (5 eligible studies, n=700, HR=1.28, 95% CI, 0.97-1.69); prognostic markers for esophageal adenocarcinoma included COX-2 (2 eligible studies, n=235, HR=3.06, 95% CI, 2.01-4.65) and HER-2 (3 eligible studies, n=291, HR=2.15, 95% CI, 1.39-3.33); prognostic markers for uncategorized ECs included p21 (9 eligible studies, n=858, HR=1.27, 95% CI, 0.75-2.16), p53 (31 eligible studies, n=2851, HR=1.34, 95% CI, 1.21-1.48), CRP (8 eligible studies, n=1382, HR=2.65, 95% CI, 1.64-4.27) and hemoglobin (5 eligible studies, n=544, HR=0.91, 95% CI, 0.83-1.00). CONCLUSIONS Although some modest bias cannot be excluded, this review supports the involvement of biomarkers to be associated with EC overall survival.
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Affiliation(s)
- Meilan Chen
- Department of Preventive Medicine, Shantou University Medical College, No.22 Xinling Road, Shantou, Guangdong 515041, China
| | - Jizheng Huang
- Department of Preventive Medicine, Shantou University Medical College, No.22 Xinling Road, Shantou, Guangdong 515041, China
| | - Zhenli Zhu
- Department of Preventive Medicine, Shantou University Medical College, No.22 Xinling Road, Shantou, Guangdong 515041, China
| | - Jun Zhang
- Department of Preventive Medicine, Shantou University Medical College, No.22 Xinling Road, Shantou, Guangdong 515041, China
| | - Ke Li
- Department of Preventive Medicine, Shantou University Medical College, No.22 Xinling Road, Shantou, Guangdong 515041, China
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Potential Therapeutic Role of Hispidulin in Gastric Cancer through Induction of Apoptosis via NAG-1 Signaling. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:518301. [PMID: 24159347 PMCID: PMC3789485 DOI: 10.1155/2013/518301] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 06/07/2013] [Accepted: 06/09/2013] [Indexed: 01/05/2023]
Abstract
Gastric cancer is one of the most common malignant cancers due to poor prognoses and high mortality rates worldwide. However, an effective chemotherapeutic drug without side effects remains lacking. Saussurea involucrata (SI) Kar. et Kir., also known as snow lotus, grows in mountainous rocky habitats at 2600 m elevation in the Tian Shan and A'er Tai regions of China. The ethyl acetate extract of SI had been shown to inhibit proliferation and induce apoptosis in various tumor cells. In this study, we demonstrated that Hispidulin, active ingredients in SI, inhibits the growth of AGS gastric cancer cells. After Hispidulin treatment, NAG-1 remained highly expressed, whereas COX-2 expression was downregulated. Flow cytometric analysis indicated that Hispidulin induces G1/S phase arrest and apoptosis in time- and concentration-dependent manners. G1/S arrest correlated with upregulated p21/WAF1 and p16 and downregulated cyclin D1 and cyclin E, independent of p53 pathway. In addition, Hispidulin can elevate Egr-1 expression and ERK1/2 activity, whereas ERK1/2 inhibitor markedly attenuated NAG-1 mediated apoptosis. Taken together, Hispidulin can efficiently activate ERK1/2 signaling followed by NAG-1 constitutive expression and trigger cell cycle arrest as well as apoptosis in cancer cell. It can be a potential compound for combination therapy of gastric cancer in the future.
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Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: current state-of-the science. Cancer Lett 2013; 345:249-57. [PMID: 24021750 DOI: 10.1016/j.canlet.2013.09.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Revised: 08/28/2013] [Accepted: 09/02/2013] [Indexed: 12/16/2022]
Abstract
Growing evidence from epidemiologic and preclinical studies suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal (GI) cancers, including esophageal, gastric, pancreatic, colorectal cancer, and hepatocellular carcinoma. However, there is also evidence indicating the absence of this benefit. The exact mechanism of NSAIDs' action on GI tumors is not known. Although some studies have suggested inhibition of carcinogenesis by NSAIDs through suppression effect on inflammation-associated cyclooxygenase-2 (COX-2) expression, other studies have suggested COX-2-independent mechanisms. Herein, we summarize the current state of-the-science regarding NSAID benefit for patients with GI cancers.
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van Heumen BWH, Roelofs HMJ, Vink-Börger ME, Dekker E, Mathus-Vliegen EMH, Dees J, Koornstra JJ, Langers AMJ, Nagtegaal ID, Kampman E, Peters WHM, Nagengast FM. Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial. Orphanet J Rare Dis 2013; 8:118. [PMID: 23919274 PMCID: PMC3750541 DOI: 10.1186/1750-1172-8-118] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 08/01/2013] [Indexed: 12/16/2022] Open
Abstract
Background Due to prophylactic colectomy, mortality in patients with familial adenomatous polyposis (FAP) has changed, with duodenal cancer currently being the main cause of death. Although celecoxib reduces duodenal polyp density in patients with FAP, its long-term use may increase the risk of cardiovascular events and alternatives need to be explored. Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy. We performed a randomized, double-blind, placebo-controlled trial to investigate the effect of celecoxib and UDCA co-treatment on duodenal adenomatosis in patients with FAP. Methods Patients with FAP received celecoxib (400 mg twice daily) and UDCA (1000-2000 mg daily, ~20-30 mg/kg/day, n=19) or celecoxib and placebo (n=18) orally for 6 months. Primary outcome was drug efficacy, assessed by comparing duodenal polyp density at pre- and post-intervention by blinded review of endoscopic recordings. As secondary outcomes, cell proliferation, apoptosis, and COX-2 levels in normal duodenal mucosa were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Results In intention-to-treat analysis, deceased polyp density was observed after celecoxib/placebo treatment (p=0.029), whereas increased polyp density was observed after celecoxib/UDCA treatment (p=0.014). The difference in change in duodenal polyp density was statistically significant between the groups (p=0.011). No changes in secondary outcomes were observed. Thirty patients (81%) reported one or more adverse events, 16 patients (84%, Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade 1–3) treated with celecoxib/UDCA and 14 patients (78%, CTCAE grade 1–2) treated with celecoxib/placebo. Nine patients (24%) discontinued intervention prematurely, 5 patients (26%) treated with celecoxib/UDCA and 4 patients (22%) treated with celecoxib/placebo. Conclusions Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect. The benefit of long term use of celecoxib for duodenal cancer prevention needs to be weighed against the (risk of) adverse events. Trial registration http://ClinicalTrials.gov, identifier
NCT00808743
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Affiliation(s)
- Bjorn W H van Heumen
- Departments of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands.
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GERD-Barrett-Adenocarcinoma: Do We Have Suitable Prognostic and Predictive Molecular Markers? Gastroenterol Res Pract 2013; 2013:643084. [PMID: 23573078 PMCID: PMC3615572 DOI: 10.1155/2013/643084] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/18/2013] [Indexed: 02/07/2023] Open
Abstract
Due to unfavorable lifestyle habits (unhealthy diet and tobacco abuse) the incidence of gastroesophageal reflux disease (GERD) in western countries is increasing. The GERD-Barrett-Adenocarcinoma sequence currently lacks well-defined diagnostic, progressive, predictive, and prognostic biomarkers (i) providing an appropriate screening method identifying the presence of the disease, (ii) estimating the risk of evolving cancer, that is, the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC), (iii) predicting the response to therapy, and (iv) indicating an overall survival—prognosis for EAC patients. Based on histomorphological findings, detailed screening and therapeutic guidelines have been elaborated, although epidemiological studies could not support the postulated increasing progression rates of GERD to BE and EAC. Additionally, proposed predictive and prognostic markers are rather heterogeneous by nature, lack substantial proofs, and currently do not allow stratification of GERD patients for progression, outcome, and therapeutic effectiveness in clinical practice. The aim of this paper is to discuss the current knowledge regarding the GERD-BE-EAC sequence mainly focusing on the disputable and ambiguous status of proposed biomarkers to identify promising and reliable markers in order to provide more detailed insights into pathophysiological mechanisms and thus to improve prognostic and predictive therapeutic approaches.
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An advanced Electron Spin Resonance (ESR) spin-trapping and LC/(ESR)/MS technique for the study of lipid peroxidation. Int J Mol Sci 2012. [PMID: 23203086 PMCID: PMC3509602 DOI: 10.3390/ijms131114648] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
There are two types of nutritionally important polyunsaturated fatty acids (PUFAs), namely ω-6s and ω-3s. PUFAs and their metabolites generated from lipid peroxidation via cyclooxygenase (COX) and lipoxygenase (LOX) are believed to be involved in a variety of physiological and pathological processes in the human body. Both COX- and LOX-catalyzed PUFA peroxidation are complex events that generate a series of radicals, which may then bind proteins, target DNA/RNA, and lead to a number of biological changes. However, due to the lack of an appropriate method, it was not possible until recently to identify the short-lived PUFA-derived radicals in COX-/LOX-catalyzed peroxidation. Failure to characterize free radicals during peroxidation has greatly restricted our knowledge about COX/LOX biology in human health. Here we review the development and refinement of combined ESR spin trapping and LC/ESR/MS to characterize PUFA-derived radicals formed from in vitro (cell-free) peroxidation. We also present the most recent approach for studying peroxidation in cells which allows us to directly assess the potential bioactivity of PUFA-derived free radicals. This advanced technique has resulted in a major breakthrough in radical structural characterization, as well as assessment of free radical-associated cell growth response, thereby greatly improving our knowledge of PUFAs, COX-/LOX-catalyzed lipid peroxidation, and their related biological consequences.
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Kipanyula MJ, Seke Etet PF, Vecchio L, Farahna M, Nukenine EN, Nwabo Kamdje AH. Signaling pathways bridging microbial-triggered inflammation and cancer. Cell Signal 2012; 25:403-16. [PMID: 23123499 DOI: 10.1016/j.cellsig.2012.10.014] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Accepted: 10/26/2012] [Indexed: 02/06/2023]
Abstract
Microbial-triggered inflammation protects against pathogens and yet can paradoxically cause considerable secondary damage to host tissues that can result in tissue fibrosis and carcinogenesis, if persistent. In addition to classical pathogens, gut microbiota bacteria, i.e. a group of mutualistic microorganisms permanently inhabiting the gastrointestinal tract and which plays a key role in digestion, immunity, and cancer prevention, can induce inflammation-associated cancer following the alterations of their microenvironment. Emerging experimental evidence indicates that microbiota members like Escherichia coli and several other genotoxic and mutagenic pathogens can cause DNA damage in various cell types. In addition, the inflammatory response induced by chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated with liver, colorectal, cervical cancers and lymphoma, for instance, can also trigger carcinogenic processes. A microenvironment including active immune cells releasing high amounts of inflammatory signaling molecules can favor the carcinogenic transformation of host cells. Pivotal molecules released during immune response such as the macrophage migration inhibitory factor (MMIF) and the reactive oxygen and nitrogen species' products superoxide and peroxynitrite, can further damage DNA and cause the accumulation of oncogenic mutations, whereas pro-inflammatory cytokines, adhesion molecules, and growth factors may create a microenvironment promoting neoplastic cell survival and proliferation. Recent findings on the implication of inflammatory signaling pathways in microbial-triggered carcinogenesis as well as the possible role of microbiota modulation in cancer prevention are herein summarized and discussed.
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Affiliation(s)
- Maulilio John Kipanyula
- Department of Veterinary Anatomy, Sokoine University of Agriculture, P.O. Box 3016, Chuo Kikuu, Morogoro, Tanzania
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Miladi-Abdennadher I, Abdelmaksoud-Dammak R, Ayed-Guerfali DB, Ayadi L, Khabir A, Amouri A, Frikha F, Tahri N, Ellouz S, Frikha M, Sellami-Boudawara T, Mokdad-Gargouri R. Expression of COX-2 and E-cadherin in Tunisian patients with colorectal adenocarcinoma. Acta Histochem 2012; 114:577-81. [PMID: 22133296 DOI: 10.1016/j.acthis.2011.11.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 10/31/2011] [Accepted: 10/31/2011] [Indexed: 12/23/2022]
Abstract
Cyclo-oxygenase 2 (COX-2) and E-cadherin are promising biomarkers for cancer diagnosis and therapy. The aim of this study was to examine the expression of these two proteins in primary colorectal adenocarcinomas and to investigate their association with clinicopathological characteristics including survival of patients. Immunostaining of E-cadherin and COX-2 was assessed in 70 primary colorectal adenocarcinomas from Tunisian patients. Membranous E-cadherin immunostaining and cytoplasmic COX-2 expression were observed in 74.3% and 68.6% of cases respectively. A significant association was found between COX-2 expression and age at diagnosis (P=0.02), and vessel invasion (P=0.037). The expression of E-cadherin correlated with age at diagnosis (P=0.01), and tumor size (P=0.02). In addition, by multivariate analysis, we revealed a significant association with 1-year disease free survival and a tendency with distant metastasis (P=0.017 and P=0.065 respectively). On the other hand, tumors exhibiting COX-2+/E-cadherin-profile were larger (P=0.006), and in an advanced stage (P=0.001). Survival analysis showed that COX-2 over-expression confers a reduced overall survival rate (Plog rank=0.036) and is an independent factor predictive for prognosis.
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Affiliation(s)
- Imen Miladi-Abdennadher
- Laboratory of Cancer Genetics and Production of Therapeutic Proteins, Center of Biotechnology, Sfax, Tunisia
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Miura T, Takada A, Ooe M. Tretinoin cyclodextrin complex (RA/CyD) causes less irritation with an equal antiwrinkle effect compared with conventional tretinoin: clinical and histologic studies of photoaged skin. Aesthetic Plast Surg 2012; 36:971-81. [PMID: 22538278 DOI: 10.1007/s00266-012-9903-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2011] [Accepted: 03/03/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND Topical tretinoin [all-trans-retinoic acid (RA)] currently is widely used to treat photoaged skin. However, undesirable side effects such as erythema, irritation, and scaling are unavoidable and limit the use of tretinoin. To address these issues, the authors developed the tretinoin cyclodextrin complex (RA/CyD), which is tretinoin encapsulated by cyclodextrin. Cyclodextrins are cyclic oligosaccharides commonly used in food additives and fabric fresheners. This study aimed to evaluate the antiwrinkle effect of RA/CyD and alleviation of the side effects compared with RA treatment alone. METHODS In this study, 12 photoaged patients completed an 8 week study using RA and RA/CyD in a double-blind manner. Before and after the treatment, the patients' evaluations, wrinkle scores, skin elasticity, and wrinkle area measurement using skin replica were evaluated. Three men were recruited for histologic analysis. RESULTS The patients reported that undesirable irritant reactions were more moderate with RA/CyD than with RA. In the assessment of wrinkle scores, skin elasticity, and wrinkle area measurement, RA/CyD demonstrated an antiwrinkle effect statistically equal to that of RA. In histology, both RA/CyD and RA demonstrated epidermal hyperplasia. In immunohistochemistry, inflammation induced by RA/CyD was more moderate than that induced by RA. CONCLUSION The findings show that RA and RA/CyD result in the equivalent clinical improvement for patients with photoaging. The use of RA/CyD overcomes the drawbacks of RA while possessing equal effect. It is expected that CyD will broaden tretinoin treatment. LEVEL OF EVIDENCE III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.
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Affiliation(s)
- Tomoe Miura
- Department of Cosmetic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan.
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Mayne GC, Watson DI, Hussey DJ. COX-2 mRNA is increased in oesophageal mucosal cells by a proton pump inhibitor. ANZ J Surg 2012; 82:691-6. [PMID: 22758658 DOI: 10.1111/j.1445-2197.2012.06124.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Barrett's oesophagus develops in some individuals with gastro-oesophageal reflux and is the precursor to oesophageal adenocarcinoma. Proton pump inhibitors (PPIs) suppress gastric acid production and are used to treat reflux. Clinical trials suggest that cyclooxygenase (COX) inhibitors might prevent oesophageal cancer, although PPIs could offset this by increasing COX-2 expression in Barrett's oesophagus. To investigate this, we evaluated the impact of a PPI on COX expression in oesophageal mucosal cells. METHODS The effect of the PPI esomeprazole on COX-1 and COX-2 mRNA levels in oesophageal cells was determined. Oesophageal cell lines OE33 (adenocarcinoma-derived) and HET-1A (immortalized squamous cells) and a control intestinal cell line HT29 (colon carcinoma) were treated for 24 h, with increasing concentrations of the esomeprazole. RESULTS COX-2, but not COX-1, mRNA levels dose-dependently increased in OE33 and HET-1A cells versus esomeprazole concentration. COX-2 mRNA levels did not increase in HT29 cells. CONCLUSIONS Exposure to esomeprazole increases COX-2 mRNA in oesophageal cells. This might contribute to the lack of benefit for COX inhibitors for oesophageal cancer prevention in recent clinical studies.
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Affiliation(s)
- George C Mayne
- Department of Surgery, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia.
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Abstract
Gastric cancer remains a leading cause of cancer-related deaths worldwide, although its incidence has been steadily declining during recent decades. Expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. COX-2 expression associates with reduced survival in gastric cancer patients, and it has also been shown to be an independent factor of poor prognosis. Several molecular mechanisms are involved in the regulation of COX-2 expression in gastric cancer cell lines, including signal transduction pathways activated by Helicobacter pylori. In gastric tumor models in vivo the role of COX-2 seems to be predominantly to facilitate tumor promotion and growth.
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Affiliation(s)
- Alexandra Thiel
- Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
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Sokołowski G, Bałdys-Waligórska A, Trofimiuk M, Adamek D, Hubalewska-Dydejczyk A, Gołkowski F. Expression of cyclooxygenase-2 (COX-2) in pituitary tumours. Med Sci Monit 2012; 18:CR252-9. [PMID: 22460097 PMCID: PMC3560830 DOI: 10.12659/msm.882625] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Microvessel density in angiogenesis is regarded as a prognostic factor of tumour invasiveness, independent of cell proliferation. In recent studies of pituitary tumours, correlation between the expression of cyclooxygenase-2 (COX-2) and micro-vascularization density and microvessel surface density has been established. We studied the expression of COX-2 in different types of pituitary adenomas to determine the usefulness of COX-2 expression as a prognostic factor of tumour progression or recurrence in patients with hypophyseal tumours. MATERIAL/METHODS We retrospectively studied a group of 60 patients of mean age 46.7±17.6 (range, 18 to 85) years who underwent pituitary tumour surgery. Expression of COX-2, as determined by immunohistochemistry, was analyzed in relation to histopathology features of tumour, clinical symptoms, MR imaging and post-operative recurrence/progression of disease. RESULTS COX-2 was expressed in adenomas of 87% of patients, with a median index value of 57.5% [IQR=60.5]. Highest COX-2 expression was observed in hormonally inactive adenomas and gonadotropinomas and lowest in prolactinomas. We found no differences in COX-2 expression with respect to patient age, gender, tumour size, degree of tumour invasiveness, or whether tumours were immunopositive or immunonegative for pituitary hormones, nor have we found any relation between COX-2 expression and recurrence or progression of tumour size. CONCLUSIONS COX-2 does not appear to be a predictive factor for recurrence or progression of tumour size. Nevertheless, due to the observed relatively high expression of COX-2 in pituitary adenomas, further studies with COX-2 inhibitors are justified in these tumours.
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Affiliation(s)
- Grzegorz Sokołowski
- Department of Endocrinology, Jagiellonian University Medical College, Cracow, Poland
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Yang L, Francois F, Pei Z. Molecular pathways: pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus. Clin Cancer Res 2012; 18:2138-44. [PMID: 22344232 DOI: 10.1158/1078-0432.ccr-11-0934] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma is preceded by the development of reflux-related intestinal metaplasia or Barrett esophagus, which is a response to inflammation of the esophageal squamous mucosa, reflux esophagitis. Gastroesophageal reflux impairs the mucosal barrier in the distal esophagus, allowing chronic exposure of the squamous epithelium to the diverse microbial ecosystem or microbiome and inducing chronic inflammation. The esophageal microbiome is altered in both esophagitis and Barrett esophagus, characterized by a significant decrease in gram-positive bacteria and an increase in gram-negative bacteria in esophagitis and Barrett esophagus. Lipopolysaccharides (LPS), a major structure of the outer membrane in gram-negative bacteria, can upregulate gene expression of proinflammatory cytokines via activation of the Toll-like receptor 4 and NF-κB pathway. The potential impact of LPS on reflux esophagitis may be through relaxation of the lower esophageal sphincter via inducible nitric oxide synthase and by delaying gastric emptying via cyclooxygenase-2. Chronic inflammation may play a critical role in the progression from benign to malignant esophageal disease. Therefore, analysis of the pathways leading to chronic inflammation in the esophagus may help to identify biomarkers in patients with Barrett esophagus for neoplastic progression and provide insight into molecular events suitable for therapeutic intervention in prevention of esophageal adenocarcinoma development in patients with reflux esophagitis and Barrett esophagus.
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Affiliation(s)
- Liying Yang
- Department of Medicine and Pathology, New York University School of Medicine, New York, New York 10010, USA
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Cyclooxygenase isoenzyme-2 and vascular endothelial growth factor are associated with poor prognosis in esophageal adenocarcinoma. J Gastrointest Surg 2012; 16:956-66. [PMID: 22258871 PMCID: PMC3324693 DOI: 10.1007/s11605-011-1814-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 12/28/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cyclooxygenase isoenzyme-2 (COX-2) and vascular endothelial growth factor (VEGF) contribute to angiogenesis and are overexpressed in various malignancies. The aim of the study was to evaluate expression, prognostic value and correlation between COX-2 and VEGF expression in esophageal adenocarcinoma (EAC). METHODS Surgical specimens of 154 patients with EAC were used to construct a tissue micro array (TMA). TMA sections were immunohistochemically stained for COX-2 and VEGF and scored on intensity of staining. RESULTS Estimated 5-year cancer specific survival was 37%. High COX-2 and VEGF expression was observed in 39 (26.5%) and in 77 (53.8%) tumors, respectively. Both markers were associated with poor cancer specific survival (p = .022 and p = .004, respectively, log rank). No significant correlation was found between VEGF and COX-2 expression (r = 063; p = .455). In multivariate analysis, high COX-2 expression (HR 1.65; 95% CI 1.04-2.61; p = .034) was associated with overall survival. In patients with T3 tumors, COX-2 expression was an independent prognostic factor for cancer specific survival (HR 1.81 95% CI 1.10-2.95; p = .019). CONCLUSIONS This is the first study that evaluated the prognostic value and correlation of COX-2 and VEGF expression in a large and homogenous population of patients with EAC. No correlation between COX-2 and VEGF expression was found. Both markers were expressed in EAC and were associated with poor prognosis. The findings support the use of COX-2 and VEGF inhibitors in future clinical studies.
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Cyclooxygenase-2 expression in esophageal epithelium before and after photodynamic therapy for Barrett's esophagus with high-grade dysplasia or intramucosal carcinoma. Virchows Arch 2011; 459:581-6. [PMID: 22081106 DOI: 10.1007/s00428-011-1167-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Revised: 10/20/2011] [Accepted: 10/31/2011] [Indexed: 01/09/2023]
Abstract
Cyclooxygenase-2 expression is upregulated in Barrett's esophagus and esophageal adenocarcinoma. Photodynamic therapy using porfimer sodium can result in ablation of dysplasia and intramucosal carcinoma, eradication of Barrett's esophagus, and restitution of squamous epithelium. The aim of this study was to determine the effect of photodynamic therapy on cyclooxygenase-2 expression in esophageal epithelium. Paired pre- and post-photodynamic therapy biopsy samples from the same anatomical levels of 20 individuals who had undergone photodynamic therapy for Barrett's esophagus with high-grade dysplasia and/or intramucosal carcinoma were immunostained using a cyclooxygenase-2 monoclonal antibody. Cyclooxygenase-2 expression was graded in squamous epithelium, Barrett's esophagus, and neoplasia (if present) as follows: grade 0 (no staining), grade 1 (staining in 1-10% of cells), grade 2 (staining in 11-90% of cells), and grade 3 (staining in >90% of cells). Pre-photodynamic therapy median cyclooxygenase-2 expression was grade 2 (range 1-3) in neoplastic foci and grade 1 (range 1-3) in nondysplastic Barrett's esophagus (P=0.0009 for pairwise comparison). With the exception of a few cells staining in the basal epithelial layers, median cyclooxygenase-2 expression was graded as 0 (similar to controls) in both pre-photodynamic therapy squamous epithelium and post-photodynamic therapy neosquamous epithelium. This was significantly lower when compared to either neoplastic foci (P<0.0001) or nondysplastic Barrett's esophagus (P<0.0001) pre-photodynamic therapy. Notably, in four patients with post-photodynamic therapy recurrent neoplasia, cyclooxygenase-2 expression returned to elevated levels. Cyclooxygenase-2 expression is elevated in Barrett's esophagus with high-grade dysplasia or intramucosal carcinoma prior to photodynamic therapy. Following successful photodynamic therapy, cyclooxygenase-2 expression in neosquamous epithelium returns to a low baseline level similar to that observed in native esophageal squamous epithelium. Post-photodynamic therapy neoplastic recurrence is associated with elevated cyclooxygenase-2 expression. Prospective studies should determine whether cyclooxygenase inhibitors have a role as adjuvant therapy to prevent recurrence of Barrett's esophagus following endoscopic therapy.
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Yachimski P, Peek RM. Biomarkers in exploring the frontiers of diagnosis, prognosis, and therapy of Barrett's esophagus. Cancer Prev Res (Phila) 2011; 4:783-6. [PMID: 21636544 DOI: 10.1158/1940-6207.capr-11-0204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Barrett's esophagus (BE) is the principal risk factor for esophageal adenocarcinoma. BE patients currently undergo periodic endoscopic surveillance with tissue sampling and histopathologic assessment for dysplasia. They frequently are prescribed proton pump inhibitors to pharmacologically suppress gastric acid that is the cause of BE. These standard endoscopic and pharmacologic approaches for managing BE are crude at best. Identification of novel tissue biomarkers within BE may allow for more accurate endoscopic risk stratification and provide potential targets for chemoprevention.
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Affiliation(s)
- Patrick Yachimski
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
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Altorki NK, Christos P, Port JL, Lee PC, Mirza F, Spinelli C, Keresztes R, Beneck D, Paul S, Stiles BM, Zhang Y, Schrump DS. Preoperative taxane-based chemotherapy and celecoxib for carcinoma of the esophagus and gastroesophageal junction: results of a phase 2 trial. J Thorac Oncol 2011; 6:1121-1127. [PMID: 21532508 PMCID: PMC7457227 DOI: 10.1097/jto.0b013e31821529a9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. METHODS Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. RESULTS All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. CONCLUSIONS Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors.
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Affiliation(s)
- Nasser K Altorki
- Thoracic Surgery Division, Department of Cardiothoracic Surgery, New York Presbyterian Hospital, Weill Cornell Medical College, New York City, New York 10021, USA.
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Vykhovanets EV, Shankar E, Vykhovanets OV, Shukla S, Gupta S. High-fat diet increases NF-κB signaling in the prostate of reporter mice. Prostate 2011; 71:147-56. [PMID: 20632379 PMCID: PMC4019972 DOI: 10.1002/pros.21230] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND High-fat diet (HFD) is considered as a major risk factor for benign prostatic diseases and cancer in the Western world. Studies have shown an association between oxidative stress and prostatic diseases. NF-κB has been implicated in stress response and is deregulated in prostrate disorders; therefore, we sought to determine whether HFD could induce oxidative stress in the prostate which could contribute to prostatic diseases. METHODS Transgenic NF-κB-Luc-Tag mice were either fed with regular diet (RD) or HFD for 12 weeks. Serial, non-invasive molecular imaging was performed to study NF-κB activation in the whole body, and in various organs including thymus, spleen, and prostate. Western blotting was used to determine the expression of NF-κB, its upstream and downstream targets in the prostate. RESULTS Twofold increase in whole body NF-κB activity in vivo and two to threefold upregulated prostate NF-κB activity ex vivo were observed after HFD intake compared with RD controls. HFD-induced NF-κB activity was elevated remarkably in the abdominal cavity, thymus, spleen, and prostate with increase in prostrate weight. In the prostrate, an increase in the protein expression of gp91(phox) , p22(phox) , and p47(phox) NADPH oxidase subunits was observed suggesting the involvement of HFD in causing oxidative stress. Nuclear extracts from the prostrate tissue showed an increased expression of p65/RelA that corresponded with elevated cytosolic levels of p-IκBα, along with increased expression of downstream targets of NF-κB, nitric oxide synthase, and cyclooxygenase-2. CONCLUSIONS Our findings suggest that HFD-mediated oxidative stress and deregulation of NADPH oxidase leads to NF-κB activation in the prostrate.
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Affiliation(s)
- Eugene V. Vykhovanets
- Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106
| | - Eswar Shankar
- Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106
| | - Olena V. Vykhovanets
- Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106
| | - Sanjeev Shukla
- Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106
- Department of Nutrition, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106
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Abstract
Barrett's metaplasia is one of the commonest premalignant lesions in the western world following colorectal adenomas. One in 50 of the adult population develops Barrett's as a consequence of chronic gastro-oesophageal reflux. The mucosal inflammation seen within patients with gastro-oesophageal reflux seems likely to drive the growth of the metaplastic mucosa and also help direct further oncological change, yet the molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood. There is hope that understanding the role of oesophageal inflammation will provide important insight into the development of Barrett's metaplasia and oesophageal cancer. This chapter will discuss the inflammation seen within context of Barrett's oesophagus and also clinical trials which hope to address this common premalignant disease. There are several ongoing clinical trials which are aiming to provide data using anti-inflammatory therapies to tackle this important premalignant condition. There is new data presented which suggests that data from the aspirin esomeprazole chemoprevention trial (AspECT) may hold the clue to disease treatment and that the cytokine TNF-α seems to be a key signalling molecule in the metaplasia-dysplasia-carcinoma sequence. Specifically it appears that both epigenetic and inherited genetics cooperate to modulate the prognosis.
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Affiliation(s)
- Anna Nicholson
- Centre for Digestive Disease, Blizard Institute, Queen Mary University of London, UK.
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Ong CAJ, Lao-Sirieix P, Fitzgerald RC. Biomarkers in Barrett’s esophagus and esophageal adenocarcinoma: Predictors of progression and prognosis. World J Gastroenterol 2010; 16:5669-81. [PMID: 21128316 PMCID: PMC2997982 DOI: 10.3748/wjg.v16.i45.5669] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Barrett’s esophagus is a well-known premalignant lesion of the lower esophagus that is characterized by intestinal metaplasia of the squamous epithelium. It is clinically important due to the increased risk (0.5% per annum) of progression to esophageal adenocarcinoma (EA), which has a poor outcome unless diagnosed early. The current clinical management of Barrett’s esophagus is hampered by the lack of accurate predictors of progression. In addition, when patients develop EA, the current staging modalities are limited in stratifying patients into different prognostic groups in order to guide the optimal therapy for an individual patient. Biomarkers have the potential to improve radically the clinical management of patients with Barrett’s esophagus and EA but have not yet entered mainstream clinical practice. This is in contrast to other cancers like breast and prostate for which biomarkers are utilized routinely to inform clinical decisions. This review aims to highlight the most promising predictive and prognostic biomarkers in Barrett’s esophagus and EA and to discuss what is required to move the field forward towards clinical application.
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The pathogenesis of Barrett's metaplasia and the progression to esophageal adenocarcinoma. Recent Results Cancer Res 2010; 182:39-63. [PMID: 20676870 DOI: 10.1007/978-3-540-70579-6_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The most important risk factor for the development of Barrett's esophagus is the reflux of both gastric and duodenal contents into the esophagus. The reason why Barrett's metaplasia develops only in a minority of patients suffering from gastroesophageal reflux disease remains unknown.The exact mechanism behind the transition of normal squamous epithelium into specialized columnar epithelium is also unclear. It is likely that stem cells are involved in this metaplastic change, as they are the only permanent residents of the epithelium. Several tumorigenic steps that lead to the underlying genetic instability, which is indispensable in the progression from columnar metaplasia to esophageal adenocarcinoma have been described. This review outlines the process of pathogenesis of Barrett's metaplasia and its progression to esophageal adenocarcinoma.
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Hermanova M, Karasek P, Tomasek J, Lenz J, Jarkovsky J, Dite P. Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer. World J Gastroenterol 2010; 16:1879-84. [PMID: 20397266 PMCID: PMC2856829 DOI: 10.3748/wjg.v16.i15.1879] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [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 perform a comparative analysis of clinicopathological correlations of cyclooxygenase-2 (COX-2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.
METHODS: The COX-2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity. COX-2 expression levels were classified into three categories (0, 1+, and 2+) and the clinicopathological correlations were statistically evaluated and analyzed.
RESULTS: The positive tumor expression rates of COX-2 were 80.5% using monoclonal antibody and 69.4% using polyclonal antibody. In the Kaplan-Meier analysis, no significant correlations were found between levels of COX-2 expression and overall survival (OS), but trends to longer OS were found in COX-2 negative cases using monoclonal antibody. Significantly longer disease free survival was revealed in COX-2 negative cases using monoclonal antibody (P = 0.019). No correlations between COX-2 expression levels and grade (G), tumor (T) status and nodal (N) status were demonstrated. Low histological grade showed a strong association with a longer OS (P < 0.001). Correlation of survival and T status revealed a shorter OS in T3 tumors, but the results reached only marginal statistical significance (P = 0.070). In the multivariate Cox proportional hazards regression model, histological grade, T and N status remained valuable predictors of a worse survival with borderline significance for T [hazards ratio (HR) = 4.18 for G (if G = 3, P < 0.001); HR = 1.64 for T (if T = 3, P = 0.065); HR = 2.53 for N (if N = 1, P = 0.006)]. Higher grade, T or N status was associated with a worse OS.
CONCLUSION: The immunohistochemically assessed level of COX-2 expression does not seem to represent a valuable independent prognostic factor and is not superior to the conventional prognostic factors.
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