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Proteomic profiling identifies markers for inflammation-related tumor-fibroblast interaction. Clin Proteomics 2017; 14:33. [PMID: 29176937 PMCID: PMC5689177 DOI: 10.1186/s12014-017-9168-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 09/25/2017] [Indexed: 02/08/2023] Open
Abstract
Background Cancer associated fibroblasts are activated in the tumor microenvironment and contribute to tumor progression, angiogenesis, extracellular matrix remodeling, and inflammation. Methods To identify proteins characteristic for fibroblasts in colorectal cancer we used liquid chromatography-tandem mass spectrometry to derive protein abundance from whole-tissue homogenates of human colorectal cancer/normal mucosa pairs. Alterations of protein levels were determined by two-sided t test with greater than threefold difference and an FDR of < 0.05. Public available datasets were used to predict proteins of stromal origin and link protein with mRNA regulation. Immunohistochemistry confirmed the localization of selected proteins. Results We identified a set of 24 proteins associated with inflammation, matrix organization, TGFβ receptor signaling and angiogenesis mainly originating from the stroma. Most prominent were increased abundance of SerpinB5 in the parenchyme and latent transforming growth factor β-binding protein, thrombospondin-B2, and secreted protein acidic-and-cysteine-rich in the stroma. Extracellular matrix remodeling involved collagens type VIII, XII, XIV, and VI as well as lysyl-oxidase-2. In silico analysis of mRNA levels demonstrated altered expression in the tumor and the adjacent normal tissue as compared to mucosa of healthy individuals indicating that inflammatory activation affected the surrounding tissue. Immunohistochemistry of 26 tumor specimen confirmed upregulation of SerpinB5, thrombospondin B2 and secreted protein acidic-and-cysteine-rich. Conclusions This study demonstrates the feasibility of detecting tumor- and compartment-specific protein-signatures that are functionally meaningful by proteomic profiling of whole-tissue extracts together with mining of RNA expression datasets. The results provide the basis for further exploration of inflammation-related stromal markers in larger patient cohorts and experimental models.
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Thrift AP, Anderson LA, Murray LJ, Cook MB, Shaheen NJ, Rubenstein JH, El-Serag HB, Vaughan TL, Schneider JL, Whiteman DC, Corley DA. Nonsteroidal Anti-Inflammatory Drug Use is Not Associated With Reduced Risk of Barrett's Esophagus. Am J Gastroenterol 2016; 111:1528-1535. [PMID: 27575711 PMCID: PMC5209791 DOI: 10.1038/ajg.2016.348] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/22/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of esophageal adenocarcinoma. Epidemiological studies examining the association between NSAID use and the risk of the precursor lesion, Barrett's esophagus, have been inconclusive. METHODS We analyzed pooled individual-level participant data from six case-control studies of Barrett's esophagus in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). We compared medication use from 1,474 patients with Barrett's esophagus separately with two control groups: 2,256 population-based controls and 2,018 gastroesophageal reflux disease (GERD) controls. Study-specific odds ratio (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models and were combined using a random-effects meta-analytic model. RESULTS Regular (at least once weekly) use of any NSAIDs was not associated with the risk of Barrett's esophagus (vs. population-based controls, adjusted OR=1.00, 95% CI=0.76-1.32, I2=61%; vs. GERD controls, adjusted OR=0.99, 95% CI=0.82-1.19, I2=19%). Similar null findings were observed among individuals who took aspirin or non-aspirin NSAIDs. We also found no association with highest levels of frequency (at least daily use) and duration (≥5 years) of NSAID use. There was evidence of moderate between-study heterogeneity; however, associations with NSAID use remained non-significant in "leave-one-out" sensitivity analyses. CONCLUSIONS Use of NSAIDs was not associated with the risk of Barrett's esophagus. The previously reported inverse association between NSAID use and esophageal adenocarcinoma may be through reducing the risk of neoplastic progression in patients with Barrett's esophagus.
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Affiliation(s)
- Aaron P. Thrift
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA,Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Lesley A. Anderson
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
| | - Liam J. Murray
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
| | - Michael B. Cook
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Nicholas J. Shaheen
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Joel H. Rubenstein
- Center for Clinical Management Research, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan, USA,Barrett's Esophagus Program, Division of Gastroenterology Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Hashem B. El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA,Department of Medicine, Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas, USA
| | - Thomas L. Vaughan
- Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jennifer L. Schneider
- Kaiser Permanente Division of Research, Oakland, California and San Francisco Medical Center, USA
| | - David C. Whiteman
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Douglas A. Corley
- Kaiser Permanente Division of Research, Oakland, California and San Francisco Medical Center, USA
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Uddin MJ, Werfel TA, Crews BC, Gupta MK, Kavanaugh TE, Kingsley PJ, Boyd K, Marnett LJ, Duvall CL. Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer. Biomaterials 2016; 92:71-80. [PMID: 27043768 DOI: 10.1016/j.biomaterials.2016.03.028] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 02/29/2016] [Accepted: 03/17/2016] [Indexed: 01/12/2023]
Abstract
Cyclooxygenase-2 (COX-2) is expressed in virtually all solid tumors and its overexpression is a hallmark of inflammation. Thus, it is a potentially powerful biomarker for the early clinical detection of inflammatory disease and human cancers. We report a reactive oxygen species (ROS) responsive micellar nanoparticle, PPS-b-POEGA, that solubilizes the first fluorescent COX-2-selective inhibitor fluorocoxib A (FA) for COX-2 visualization in vivo. Pharmacokinetics and biodistribution of FA-PPS-b-POEGA nanoparticles (FA-NPs) were assessed after a fully-aqueous intravenous (i.v.) administration in wild-type mice and revealed 4-8 h post-injection as an optimal fluorescent imaging window. Carrageenan-induced inflammation in the rat and mouse footpads and 1483 HNSCC tumor xenografts were successfully visualized by FA-NPs with fluorescence up to 10-fold higher than that of normal tissues. The targeted binding of the FA cargo was blocked by pretreatment with the COX-2 inhibitor indomethacin, confirming COX-2-specific binding and local retention of FA at pathological sites. Our collective data indicate that FA-NPs are the first i.v.-ready FA formulation, provide high signal-to-noise in inflamed, premalignant, and malignant tissues, and will uniquely enable clinical translation of the poorly water-soluble FA compound.
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Affiliation(s)
- Md Jashim Uddin
- A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Thomas A Werfel
- Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA
| | - Brenda C Crews
- A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Mukesh K Gupta
- Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA
| | - Taylor E Kavanaugh
- Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA
| | - Philip J Kingsley
- A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Kelli Boyd
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Lawrence J Marnett
- A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Craig L Duvall
- Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA.
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Chansaenpak K, Wang M, Liu S, Wu Z, Yuan H, Conti PS, Li Z, Gabbaï FP. Synthesis and in vivo stability studies of [18F]-zwitterionic phosphonium aryltrifluoroborate/indomethacin conjugates. RSC Adv 2016. [DOI: 10.1039/c5ra26323a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Conjugation of ortho-phosphonium phenyltrifluoroborates with indomethacin affords conjugates which have been radiolabeled by 18F–19F isotopic exchange in aqueous solutions and imaged by positron emission tomography in mice.
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Affiliation(s)
| | - Mengzhe Wang
- Department of Radiology
- Biomedical Research Imaging Center
- University of North Carolina
- Chapel Hill 27599
- USA
| | - Shuanglong Liu
- Molecular Imaging Center
- Department of Radiology
- University of Southern California
- Los Angeles 90033
- USA
| | - Zhanhong Wu
- Department of Radiology
- Biomedical Research Imaging Center
- University of North Carolina
- Chapel Hill 27599
- USA
| | - Hong Yuan
- Department of Radiology
- Biomedical Research Imaging Center
- University of North Carolina
- Chapel Hill 27599
- USA
| | - Peter S. Conti
- Molecular Imaging Center
- Department of Radiology
- University of Southern California
- Los Angeles 90033
- USA
| | - Zibo Li
- Department of Radiology
- Biomedical Research Imaging Center
- University of North Carolina
- Chapel Hill 27599
- USA
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Uddin MJ, Crews BC, Huda I, Ghebreselasie K, Daniel CK, Marnett LJ. Trifluoromethyl fluorocoxib a detects cyclooxygenase-2 expression in inflammatory tissues and human tumor xenografts. ACS Med Chem Lett 2014; 5:446-50. [PMID: 24900856 DOI: 10.1021/ml400485g] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 01/23/2014] [Indexed: 02/02/2023] Open
Abstract
Fluorocoxib A is an effective COX-2-targeted optical imaging agent, used for in vivo detection of inflammatory tissues and premalignant and malignant tumors that express elevated levels of COX-2 (Uddin et al. Cancer Res. 2010, 70, 3618-3627). In an effort to discover novel optical probes for COX-2, a trifluoromethyl analogue of fluorocoxib A (CF3-fluorocoxib A) was synthesized and evaluated for its ability to inhibit COX-2 in vitro purified enzyme and human cancer cell lines. Kinetic analysis revealed that CF3-fluorocoxib A is a slow, tight binding inhibitor of COX-2 that exhibits low nanomolar inhibitory potency. While CF3-fluorocoxib A and fluorocoxib A are similar in structure, CF3-fluorocoxib A shows improved potency in inhibition of wtCOX-2 and with a series of site-directed COX-2 mutants. After intraperitoneal injection, selective uptake of CF3-fluorocoxib A is detected in inflamed mouse paws compared to noninflamed contralateral paws by optical imaging, and uptake is blocked by pretreatment with the COX-2 inhibitor, celecoxib. Selective uptake is also detected in the COX-2-positive human tumor xenografts (1483 HNSCC) as compared with the COX-2-negative tumor xenografts (HCT116) in an in vivo nude mouse tumor model. These in vitro and in vivo studies suggest that binding to COX-2 is the major determinant of uptake of CF3-fluorocoxib A into the inflamed tissues and tumor xenografts. Thus, this new COX-2-targeted imaging probe should find utility in the detection and evaluation of COX-2 status in naturally occurring malignancies.
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Affiliation(s)
- Md. Jashim Uddin
- A. B. Hancock, Jr., Memorial
Laboratory for Cancer Research, Department of Biochemistry, Chemistry
and Pharmacology, Vanderbilt Institute of Chemical Biology, Center
for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Brenda C. Crews
- A. B. Hancock, Jr., Memorial
Laboratory for Cancer Research, Department of Biochemistry, Chemistry
and Pharmacology, Vanderbilt Institute of Chemical Biology, Center
for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Imran Huda
- A. B. Hancock, Jr., Memorial
Laboratory for Cancer Research, Department of Biochemistry, Chemistry
and Pharmacology, Vanderbilt Institute of Chemical Biology, Center
for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Kebreab Ghebreselasie
- A. B. Hancock, Jr., Memorial
Laboratory for Cancer Research, Department of Biochemistry, Chemistry
and Pharmacology, Vanderbilt Institute of Chemical Biology, Center
for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Cristina K. Daniel
- A. B. Hancock, Jr., Memorial
Laboratory for Cancer Research, Department of Biochemistry, Chemistry
and Pharmacology, Vanderbilt Institute of Chemical Biology, Center
for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Lawrence J. Marnett
- A. B. Hancock, Jr., Memorial
Laboratory for Cancer Research, Department of Biochemistry, Chemistry
and Pharmacology, Vanderbilt Institute of Chemical Biology, Center
for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
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Concurrent targeting of eicosanoid receptor 1/eicosanoid receptor 4 receptors and COX-2 induces synergistic apoptosis in Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus associated non-Hodgkin lymphoma cell lines. Transl Res 2013; 161:447-68. [PMID: 23523954 PMCID: PMC4672642 DOI: 10.1016/j.trsl.2013.02.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 02/13/2013] [Accepted: 02/21/2013] [Indexed: 01/13/2023]
Abstract
The effective antitumorigenic potential of nonsteroidal anti-inflammatory drugs (NSAIDs) and eicosonoid (EP; EP1-4) receptor antagonists prompted us to test their efficacy in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) related lymphomas. Our study demonstrated that (1) EP1-4 receptor protein levels vary among the various non-Hodgkin's lymphoma (NHL) cell lines tested (BCBL-1:KSHV+/EBV-;BC-3: KSHV+/EBV-; Akata/EBV+: KSHV-/EBV+; and JSC-1 cells: KSHV+/EBV + cells); (2) 5.0 μM of EP1 antagonist (SC-51322) had a significant antiproliferative effect on BCBL-1, BC-3, Akata/EBV+, and JSC-1 cells; (3) 50.0 μM of EP2 antagonist (AH6809) was required to induce a significant antiproliferative effect on BCBL-1, Akata/EBV+, and JSC-1 cells; (4) 5.0 μM of EP4 antagonist (GW 627368X) had a significant antiproliferative effect on BC-3, Akata/EBV+, and JSC-1 cells; (5) COX-2 selective inhibitor celecoxib (5.0 μM) had significant antiproliferative effects on BCBL-1, BC-3, Akata/EBV+, and JSC-1 cells; and (6) a combination of 1.0 μM each of celecoxib, SC-51322 and GW 627368X could potentiate the proapoptotic properties of celecoxib or vice-versa. Overall, our studies identified the synergistic antiproliferative effect of NSAIDs and EP receptor blockers on KSHV and EBV related B cell malignancies.
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Uddin MJ, Crews BC, Ghebreselasie K, Marnett LJ. Design, synthesis, and structure-activity relationship studies of fluorescent inhibitors of cycloxygenase-2 as targeted optical imaging agents. Bioconjug Chem 2013; 24:712-23. [PMID: 23488616 PMCID: PMC3630741 DOI: 10.1021/bc300693w] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and premalignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for the ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors grown in mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.
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Affiliation(s)
- Md Jashim Uddin
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA
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Lin YM, Li F, Shi XZ. Mechano-transcription of COX-2 is a common response to lumen dilation of the rat gastrointestinal tract. Neurogastroenterol Motil 2012; 24:670-7, e295-6. [PMID: 22489918 PMCID: PMC4183192 DOI: 10.1111/j.1365-2982.2012.01918.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND In obstructive bowel disorders (OBDs) such as achalasia, pyloric stenosis, and bowel obstruction, the lumen of the affected segments is markedly dilated and the motility function is significantly impaired. We tested the hypothesis that mechanical stress in lumen dilation leads to induction of cyclooxygenase-2 (COX-2) in smooth muscle throughout the gastrointestinal (GI) tract, contributing to motility dysfunction. METHODS Lumen dilation was induced in vivo with obstruction bands (12 × 3 mm) applied over the lower esophageal sphincter (LES), the pyloric sphincter, and the ileum in rats for 48 h. Mechanical stretch in vivo was also emulated by balloon distension of the distal colon. Direct stretch of muscle strips from the esophagus, gastric fundus, and ileum was mimicked in an in vitro tissue culture system. KEY RESULTS Partial obstruction in the LES, pylorus, and ileum significantly increased the expression of COX-2 mRNA and protein in the muscularis externae of the dilated segment oral to the occlusions, but not in the aboral segment. Direct stretch of the lumen in vivo or of muscle strips in vitro markedly induced COX-2 expression. The smooth muscle contractility was significantly suppressed in the balloon-distended segments. However, treatment with COX-2 inhibitor NS-398 restored the contractility. Furthermore, in vivo administration of NS-398 in gastric outlet obstruction significantly improved gastric emptying. CONCLUSIONS & INFERENCES Mechanical dilation of the gut lumen by occlusion or direct distension induces gene expression of COX-2 throughout the GI tract. Mechanical stress-induced COX-2 contributes to motility dysfunction in conditions with lumen dilation.
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Affiliation(s)
| | | | - Xuan-Zheng Shi
- Address requests for reprints to: Xuan-Zheng “Peter” Shi, Department of Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, 301 University Boulevard, Basic Science Building 4.106, Galveston, TX 77555-0655,
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Liao LM, Vaughan TL, Corley DA, Cook MB, Casson AG, Kamangar F, Abnet CC, Risch HA, Giffen C, Freedman ND, Chow WH, Sadeghi S, Pandeya N, Whiteman DC, Murray LJ, Bernstein L, Gammon MD, Wu AH. Nonsteroidal anti-inflammatory drug use reduces risk of adenocarcinomas of the esophagus and esophagogastric junction in a pooled analysis. Gastroenterology 2012; 142:442-452.e5; quiz e22-3. [PMID: 22108196 PMCID: PMC3488768 DOI: 10.1053/j.gastro.2011.11.019] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Revised: 10/12/2011] [Accepted: 11/07/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported to reduce risks of esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations. METHODS We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model. RESULTS Compared with nonusers, individuals who have used NSAIDs had a statistically significant reduced risk of EAC (OR, 0.68; 95% CI, 0.56-0.83); they also appeared to have a reduced risk of EGJA (OR, 0.83; 95% CI, 0.66-1.03). Similar reductions in risk were observed among individuals who took aspirin or nonaspirin NSAIDs. The highest levels of frequency (daily or more frequently) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk of EAC, with ORs of 0.56 (95% CI, 0.43-0.73; P(trend) < .001) and 0.63 (95% CI, 0.45-0.90; P(trend) = .04), respectively. CONCLUSIONS Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, our pooled analysis suggests a possible role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
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Affiliation(s)
- Linda M Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20852, USA.
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Ye F, Zhang GH, Guan BX, Xu XC. Suppression of esophageal cancer cell growth using curcumin, (-)-epigallocatechin-3-gallate and lovastatin. World J Gastroenterol 2012; 18:126-35. [PMID: 22253518 PMCID: PMC3257439 DOI: 10.3748/wjg.v18.i2.126] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Revised: 07/28/2011] [Accepted: 08/04/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the effects of curcumin, (-)-epigallocatechin-3-gallate (EGCG), lovastatin, and their combinations on inhibition of esophageal cancer.
METHODS: Esophageal cancer TE-8 and SKGT-4 cell lines were subjected to cell viability methyl thiazolyl tetrazolium and tumor cell invasion assays in vitro and tumor formation and growth in nude mouse xenografts with or without curcumin, EGCG and lovastatin treatment. Gene expression was detected using immunohistochemistry and Western blotting in tumor cell lines, tumor xenografts and human esophageal cancer tissues, respectively.
RESULTS: These drugs individually or in combinations significantly reduced the viability and invasion capacity of esophageal cancer cells in vitro. Molecularly, these three agents reduced the expression of phosphorylated extracellular-signal-regulated kinases (Erk1/2), c-Jun and cyclooxygenase-2 (COX-2), but activated caspase 3 in esophageal cancer cells. The nude mouse xenograft assay showed that EGCG and the combinations of curcumin, EGCG and lovastatin suppressed esophageal cancer cell growth and reduced the expression of Ki67, phosphorylated Erk1/2 and COX-2. The expression of phosphorylated Erk1/2 and COX-2 in esophageal cancer tissue specimens was also analyzed using immunohistochemistry. The data demonstrated that 77 of 156 (49.4%) tumors expressed phosphorylated Erk1/2 and that 121 of 156 (77.6%) esophageal cancers expressed COX-2 protein. In particular, phosphorylated Erk1/2 was expressed in 23 of 50 (46%) cases of esophageal squamous cell carcinoma (SCC) and in 54 of 106 (50.9%) cases of adenocarcinoma, while COX-2 was expressed in 39 of 50 (78%) esophageal SCC and in 82 of 106 (77.4%) esophageal adenocarcinoma.
CONCLUSION: The combinations of curcumin, EGCG and lovastatin were able to suppress esophageal cancer cell growth in vitro and in nude mouse xenografts, these drugs also inhibited phosphorylated Erk1/2, c-Jun and COX-2 expression.
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Uddin MJ, Crews BC, Ghebreselasie K, Tantawy MN, Marnett LJ. [I]-Celecoxib Analogues as SPECT Tracers of Cyclooxygenase-2 in Inflammation. ACS Med Chem Lett 2011; 2:160-164. [PMID: 21318094 PMCID: PMC3037034 DOI: 10.1021/ml100232q] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Accepted: 11/10/2010] [Indexed: 02/02/2023] Open
Abstract
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We report the synthesis and evaluation of a series of iodinated celecoxib analogues as cyclooxygenase-2 (COX-2)-targeted single photon emission computerized tomography (SPECT) imaging agents for the detection of inflammation. The structure−activity relationship identified 5-(4-iodophenyl)-1-{4-(methylsulfonyl)phenyl}-3-(trifluoromethyl)-1H-pyrazole (8) as a promising compound with IC50 values of 0.05 μM against purified COX-2 and 0.03 μM against COX-2 in activated macrophages. The arylstannane of 8 undergoes facile radio-[123I]-iodination upon treatment with Na123I/NaI and chloramine T using an EtOAc/H2O two-phase system. The [123I]-8 was produced in a radiochemical yield of 85% and a radiochemical purity of 99%. In vivo SPECT imaging demonstrated that the radiotracer was taken up by inflamed rat paws with an average 1.7-fold enrichment over contralateral noninflamed paws. This study suggests that conversion of celecoxib into its isomeric iodo-[123I]-analogues is a useful approach for generating novel and efficacious agents for COX-2-targeted SPECT imaging of inflammation.
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Affiliation(s)
- Md. Jashim Uddin
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
| | - Brenda C. Crews
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
| | - Kebreab Ghebreselasie
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
| | - Mohammed N. Tantawy
- Department of Radiology, Vanderbilt University Institute of Imaging Science, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Lawrence J. Marnett
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
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12
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Mehta SP, Boddy AP, Cook J, Sams V, Lund EK, Johnson IT, Rhodes M. Effect of n-3 polyunsaturated fatty acids on Barrett's epithelium in the human lower esophagus. Am J Clin Nutr 2008; 87:949-56. [PMID: 18400718 DOI: 10.1093/ajcn/87.4.949] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Epidemiologic studies suggest a reduced risk of esophageal adenocarcinoma in populations with a high consumption of fish, and n-3 fatty acids inhibit experimental carcinogenesis. One possible explanation is the suppression of eicosanoid production through inhibition of cyclooxygenase 2 (COX-2). OBJECTIVE The objective was to determine the effects of dietary supplementation with the n-3 fatty acid eicosapentaenoic acid (EPA) on a number of biological endpoints in Barrett's esophagus. DESIGN Fifty-two participants with known Barrett's esophagus underwent endoscopy. Biopsy samples were obtained from a recorded level within the area of Barrett's esophagus, and then 27 patients were randomly assigned to consume EPA capsules (1.5 g/d) for 6 mo or no supplement (controls). At the end of this period, patients again underwent endoscopy, and biopsy samples were collected at the same level. Tissue samples were analyzed for mucosal lipid, prostaglandin E2, leukotriene B4, COX-2 protein, and RNA concentrations. Cellular proliferation was also measured, by Ki-67 immunohistochemistry. RESULTS The EPA content of esophageal mucosa increased over the study period in the n-3-supplemented subjects and was significantly different from the content in the controls (P < 0.01). There was also a significant decline in COX-2 protein concentrations (measured by immunoblotting) in the n-3 group, and the difference was significant from that in the controls (P < 0.05); no difference in COX-2 RNA concentrations was observed between groups. This change in COX-2 protein was inversely related to the change in EPA content (P < 0.05). There was no significant difference in the change in prostaglandin E2, leukotriene B4, or cellular proliferation between the 2 groups. CONCLUSION Supplementation with EPA significantly changed n-3 fatty acid concentrations and reduced COX-2 concentrations in Barrett's tissue.
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Affiliation(s)
- Samir P Mehta
- Department of Upper Gastrointestinal Surgery and the Department of Histopathology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
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Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD, Ayub K, Rabinovitch PS, Vaughan TL, Reid BJ. NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med 2007; 4:e67. [PMID: 17326708 PMCID: PMC1808095 DOI: 10.1371/journal.pmed.0040067] [Citation(s) in RCA: 215] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Accepted: 01/04/2007] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barrett's esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE. METHODS AND FINDINGS Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2-21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1-6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8-138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001). CONCLUSIONS A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.
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Affiliation(s)
- Patricia C Galipeau
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
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Gomer CJ, Ferrario A, Luna M, Rucker N, Wong S. Photodynamic therapy: combined modality approaches targeting the tumor microenvironment. Lasers Surg Med 2007; 38:516-21. [PMID: 16607618 DOI: 10.1002/lsm.20339] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Photodynamic therapy causes direct cytotoxicity to malignant cells within a tumor. Photodynamic therapy (PDT) can also have both direct and indirect effects upon various non-malignant components of the tumor microenvironment. This action can lead to PDT-mediated angiogenesis and inflammation, which are emerging as important determinants of PDT responsiveness. STUDY DESIGN/MATERIALS AND METHODS Preclinical studies have been performed to document how PDT modulates the tumor microenvironment. The expression, function, and treatment relevance of angiogenic growth factors, proteinases, and inflammatory molecules have been monitored following PDT using mouse tumor models. RESULTS Photofrin-mediated PDT was shown to be a strong activator of VEGF, MMPs, and COX-2 derived prostaglandins within the tumor microenvironment. Inhibitors that target these angiogenic and pro-survival molecules can enhance the effectiveness of PDT. CONCLUSIONS Improvements in PDT tumor responsiveness may be achieved by employing combined modality regimens targeting malignant cells as well as treatment-induced angiogenesis and/or inflammation.
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Affiliation(s)
- Charles J Gomer
- The Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027, USA.
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15
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Mehta S, Boddy A, Johnson IT, Rhodes M. Systematic review: Cyclo-oxygenase-2 in human oesophageal adenocarcinogenesis. Aliment Pharmacol Ther 2006; 24:1321-31. [PMID: 17059513 DOI: 10.1111/j.1365-2036.2006.03119.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Published in vitro and animal in vivo studies have demonstrated that cyclo-oxygenase-2 plays an important role during oesophageal adenocarcinogenesis. However, the extent to which these studies are directly relevant to events in the human lower oesophagus is questionable. AIM To perform a systematic review of all available human studies that have evaluated levels of cyclo-oxygenase-2 expression during the progression from Barrett's metaplasia to oesophageal adenocarcinoma. METHODS A literature search was performed to identify all studies which qualitatively or quantitatively assessed cyclo-oxygenase-2 protein or gene expression in either Barrett's, dysplastic or adenocarcinoma tissue in humans. RESULTS A total of 27 studies met the inclusion criteria. There was general agreement that cyclo-oxygenase-2 was either absent or very weakly expressed in normal oesophageal squamous mucosa, but considerable disagreement regarding the presence of cyclo-oxygenase-2 in Barrett's and low-grade dysplasia. All studies agreed that high-grade dysplasia and adenocarcinoma expressed cyclo-oxygenase-2 to some extent although levels varied considerably between tissue samples. CONCLUSIONS There is conflicting evidence in the literature for cyclo-oxygenase-2 playing an important role in early oesophageal adenocarcinogenesis. Other non-cyclo-oxygenase-2 targets may account for the epidemiological data supporting the use of non-steroidal anti-inflammatory drugs in the chemoprevention of oesophageal adenocarcinoma.
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Affiliation(s)
- S Mehta
- Department of Upper Gastrointestinal Surgery, Norfolk and Norwich University Hospital, Colney Lane, Norwich, UK
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Ferrario A, Fisher AM, Rucker N, Gomer CJ. Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors. Cancer Res 2005; 65:9473-8. [PMID: 16230411 DOI: 10.1158/0008-5472.can-05-1659] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Photodynamic therapy (PDT) elicits both apoptotic and necrotic responses within treated tumors and produces microvascular injury leading to inflammation and hypoxia. PDT also induces expression of angiogenic and survival molecules including vascular endothelial growth factor, cyclooxygenase-2 (COX-2), and matrix metalloproteinases. Adjunctive administration of inhibitors to these molecules improves PDT responsiveness. In the current study, we examined how the combination of PDT and COX-2 inhibitors improve treatment responsiveness. Photofrin-mediated PDT combined with either celecoxib or NS-398 increased cytotoxicity and apoptosis in mouse BA mammary carcinoma cells. Immunoblot analysis of protein extracts from PDT-treated cells also showed poly(ADP-ribose) polymerase cleavage and Bcl-2 degradation, which were further enhanced following combined therapy. Tumor-bearing mice treated with PDT and either celecoxib or NS-398 exhibited significant improvement in long-term tumor-free survival when compared with PDT or COX-2 inhibitor treatments alone. The combined procedures did not increase in vivo tumor-associated apoptosis. Administration of celecoxib or NS-398 attenuated tissue levels of prostaglandin E2 and vascular endothelial growth factor induced by PDT in treated tumors and also decreased the expression of proinflammatory mediators interleukin-1beta and tumor necrosis factor-alpha. Increased tumor levels of the antiinflammatory cytokine, interleukin 10, were also observed following combined treatment. This study documents for the first time that adjunctive use of celecoxib enhances PDT-mediated tumoricidal action in an in vivo tumor model. Our results also show that administration of COX-2 inhibitors enhance in vitro photosensitization by increasing apoptosis and improve in vivo PDT responsiveness by decreasing expression of angiogenic and inflammatory molecules.
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Affiliation(s)
- Angela Ferrario
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
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Abstract
The incidence of oesophageal adenocarcinoma is increasing in the UK faster than any other malignancy. Despite its relatively poor prognosis and the limited success of existing treatments, there is enthusiasm that chemopreventive agents might be able to stem the transition from normal squamous epithelium to adenocarcinoma. We discuss gastro-oesophageal reflux as the main risk factor for the development of Barrett's metaplasia, the only known precursor of oesophageal adenocarcinoma. Treatment options for reflux disease are considered with regard to their effects on cancer risk. Recent advances in the molecular and cell biology of Barrett's are outlined, and potential targets for chemoprevention examined. Available treatments for reflux disease have not convincingly altered the likelihood of cancer development. Epidemiological and animal studies support the use of non-steroidal anti-inflammatory drugs as potential chemopreventive agents. Dietary agents, however, have a more favourable side-effect profile and may prove to be an attractive alternative, although more work is needed to fully explore this prospect.
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Affiliation(s)
- S Mehta
- Department of Upper Gastrointestinal Surgery, Norfolk and Norwich University Hospital, Colney Lane, Norwich, UK
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Herrera LJ, El-Hefnawy T, Queiroz de Oliveira PE, Raja S, Finkelstein S, Gooding W, Luketich JD, Godfrey TE, Hughes SJ. The HGF receptor c-Met is overexpressed in esophageal adenocarcinoma. Neoplasia 2005; 7:75-84. [PMID: 15720819 PMCID: PMC1490312 DOI: 10.1593/neo.04367] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The hepatocyte growth factor (HGF) receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA) remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE), and normal esophagus (NE) using immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100%) EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2-overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted.
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Affiliation(s)
- Luis J Herrera
- Department of Surgery, University of Pittsburgh and the Hillman Cancer Center, Pittsburgh, PA 15261, USA
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Abstract
BACKGROUND & AIMS Chemoprevention of esophageal adenocarcinoma using nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of cancer in patients with Barrett's esophagus. The aim of the study was to assess the cost-effectiveness of this strategy. METHODS The incremental cost-effectiveness ratio (ICER) of chemoprevention (compared with endoscopic surveillance or with no surveillance) was analyzed with a computer model of a Markov process. RESULTS Under baseline conditions for all patients with Barrett's esophagus (neoplastic and nonneoplastic), the ICER of chemoprevention ranges between $12,700 and $18,500 US dollars per life-year saved. However, these cost values are sensitive to variations in the costs of chemoprevention, incidence of cancer in patients with Barrett's esophagus, and efficacy of NSAIDs in reducing the incidence of cancer, which can shift the ICER into a cost range that is prohibitively expensive. Conversely, in those patients with Barrett's esophagus and high-grade dysplasia, the ICER ranges between $3900 and $5000 US dollars. Chemoprevention remains a cost-effective option even under rather unfavorable conditions, such as higher cost and lower efficacy of chemoprevention and lower incidence of cancer. CONCLUSIONS This model suggests that a high incidence of esophageal adenocarcinoma in high-grade dysplasia renders chemoprevention cost-effective even in the presence of less-favorable conditions. However, chemoprevention may not be a cost-effective measure in the general population of all patients with Barrett's esophagus, depending on unknown factors such as cost and efficacy of chemoprevention as well as true incidence of cancer.
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Affiliation(s)
- Amnon Sonnenberg
- Portland VA Medical Center P3-G1, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
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Abstract
Barrett's esophagus (BE) is a complication observed in a small subset of patients with chronic gastroesophageal reflux. It is characterized by the presence of intestinal-type goblet cells in biopsies from the lower esophagus. The prevalence of BE increases with age, affecting 1% of the population older than 60 years. A genetic predisposition to reflux disease has been proposed. In a twin study of reflux disease, concordance was greater in monozygotic than dizygotic twins. An association between BE and esophageal adenocarcinoma, the incidence of which has increased remarkably in the last few decades, has been established. Esophagogastric junction cancers can arise from small areas of cardia intestinal metaplasia (CIM). Regular endoscopic and histologic follow-up of BE patients is recommended. Surveillance of patients with CIM is not advised. Chromoendoscopy may help to detect areas of high-grade dysplasia (HGD). The ablation of BE, e.g. by PDT or argon plasma coagulation, is not yet proven to reduce the cancer risk. Esophagectomy is still the standard management of HGD. Endoscopic mucosal resection may be used for visible, localized lesions with HGD, and this technique may be combined with thermal ablation for areas of HGD without visible abnormality.
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Affiliation(s)
- Massimo Conio
- Department of Gastroenterology, National Institute for Cancer Research, Via Trento 42/14, Genoa 16145, Italy.
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