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Abstract
BACKGROUND Patients with Barrett esophagus (BE) are predisposed to developing dysplasia and cancer. Adenocarcinoma, which is associated with BE, is the most common type of esophageal tumor and, typically, it has an aggressive clinical course and a high rate of mortality. METHODS The English-language literature relating to tumor epidemiology, etiology, and the pathogenesis of BE was reviewed and summarized. RESULTS The role of pathologists in the diagnosis and pitfalls associated with grading Barrett dysplasia is addressed. Current molecular testing for Barrett neoplasia, as well as testing methods currently in development, is discussed, focusing on relevant tests for diagnosing tumor types, determining prognosis, and assessing therapeutic response. CONCLUSIONS Grading is essential for developing appropriate treatment plans, follow-up visits, and therapeutic interventions for each patient. Familiarity with current molecular testing methods will help physicians correctly diagnose the disease and select the most appropriate therapy for each of their patients.
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Affiliation(s)
- Sherma Zibadi
- Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL 33612, USA.
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The role of Dickkopf-3 overexpression in esophageal adenocarcinoma. J Thorac Cardiovasc Surg 2015; 150:377-385.e2. [PMID: 26093488 DOI: 10.1016/j.jtcvs.2015.05.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/31/2015] [Accepted: 05/02/2015] [Indexed: 12/21/2022]
Abstract
OBJECTIVES Ninety percent of patients with esophageal adenocarcinoma ultimately die of their disease, highlighting the need for novel therapeutic targets. The goal of this study was to define the functional significance of overexpression of Dickkopf-3 (DKK3) in esophageal adenocarcinoma. METHODS DKK3 expression was analyzed by real-time polymerase chain reaction in 95 chemonaive and 21 chemoresistant esophageal adenocarcinomas. The esophageal adenocarcinoma cell line OE33 was stably transfected with DKK3 (OE33/DKK3) and evaluated using WST-1 (Roche, Basel, Switzerland), Matrigel (BD Biosciences, San Jose, Calif), endothelial tube formation, and chemosensitivity assays. Tumorigenesis was evaluated by injecting 1 × 10(6) OE33/DKK3 and vector cells in NOD/SCIDγ mice. RESULTS DKK3 was overexpressed (>2-fold) in 75.8% (72/95) of esophageal adenocarcinomas. DKK3 protein was present at moderate to high levels in 46.8% (29/62) of esophageal adenocarcinomas on tissue microarray. Stable transfection of DKK3 significantly increased proliferation (P < .05) and Matrigel invasion (P < .001). Levels of SMAD4, a key mediator of the transforming growth factor-ß pathway, increased after activin treatment of OE33/DKK3, and siSMAD4 significantly decreased Matrigel invasion, suggesting that DKK3 acts through the transforming growth factor-β pathway. OE33/DKK3 cells increased endothelial tube formation and were significantly more resistant to 5-fluorouracil and cisplatin, and DKK3 expression was significantly higher in chemoresistant esophageal adenocarcinomas (P < .005). In NOD/SCIDγ mice, OE33/DKK3 cells resulted in tumors at all sites (8/8), whereas vector cells grew in only 1 of 8 sites. Nodal metastases were also significantly increased in patients with esophageal adenocarcinomas highly overexpressing DKK3, 28 of 32 (88%) versus 42 of 63 (68%) (P < .05). CONCLUSIONS These findings suggest that DKK3 may be important in mediating invasion in esophageal adenocarcinoma and could be a novel target in the treatment and prevention of metastatic disease.
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Shackelford RE, Abdelbaqi MQ, Almhanna K, Meredith K, Coppola D. Molecular Pathology and Diagnostics in Esophago-gastric Cancer. MOLECULAR PATHOLOGY AND DIAGNOSTICS OF CANCER 2014:177-210. [DOI: 10.1007/978-94-007-7192-5_6] [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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Chen H, Ma J, Sunkel B, Luo A, Ding F, Li Y, He H, Zhang S, Xu C, Jin Q, Wang Q, Liu Z. S100A14: Novel Modulator of Terminal Differentiation in Esophageal Cancer. Mol Cancer Res 2013; 11:1542-53. [DOI: 10.1158/1541-7786.mcr-13-0317] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Yoon HH, Shi Q, Sukov WR, Wiktor AE, Khan M, Sattler CA, Grothey A, Wu TT, Diasio RB, Jenkins RB, Sinicrope FA. Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. Clin Cancer Res 2012; 18:546-54. [PMID: 22252257 DOI: 10.1158/1078-0432.ccr-11-2272] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). EXPERIMENTAL DESIGN HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3-4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. RESULTS Overall, 17% of EACs were HER2 positive (i.e., IHC3(+) or IHC2(+) with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1-2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (P(interaction) = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35-0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. CONCLUSIONS HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival.
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Affiliation(s)
- Harry H Yoon
- Departments of Medical Oncology, Health Sciences Research, Cytogenetics, Anatomic Pathology, Cancer Center, Laboratory Medicine and Pathology, and Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.
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Barrett's Esophagus: Emerging Knowledge and Management Strategies. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:814146. [PMID: 22701199 PMCID: PMC3369502 DOI: 10.1155/2012/814146] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 03/08/2012] [Accepted: 03/26/2012] [Indexed: 12/14/2022]
Abstract
The incidence of esophageal adenocarcinoma (EAC) has increased exponentially in the last 3 decades. Barrett's esophagus (BE) is the only known precursor of EAC. Patients with BE have a greater than 40 folds higher risk of EAC compared with the general population. Recent years have witnessed a revolution in the clinical and molecular research related to BE. However, several aspects of this condition remain controversial. Data regarding the true prevalence of BE have varied widely. Recent studies have suggested a lower incidence of EAC in nondysplastic BE (NDBE) than previously reported. There is paucity of prospective data showing a survival benefit of screening or surveillance for BE. Furthermore, the ever-increasing emphasis on healthcare cost containment has called for reexamination of the screening and surveillance strategies for BE. There is a need for identification of reliable clinical predictors or molecular biomarkers to risk-stratify patients who might benefit the most from screening or surveillance for BE. Finally, new therapies have emerged for the management of dysplastic BE. In this paper, we highlight the key areas of controversy and uncertainty surrounding BE. The paper discusses, in detail, the current literature about the molecular pathogenesis, biomarkers, histopathological diagnosis, and management strategies for BE.
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Schauer MC, Stoecklein NH, Theisen J, Kröpil F, Baldus S, Hoelscher A, Feith M, Bölke E, Matuschek C, Budach W, Knoefel WT. The simultaneous expression of both ephrin B3 receptor and E-cadherin in Barrett`s adenocarcinoma is associated with favorable clinical staging. Eur J Med Res 2012; 17:10. [PMID: 22583970 PMCID: PMC3471084 DOI: 10.1186/2047-783x-17-10] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 05/14/2012] [Indexed: 11/21/2022] Open
Abstract
Background In intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Eph B3 in esophageal adenocarcinoma we analyzed the simultaneous expression of Eph B3 and E-cadherin in both the healthy esophagus and in Barrett’s carcinoma. Methods Simultaneous expression of Eph B3 and E-cadherin was investigated in samples from 141 patients with Barrett’s carcinoma and from 20 healthy esophagi using immunhistology and quantitative PCR. Results from healthy squamous epithelium, Barrett’s metaplasia and staging-specific esophageal adenocarcinoma were correlated. Results A significantly reduced E-cadherin mRNA expression could be detected in adenocarcinoma compared to dysplasia. The immunhistological activity of E-cadherin and Eph B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when the Eph receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Eph B3 showed a significant inverse correlation to tumor stage. Conclusions We present novel evidence of the tumor suppressor activity of Eph B3 in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma sequence, the infiltrative growth pattern and the development of lymph node metastases.
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Affiliation(s)
- Matthias C Schauer
- Department of Radiotherapy, Heinrich Heine University, Duesseldorf, Germany
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Kashyap S, Sethi S, Meel R, Pushker N, Sen S, Bajaj MS, Chandra M, Ghose S. A Histopathologic Analysis of Eyes Primarily Enucleated for Advanced Intraocular Retinoblastoma From a Developing Country. Arch Pathol Lab Med 2012; 136:190-3. [PMID: 22288967 DOI: 10.5858/arpa.2010-0759-oa] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Seema Kashyap
- Ocular Pathology Services, Dr R. P. Centre for Ophthalmic Sciences, All India Institute of Ophthalmic Sciences, Ansari Nagar, New Delhi, India
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Zhang C, Chen P, Fei Y, Liu B, Ma K, Fu X, Zhao Z, Sun T, Sheng Z. Wnt/β-catenin signaling is critical for dedifferentiation of aged epidermal cells in vivo and in vitro. Aging Cell 2012; 11:14-23. [PMID: 21967252 DOI: 10.1111/j.1474-9726.2011.00753.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Aged epidermal cells have the capacity to dedifferentiate into stem cell-like cells. However, the signals that regulate the dedifferentiation of aged epidermal cells remain unclear. Here, we provide evidence that Wnt/β-catenin is critical for aged epidermal cell dedifferentiation in vivo and in vitro. Some aged epidermal cells in human ultrathin epidermal sheets lacking basal stem cells transplanted onto wounds dedifferentiated into stem cell-like cells that were positive for CK19 and β1 integrin but negative for CK10. In addition, Wnt/β-catenin pathway was activated during this process. There was increased expression of Wnt-1, Wnt-4, Wnt-7a, β-catenin, cyclin D1, and c-myc. Secreted frizzled-related protein 1, a Wnt/β-catenin pathway inhibitor, blocked dedifferentiation in vivo. Then, the activator, a highly specific glycogen synthase kinase (GSK)-3β inhibitor, of Wnt/β-catenin pathway was added to the culture medium of aged epidermal cells. Surprisingly, we found that the activator induced higher expression of CK19, β1 integrin, Oct4, and Nanog proteins. The induced aged epidermal cells exhibited high colony-forming efficiency, long-term proliferative potential and could regenerate a skin equivalent (as do epidermal stem cells). These results suggested that activation of Wnt/β-catenin pathway induced the dedifferentiation of aged epidermal cells, which suggest a new approach to generate epidermal stem cell-like cells.
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Affiliation(s)
- Cuiping Zhang
- Wound Healing and Cell Biology Laboratory, Burns Institute, The First Affiliated Hospital, General Hospital of PLA, Beijing, China
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Allott EH, Lysaght J, Cathcart MC, Donohoe CL, Cummins R, McGarrigle SA, Kay E, Reynolds JV, Pidgeon GP. MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation. Mol Carcinog 2011; 52:144-54. [PMID: 22121096 DOI: 10.1002/mc.21840] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 10/18/2011] [Accepted: 10/19/2011] [Indexed: 01/09/2023]
Abstract
Overweight and obesity is linked to increased incidence and mortality of many cancer types. Of all cancers, oesophageal adenocarcinoma (OAC) displays one of the strongest epidemiological links with obesity, accounting for up to 40% of cases, but molecular pathways driving this association remain largely unknown. This study aimed to elucidate mechanisms underpinning the association of obesity and cancer, and to determine if visceral obesity is associated with aggressive tumour biology in OAC. Following co-culture with visceral adipose tissue explants, expression of genes involved in tumour cell invasion and metastasis (matrix metalloproteinase (MMP)2 and MMP9) were upregulated between 10-fold (MMP2) and 5000-fold (MMP9), and expression of tumour suppressor p53 was downregulated 2-fold in OAC cell lines. Western blotting confirmed these results at the protein level, while zymographic analysis detected increased activity of MMPs in OAC cell lines following co-culture with adipose tissue explants. When OAC cell lines were cultured with adipose tissue conditioned media (ACM) from visceral adipose tissue, increased proliferative, migratory and invasive capacity of tumour cells was observed. In OAC patient tumour biopsies, elevated gene expression of MMP9 was associated with visceral obesity, measured by visceral fat area, while increased gene expression of MMP9 and decreased gene expression of tumour suppressor p53 was associated with poor tumour differentiation. These novel data highlight an important role for visceral obesity in upregulation of pro-tumour pathways contributing to aggressive tumour biology, and may ultimately lead to development of stratified treatment for viscerally obese OAC patients.
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Affiliation(s)
- Emma H Allott
- Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
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Nancarrow DJ, Clouston AD, Smithers BM, Gotley DC, Drew PA, Watson DI, Tyagi S, Hayward NK, Whiteman DC. Whole genome expression array profiling highlights differences in mucosal defense genes in Barrett's esophagus and esophageal adenocarcinoma. PLoS One 2011; 6:e22513. [PMID: 21829465 PMCID: PMC3145652 DOI: 10.1371/journal.pone.0022513] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2011] [Accepted: 06/26/2011] [Indexed: 12/15/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene groups are the most frequently represented differentially expressed gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate between squamous epithelium, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation (LOOCV) analysis. While this method was satisfactory for discriminating squamous epithelium and BE, it demonstrates the need for more detailed investigations into profiling changes between BE and EAC.
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Affiliation(s)
- Derek J Nancarrow
- Oncogenomics, Queensland Institute of Medical Research, Herston, Queensland, Australia.
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Smith CM, Watson DI, Leong MP, Mayne GC, Michael MZ, Wijnhoven BPL, Hussey DJ. miR-200 family expression is downregulated upon neoplastic progression of Barrett’s esophagus. World J Gastroenterol 2011; 17:1036-44. [PMID: 21448356 PMCID: PMC3057147 DOI: 10.3748/wjg.v17.i8.1036] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 09/13/2010] [Accepted: 09/20/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate miR-200 family expression in Barrett’s epithelium, gastric and duodenal epithelia, and esophageal adenocarcinoma.
METHODS: Real-time reverse transcriptase-polymerase chain reaction was used to measure miR-200, ZEB1 and ZEB2 expression. Ingenuity Pathway Analysis of miR-200 targets was used to predict biological outcomes.
RESULTS: Barrett’s epithelium expressed lower levels of miR-141 and miR-200c than did gastric and duodenal epithelia (P < 0.001). In silico analysis indicated roles for the miR-200 family in molecular pathways that distinguish Barrett’s epithelium from gastric and duodenal epithelia, and which control apoptosis and proliferation. All miR-200 members were downregulated in adenocarcinoma (P < 0.02), and miR-200c expression was also downregulated in non-invasive epithelium adjacent to adenocarcinoma (P < 0.02). The expression of all miR-200 members was lower in Barrett’s epithelium derived high-grade dysplastic cell lines than in a cell line derived from benign Barrett’s epithelium. We observed significant inverse correlations between miR-200 family expression and ZEB1 and ZEB2 expression in Barrett’s epithelium and esophageal adenocarcinoma (P < 0.05).
CONCLUSION: miR-200 expression might contribute to the anti-apoptotic and proliferative phenotype of Barrett’s epithelium and regulate key neoplastic processes in this epithelium.
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Zhang C, Fu X, Chen P, Bao X, Li F, Sun X, Lei Y, Cai S, Sun T, Sheng Z. Dedifferentiation derived cells exhibit phenotypic and functional characteristics of epidermal stem cells. J Cell Mol Med 2010; 14:1135-45. [PMID: 19426155 PMCID: PMC3822750 DOI: 10.1111/j.1582-4934.2009.00765.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Differentiated epidermal cells can dedifferentiate into stem cells or stem cell-like cells in vivo. In this study, we report the isolation and characterization of dedifferentiation-derived cells. Epidermal sheets eliminated of basal stem cells were transplanted onto the skin wounds in 47 nude athymic (BALB/c-nu/nu) mice. After 5 days, cells negative for CK10 but positive for CK19 and β1-integrin emerged at the wound-neighbouring side of the epidermal sheets. Furthermore, the percentages of CK19 and β1-integrin+ cells detected by flow cytometric analysis were increased after grafting (P < 0.01) and CK10+ cells in grafted sheets decreased (P < 0.01). Then we isolated these cells on the basis of rapid adhesion to type IV collagen and found that there were 4.56% adhering cells (dedifferentiation-derived cells) in the grafting group within 10 min. The in vitro phenotypic assays showed that the expressions of CK19, β1-integrin, Oct4 and Nanog in dedifferentiation-derived cells were remarkably higher than those in the control group (differentiated epidermal cells) (P < 0.01). In addition, the results of the functional investigation of dedifferentiation-derived cells demonstrated: (1) the numbers of colonies consisting of 5–10 cells and greater than 10 cells were increased 5.9-fold and 6.7-fold, respectively, as compared with that in the control (P < 0.01); (2) more cells were in S phase and G2/M phase of the cell cycle (proliferation index values were 21.02% in control group, 45.08% in group of dedifferentiation); (3) the total days of culture (28 days versus 130 days), the passage number of cells (3 passages versus 20 passages) and assumptive total cell output (1 × 105 cells versus 1 × 1012 cells) were all significantly increased and (4) dedifferentiation-derived cells, as well as epidermal stem cells, were capable of regenerating a skin equivalent, but differentiated epidermal cells could not. These results suggested that the characteristics of dedifferentiation-derived cells cultured in vitro were similar to epidermal stem cells. This study may also offer a new approach to yield epidermal stem cells for wound repair and regeneration.
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Affiliation(s)
- Cuiping Zhang
- Wound Healing and Cell Biology Laboratory, Burns Institute, The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, PR China
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Garg M, Kanojia D, Suri S, Suri A. Small interfering RNA-mediated down-regulation of SPAG9 inhibits cervical tumor growth. Cancer 2010; 115:5688-99. [PMID: 19813278 DOI: 10.1002/cncr.24658] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND The expression of the SPAG9 is associated with various human malignancies. Earlier work revealed a significant association of SPAG9 expression with the early spread of cervical cancer, making it an attractive therapeutic target. Here, the authors investigated the role of SPAG9 in carcinogenesis of squamous cell carcinoma (SCC) of the cervix. Furthermore, they sought to determine whether ablation of SPAG9 expression reduces the tumor growth of cervical SCC in vivo. METHODS A plasmid-based small interfering RNA approach was used to specifically knock down the expression of SPAG9 in SiHa cells derived from SCC of the cervix in vitro and in vivo. Reverse transcriptase polymerase chain reaction, immunofluorescence staining, flow cytometry, cellular growth, colony formation, migration, invasion, and wound healing assays were studied to characterize SPAG9 in vitro. Furthermore, a cervical cancer xenograft model in nude mice was established to investigate whether knockdown of SPAG9 reduces the tumor growth of cervical SCC in vivo. RESULTS The results demonstrated that silencing the SPAG9 by small interfering RNA resulted in inhibition of cell growth, colony formation, migration, and invasion. The authors showed for the first time that the knockdown of SPAG9 expression by small interfering RNA significantly suppressed the tumor growth of cervical SCC in vivo. CONCLUSIONS These results suggest that SPAG9 expression may play a pivotal role in tumor growth and could contribute to the early spread of cervical cancer. Small interfering RNA-mediated down-regulation of SPAG9 represents a promising therapeutic approach for the treatment of cervical cancer.
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Affiliation(s)
- Manoj Garg
- Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India
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Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer 2010; 10:87-101. [PMID: 20094044 PMCID: PMC2879265 DOI: 10.1038/nrc2773] [Citation(s) in RCA: 292] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The public health importance of Barrett's oesophagus lies in its association with oesophageal adenocarcinoma. The incidence of oesophageal adenocarcinoma has risen at an alarming rate over the past four decades in many regions of the Western world, and there are indications that the incidence of this disease is on the rise in Asian populations in which it has been rare. Much has been learned of host and environmental risk factors that affect the incidence of oesophageal adenocarcinoma, and data indicate that patients with Barrett's oesophagus rarely develop oesophageal adenocarcinoma. Given that 95% of oesophageal adenocarcinomas arise in individuals without a prior diagnosis of Barrett's oesophagus, what strategies can be used to reduce late diagnosis of oesophageal adenocarcinoma?
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Affiliation(s)
- Brian J Reid
- Divisions of Public Health Sciences and Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, 98109 Seattle, USA.
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Shimada Y, Sato F, Shimizu K, Tsujimoto G, Tsukada K. cDNA microarray analysis of esophageal cancer: discoveries and prospects. Gen Thorac Cardiovasc Surg 2009; 57:347-56. [DOI: 10.1007/s11748-008-0406-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Indexed: 12/23/2022]
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di Pietro M, Fitzgerald RC. Barrett’s oesophagus: an ideal model to study cancer genetics. Hum Genet 2009; 126:233-46. [DOI: 10.1007/s00439-009-0665-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Accepted: 04/01/2009] [Indexed: 12/16/2022]
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Wang J, Qin R, Ma Y, Wu H, Peters H, Tyska M, Shaheen NJ, Chen X. Differential gene expression in normal esophagus and Barrett's esophagus. J Gastroenterol 2009; 44:897-911. [PMID: 19468668 PMCID: PMC3811010 DOI: 10.1007/s00535-009-0082-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Accepted: 04/15/2009] [Indexed: 02/04/2023]
Abstract
PURPOSE As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett's esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE. METHODS We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression. RESULTS Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (> or =4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFbeta pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE. CONCLUSION Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.
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Affiliation(s)
- Jacob Wang
- Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Rong Qin
- Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707
| | - Yan Ma
- Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707
| | - Huiyun Wu
- Department of Biostatistics, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center/Biostatistics Shared Resource, Nashville, TN 37232-2158
| | - Heiko Peters
- Institute of Human Genetics, International Centre for Life, University of Newcastle upon Tyne, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
| | - Matthew Tyska
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Nicholas J. Shaheen
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Xiaoxin Chen
- Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
- Correspondence: Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707. Tel: 919-530-6425; Fax: 919-530-7780;
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Sabo E, Meitner PA, Tavares R, Corless CL, Lauwers GY, Moss SF, Resnick MB. Expression analysis of Barrett's esophagus-associated high-grade dysplasia in laser capture microdissected archival tissue. Clin Cancer Res 2008; 14:6440-8. [PMID: 18927283 DOI: 10.1158/1078-0432.ccr-08-0302] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE Identifying genes differentially expressed in nondysplastic BE (NDBE) from those expressed in high-grade dysplasia (HGD) should be of value in improving our understanding of this transition and may yield new diagnostic and/or prognostic markers. The aim of this study was to determine the differential transcriptome of HGD compared with NDBE through gene microarray analysis of epithelial cells microdissected from archival tissue specimens. EXPERIMENTAL DESIGN Laser capture microdissection was used to isolate epithelial cells from adjacent inflammatory and stromal cells. Epithelial mRNA was extracted from areas of NDBE and HGD in matched biopsies from 11 patients. mRNA was reverse transcribed and applied on Affymetrix cDNA microarray chips customized for formalin-exposed tissue. For a subset of these genes, differential gene expression was confirmed by real-time PCR and immunohistochemistry. RESULTS There were 131 genes overexpressed by at least 2.5-fold in HGD versus NDBE and 16 genes that were underexpressed by at least 2.5-fold. Among the overexpressed genes are several previously shown to be increased in the neoplastic progression of BE, as well as novel genes such as lipocalin-2, S100A9, matrix metallopeptidase 12, secernin 1, and topoisomerase IIalpha. Genes decreased in dysplastic epithelium include MUC5AC, trefoil factor 1 (TFF1), meprin A, and CD13. Real-time PCR validated the changes in expression in 24 of 28 selected genes. Immunohistochemistry confirmed increased protein expression for topoisomerase IIalpha, S100A9, and lipocalin-2 and decreased expression of TFF1 across the spectrum of BE-associated dysplasia from NDBE through adenocarcinoma. CONCLUSIONS This is the first study to identify epithelial genes differentially expressed in HGD versus NDBE in matched patient samples. The genes identified include several previously implicated in the pathogenesis of BE-associated dysplasia and new candidates for further investigation.
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Affiliation(s)
- Edmond Sabo
- Department of Pathology and Medicine, Rhode Island Hospital, Providence, Rhode Island 02903, USA
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20
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Cen P, Correa AM, Lee JH, Maru D, Anandasabapathy S, Liao Z, Hofstetter WL, Swisher SG, Komaki R, Ross WA, Vaporciyan A, Ajani JA. Adenocarcinoma of the lower esophagus with Barrett's esophagus or without Barrett's esophagus: differences in patients' survival after preoperative chemoradiation. Dis Esophagus 2008; 22:32-41. [PMID: 19021684 DOI: 10.1111/j.1442-2050.2008.00881.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
It remains unclear whether the overall survival (OS) of patients with localized esophageal adenocarcinoma (LEA) with Barrett's esophagus (BE) (Barrett's-positive) and those with LEA without BE (Barrett's-negative) following preoperative chemoradiation is different. Based on the published differences in the molecular biology of the two entities, we hypothesized that the two groups will have a different clinical biology (and OS). In this retrospective analysis, all patients with LEA had surgery following preoperative chemoradiation. Apart from age, gender, baseline clinical stage, location, class of cytotoxics, post-therapy stage, and OS, LEAs were divided up into Barrett's-positive and Barrett's-negative groups based on histologic documentation of BE. The Kaplan-Meier and Cox regression analytic methods were used. We analyzed 362 patients with LEA (137 Barrett's-positive and 225 Barrett's-negative). A higher proportion of Barrett's-positive patients had (EUS)T2 cancers (27%) than those with Barrett's-negative cancer (17%). More Barrett's-negative LEAs involved gastroesophageal junction than Barrett's-positive ones (P = 0.001). The OS was significantly shorter for Barrett's-positive patients than that for Barrett's-negative patients (32 months vs. 51 months; P = 0.04). In a multivariate analysis for OS, Barrett's-positive LEA (P = 0.006), old age (P = 0.016), baseline positive nodes (P = 0.005), more than 2 positive (yp)N (P = 0.0001), higher (yp)T (P = 0.003), and the use of a taxane (0.04) were the independent prognosticators. Our data demonstrate that the clinical biology (reflected in OS) is less favorable for patients with Barrett's-positive LEA than for patients with Barrett's-negative LEA. Our intriguing findings need confirmation followed by in-depth molecular study to explain these differences.
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Affiliation(s)
- P Cen
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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21
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Garg M, Kanojia D, Khosla A, Dudha N, Sati S, Chaurasiya D, Jagadish N, Seth A, Kumar R, Gupta S, Gupta A, Lohiya NK, Suri A. Sperm-associated antigen 9 is associated with tumor growth, migration, and invasion in renal cell carcinoma. Cancer Res 2008; 68:8240-8. [PMID: 18922895 DOI: 10.1158/0008-5472.can-08-1708] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Renal cell carcinoma (RCC) represents one of the most resistant tumors to radiation and chemotherapy. Current therapies for RCC patients are inefficient due to the lack of diagnostic and therapeutic markers. Our recent studies have suggested an association of sperm-associated antigen 9 (SPAG9) with ovarian carcinomas. In the present study, we investigated the clinical relevance of SPAG9 in RCC patients. RT-PCR analysis showed expression of SPAG9 transcript in RCC tissues and RCC cell lines. In situ RNA hybridization and immunohistochemistry analyses confirmed the expression of SPAG9 in 88% of cancer patients, suggesting that SPAG9 participates in renal cancer. In addition, immunoblotting and ELISA analyses revealed a humoral immune response against SPAG9 in the sera of RCC patients but not in healthy individuals. Consistent with the clinical findings, knockdown of SPAG9 expression in RCC cells with specific siRNA significantly reduced cell growth and colony formation. Using in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also significantly inhibited. Furthermore, in vivo xenograft studies in nude mice revealed that administration of a SPAG9 siRNA plasmid significantly inhibited tumor growth. In conclusion, SPAG9 expression is associated with clinicopathologic features of tumors, suggesting that SPAG9 could contribute to the early spread of cancer. These results indicate that SPAG9 may have a role in tumor development and metastasis and thus could serve as a novel target for early detection and treatment of RCC.
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Affiliation(s)
- Manoj Garg
- Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, All India Institute of Medical Sciences, Research and Referral, New Delhi, India
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22
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Tischoff I, Tannapfel A. Barrett's esophagus: can biomarkers predict progression to malignancy? Expert Rev Gastroenterol Hepatol 2008; 2:653-63. [PMID: 19072343 DOI: 10.1586/17474124.2.5.653] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Barrett's esophagus (BE) is one of the most common premalignant lesions and can progress to esophageal adenocarcinoma. It is characterized histologically by a specialized intestinal metaplasia that replaces the squamous epithelium of the distal esophagus, and is associated with chronic gastroesophageal reflux disease and obesity. Similar to the adenoma-carcinoma sequence of colorectal carcinomas, esophageal adenocarcinoma develops through progression from BE to low- and high-grade dysplasia, then to adenocarcinoma with accumulation of genetic and epigenetic abnormalities. The exact malignancy potential of BE is uncertain. Dysplasia is the most predictive marker for risk of esophageal adenocarcinoma, whereas endoscopic and histological diagnoses are still the gold standard for surveillance of patients with BE. However, both are limited, either by sampling errors in biopsies or by differences in histological interpretation. Several studies have identified candidate biomarkers that may have predictive value and may serve as additional factors for the risk assessment of esophageal adenocarcinoma. This review discusses the role of biomarkers in the progression from BE to adenocarcinoma, focusing on clinical and molecular markers.
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Affiliation(s)
- Iris Tischoff
- Institute of Pathology, Ruhr-University of Bochum, Bürkle-de-la-Camp-Platz, Bochum 44789, Germany.
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23
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Lagarde SM, Ver Loren van Themaat PE, Moerland PD, Gilhuijs-Pederson LA, Ten Kate FJW, Reitsma PH, van Kampen AHC, Zwinderman AH, Baas F, van Lanschot JJB. Analysis of gene expression identifies differentially expressed genes and pathways associated with lymphatic dissemination in patients with adenocarcinoma of the esophagus. Ann Surg Oncol 2008; 15:3459-70. [PMID: 18825457 DOI: 10.1245/s10434-008-0165-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2008] [Revised: 08/22/2008] [Accepted: 08/23/2008] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The presence of lymphatic dissemination is an important predictor of survival in esophageal adenocarcinoma (EA). The aim of this study was to discover a prognostic gene expression profile for lymphatic dissemination in EA and to identify genes and pathways that provide oncological insight in lymphatic dissemination. METHODS Patients who had lymphatic dissemination (N = 55) were compared with patients without lymphatic dissemination (N = 22). Whole-genome oligonucleotide microarrays were used to evaluate the genetic signature of 77 esophageal cancers. Multiple random validation was used to analyze the stability of the molecular signature and predictive power. Gene set enrichment analysis (GSEA) was applied to elucidate oncogenetic pathways. RESULTS Lymphatic dissemination was correctly predicted in 75 +/- 14% of lymph node positive patients. The absence of lymphatic dissemination was correctly predicted in 41 +/- 23% of lymph-node-negative patients. Argininosuccinate synthetase (ASS) was selected for validation on the protein level because it was present in most prognostic signatures as well as the list of differentially expressed genes. ASS expression was lower (P = 0.048) in patients with lymphatic dissemination than in patients without. GSEA identified that arginine metabolism pathways and lipid metabolism pathways are related to less chance of developing lymphatic dissemination. DISCUSSION The predictive profile does not outperform current clinical practice to predict the presence of lymphatic dissemination in patients with EA. Several genes, including ASS, and genetic pathways which are important in the development of lymphatic dissemination in EA, were identified.
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Affiliation(s)
- S M Lagarde
- Department of Surgery, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands.
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24
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Schauer M, Stein H, Lordick F, Feith M, Theisen J, Siewert JR. Results of a Multimodal Therapy in Patients with Stage IV Barrett’s Adenocarcinoma. World J Surg 2008; 32:2655-60. [DOI: 10.1007/s00268-008-9722-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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25
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Abstract
Gene chip methods are applied to the study of gene expression. The differentially expressed genes in different specimens may be detected with parallel analysis by gene chip, which has greatly improved the traditional experiments in that only a single or several gene expressions need to be observed for each test, thereby speeding up the identification of differentially expressed genes and the construction of differential expression profiles. Many studies have applied this technology for Barrett's metaplasia and adenocarcinoma, and identified a number of candidate genes useful as biomarkers in cancer staging, prediction of recurrence, prognosis and treatment selection. This review described the gene expression profile and molecular changes related to Barrett's metaplasia and adenocarcinoma of the esophagus, with emphasis on its prognostic value and possibilities for targeted therapy in a clinical setting.
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Affiliation(s)
- Xing Wei Wang
- Gastroenterology Research Center, South-west Hospital, The Third Military Medical University, Chongqing, China
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26
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Breton J, Gage MC, Hay AW, Keen JN, Wild CP, Donnellan C, Findlay JBC, Hardie LJ. Proteomic screening of a cell line model of esophageal carcinogenesis identifies cathepsin D and aldo-keto reductase 1C2 and 1B10 dysregulation in Barrett's esophagus and esophageal adenocarcinoma. J Proteome Res 2008; 7:1953-62. [PMID: 18396902 DOI: 10.1021/pr7007835] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Esophageal adenocarcinoma (EA) incidence is increasing rapidly and is associated with a poor prognosis. Identifying biomarkers of disease development and progression would be invaluable tools to inform clinical practice. Two-dimensional polyacrylamide gel electrophoresis was used to screen 10 esophageal cell lines representing distinct stages in the development of esophageal cancer. Thirty-three proteins were identified by MALDI-TOF-MS which demonstrated differences in expression across the cell lines. Western blotting and qRT-PCR confirmed increased cathepsin D and aldo-keto reductases 1C2 and 1B10 expression in metaplastic and dysplastic cell lines. Expression of these proteins was further assessed in esophageal epithelium from patients with nonerosive (NERD) and erosive gastro-esophageal reflux disease, Barrett's esophagus (BE) and EA. When compared with normal epithelium of NERD patients, (i) cathepsin D mRNA levels demonstrated a stepwise increase in expression (p<0.05) in erosive, metaplastic and EA tissue; (ii) AKR1B10 expression increased (p<0.05) 3- and 9-fold in erosive and Barrett's epithelium, respectively; and (iii) AKR1C2 levels increased (p<0.05) in erosive and Barrett's epithelium, but were reduced (p<0.05) in EA. These proteins may contribute to disease development via effects on apoptosis, transport of bile acids and retinoid metabolism and should be considered as candidates for further mechanistic and clinical investigations.
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Affiliation(s)
- Jean Breton
- Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, University of Leeds, Leeds LS2 9JT, United Kingdom
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27
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Kaiser S, Park YK, Franklin JL, Halberg RB, Yu M, Jessen WJ, Freudenberg J, Chen X, Haigis K, Jegga AG, Kong S, Sakthivel B, Xu H, Reichling T, Azhar M, Boivin GP, Roberts RB, Bissahoyo AC, Gonzales F, Bloom GC, Eschrich S, Carter SL, Aronow JE, Kleimeyer J, Kleimeyer M, Ramaswamy V, Settle SH, Boone B, Levy S, Graff JM, Doetschman T, Groden J, Dove WF, Threadgill DW, Yeatman TJ, Coffey RJ, Aronow BJ. Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biol 2008; 8:R131. [PMID: 17615082 PMCID: PMC2323222 DOI: 10.1186/gb-2007-8-7-r131] [Citation(s) in RCA: 285] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2006] [Revised: 02/12/2007] [Accepted: 07/05/2007] [Indexed: 12/27/2022] Open
Abstract
Colon tumors from four independent mouse models and 100 human colorectal cancers all exhibited striking recapitulation of embryonic colon gene expression from embryonic days 13.5-18.5. Background The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. Results We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear β-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF). Conclusion Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.
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Affiliation(s)
- Sergio Kaiser
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Young-Kyu Park
- Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Jeffrey L Franklin
- Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Richard B Halberg
- McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA
| | - Ming Yu
- Department of Genetics and Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Walter J Jessen
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Johannes Freudenberg
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Xiaodi Chen
- McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA
| | - Kevin Haigis
- Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Anil G Jegga
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Sue Kong
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Bhuvaneswari Sakthivel
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Huan Xu
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Timothy Reichling
- Division of Human Cancer Genetics, The Ohio State University College of Medicine, Columbus, Ohio 43210-2207, USA
| | - Mohammad Azhar
- Institute for Collaborative BioResearch, University of Arizona, Tucson, AZ 85721-0036, USA
| | - Gregory P Boivin
- University of Cincinnati, Department of Pathology and Laboratory Medicine, Cincinnati, OH 45267, USA
| | - Reade B Roberts
- Department of Genetics and Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Anika C Bissahoyo
- Department of Genetics and Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Fausto Gonzales
- H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Greg C Bloom
- H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Steven Eschrich
- H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Scott L Carter
- Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology (CHIP@HST), Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Jeremy E Aronow
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - John Kleimeyer
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Michael Kleimeyer
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Vivek Ramaswamy
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Stephen H Settle
- Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Braden Boone
- Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Shawn Levy
- Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Jonathan M Graff
- University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Thomas Doetschman
- Institute for Collaborative BioResearch, University of Arizona, Tucson, AZ 85721-0036, USA
| | - Joanna Groden
- Division of Human Cancer Genetics, The Ohio State University College of Medicine, Columbus, Ohio 43210-2207, USA
| | - William F Dove
- McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA
| | - David W Threadgill
- Department of Genetics and Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Timothy J Yeatman
- H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Robert J Coffey
- Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Bruce J Aronow
- Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
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Madhavan J, Ganesh A, Roy J, Biswas J, Kumaramanickavel G. The relationship between tumor cell differentiation and age at diagnosis in retinoblastoma. J Pediatr Ophthalmol Strabismus 2008; 45:22-5. [PMID: 18286958 DOI: 10.3928/01913913-20080101-16] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
PURPOSE To determine the relationship between tumor cell differentiation and age at diagnosis in retinoblastoma. METHODS Medical records of 170 patients with retinoblastoma treated by enucleation were reviewed retrospectively. Age at diagnosis and histopathological features were analyzed. RESULTS Well-differentiated tumors presented earlier than poorly differentiated tumors. The frequency of presentation was highest in the first year of age for well-differentiated tumors and in the third year of age for poorly differentiated tumors (P < .0001). Bilateral well-differentiated tumors presented earlier than bilateral poorly differentiated tumors. Similarly, unilateral well-differentiated tumors presented earlier than unilateral poorly differentiated tumors. CONCLUSIONS Differentiated tumors present earlier than poorly differentiated tumors, irrespective of laterality in retinoblastoma.
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Affiliation(s)
- Jagadeesan Madhavan
- SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India
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Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M, Swanson SJ, Godfrey TE, Litle VR. MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg 2007; 135:255-60; discussion 260. [PMID: 18242245 DOI: 10.1016/j.jtcvs.2007.08.055] [Citation(s) in RCA: 301] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Revised: 08/12/2007] [Accepted: 08/15/2007] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Expression of microRNAs by array analysis provides unique profiles for classifying tissues and tumors. The purpose of our study was to examine microRNA expression in Barrett esophagus and esophageal cancer to identify potential markers for disease progression. METHODS MicroRNA was isolated from 35 frozen specimens (10 adenocarcinoma, 10 squamous cell carcinoma, 9 normal epithelium, 5 Barrett esophagus, and 1 high-grade dysplasia). MicroRNA expression was analyzed with Ambion bioarrays (Ambion, Austin, Tex) containing 328 human microRNA probes. RESULTS Unsupervised hierarchic clustering resulted in four major branches corresponding with four histologic groups. One branch consisted of 7 normal epithelium samples and 1 squamous cell carcinoma sample. The second branch consisted of 7 squamous cell carcinoma samples and 1 normal epithelium sample. The third branch contained 4 Barrett esophagus samples and 1 squamous cell carcinoma sample. The fourth contained all the adenocarcinoma samples and 1 sample each of Barrett esophagus, normal epithelium, squamous cell carcinoma, and high-grade dysplasia. Supervised classification with principal component analysis determined that the normal epithelium samples were more similar to the squamous cell carcinoma tumors, whereas the Barrett esophagus samples were more similar to adenocarcinoma. Pairwise comparisons between sample types revealed microRNAs that may be markers of tumor progression. Both mir_203 and mir_205 were expressed 2- to 10-fold lower in squamous cell carcinoma and adenocarcinomas than in normal epithelium. The mir_21 expression was 3- to 5-fold higher in both tumors than in normal epithelium. Prediction analysis of microarray classified 3 Barrett esophagus samples as Barrett esophagus, 1 as adenocarcinoma, and 1 as normal epithelium. CONCLUSION Expression profiles of miRNA distinguish esophageal tumor histology and can discriminate normal tissue from tumor. MicroRNA expression may prove useful for identifying patients with Barrett esophagus at high risk for progression to adenocarcinoma.
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Affiliation(s)
- Andrew Feber
- Department of Pathology, Mount Sinai Medical Center, New York, NY 10029, USA
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Abstract
Barrett's oesophagus is a frequent complication of gastro-oesophageal reflux disease predicting oesophageal adenocarcinoma. The majority of Barrett's patients will not develop cancer, so that specific methods of identification of those at risk are required. Recent molecular studies have identified a selection of candidate biomarkers that need validation in prospective studies. They reflect various changes in cell behaviour during neoplastic progression. The ASPECT trial in the UK aims to establish whether chemoprevention with aspirin and a proton pump inhibitor will reduce adenocarcinoma development and mortality in patients with Barrett's oesophagus. It will also validate biomarkers for progression and clinical response and further study disease pathogenesis.
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Affiliation(s)
- Edyta Zagorowicz
- Department of Gastroenterology, Institute of Oncology, Warsaw, Poland
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Hennig EE, Mikula M, Orlowska J, Jarosz D, Bielasik A, Regula J, Ostrowski J. Large intra- and inter-individual variability of genes expression levels limits potential predictive value of molecular diagnosis of dysplasia in Barrett's esophagus. J Mol Med (Berl) 2007; 86:233-42. [PMID: 17952395 DOI: 10.1007/s00109-007-0271-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2007] [Revised: 09/03/2007] [Accepted: 09/19/2007] [Indexed: 12/18/2022]
Abstract
Barrett's esophagus represents a well-defined precursor lesion of esophageal adenocarcinoma, although only a subset of patients with these lesions advances to invasive cancer. Currently, reliable markers predicting neoplastic progression in Barrett's esophagus are lacking. The only clinically useful risk factor is the presence of dysplasia in Barrett's epithelium, but its use as a prognostic marker of disease progression has several significant limitations. Thus, identification of biomarkers of potential prognostic value in dysplasia development in Barrett's esophagus is highly important. The aim of the study was to determine if expression levels of selected genes support histologic diagnosis of dysplastic changes in Barrett's esophagus. Upon rigorous sampling and independent histopathologic examination of endoscopic specimens by two experienced gastrointestinal pathologists, 56 patients with Barrett's esophagus (16 negative for dysplasia, 15 with indefinite, 21 with low-grade, and 4 with high-grade dysplasia) were selected for molecular analysis. The relative mRNA levels of ten selected genes were estimated by quantitative real-time polymerase chain reaction (PCR) analysis. Although expression of nine genes showed trends toward down- or upregulation during progression from Barrett's esophagus without dysplasia to Barrett's esophagus with high-grade dysplasia, only a decrease in S100A2 mRNA levels was statistically significant (P<0.05). However, there was considerable variation among individuals and significant overlapping of ranges. Furthermore, detailed, comparative analysis of serial samples from Barrett's mucosa and normal squamous epithelium shows large intra-individual variability of gene expression levels. In conclusion, expression of this set of ten genes cannot be used as a molecular marker aiding histological examination of dysplasia in Barrett's esophagus. Significant inter- and intra-patient variations of gene expression levels makes use of the selected genes impractical.
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Affiliation(s)
- Ewa E Hennig
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
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Garg M, Chaurasiya D, Rana R, Jagadish N, Kanojia D, Dudha N, Kamran N, Salhan S, Bhatnagar A, Suri S, Gupta A, Suri A. Sperm-associated antigen 9, a novel cancer testis antigen, is a potential target for immunotherapy in epithelial ovarian cancer. Clin Cancer Res 2007; 13:1421-8. [PMID: 17332284 DOI: 10.1158/1078-0432.ccr-06-2340] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE Cancer testis antigens are a group of tumor antigens with gene expression restricted to male germ cells in the testis and in various cancerous tissues. Recently, we reported a novel testis-specific sperm-associated antigen 9 (SPAG9) gene, a new member of the c-Jun NH(2)-terminal kinase-interacting protein family, having functional role in sperm-egg fusion and mitogen-activated protein kinase signaling pathway. National Center for Biotechnology Information Blast searches revealed SPAG9 nucleotide sequence similarities with expressed sequence tags of various cancerous tissues. In an effort to examine the clinical utility of SPAG9, we investigated the SPAG9 mRNA and protein expression in epithelial ovarian cancer (EOC). Humoral immune response to SPAG9 was also evaluated in EOC patients. EXPERIMENTAL DESIGN We determined the expression profile of SPAG9 transcript by reverse transcription-PCR and RNA in situ hybridization and SPAG9 protein expression by immunohistochemistry in EOC specimens and human ovarian cancer cell lines. Using ELISA and Western blotting, we analyzed specific antibodies for SPAG9 in sera from patients with EOC. RESULTS SPAG9 mRNA and protein expression was detected in 90% of EOC tissues and in all three human ovarian cancer cell lines. Specific SPAG9 antibodies were detected in 67% of EOC patients and not in sera from healthy individuals. CONCLUSIONS Our findings indicate that SPAG9 is highly expressed in EOC and immunogenic in patients. Humoral immune response against SPAG9 in early stages of EOC suggests its important role in early diagnostics. These results collectively suggest that SPAG9, a novel member of cancer testis antigen family, could be a potential target for the development of diagnostic and therapeutic methods in EOC.
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MESH Headings
- Adaptor Proteins, Signal Transducing/immunology
- Adaptor Proteins, Signal Transducing/metabolism
- Antibodies, Neoplasm/blood
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/analysis
- Blotting, Western
- Cell Line, Tumor
- Enzyme-Linked Immunosorbent Assay
- Female
- Flow Cytometry
- Gene Expression
- Gene Expression Profiling
- Humans
- Immunohistochemistry
- Immunotherapy
- In Situ Hybridization
- Neoplasms, Glandular and Epithelial/blood
- Neoplasms, Glandular and Epithelial/immunology
- Neoplasms, Glandular and Epithelial/metabolism
- Ovarian Neoplasms/blood
- Ovarian Neoplasms/immunology
- Ovarian Neoplasms/metabolism
- RNA, Messenger/analysis
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Manoj Garg
- Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India
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Greenawalt DM, Duong C, Smyth GK, Ciavarella ML, Thompson NJ, Tiang T, Murray WK, Thomas RJS, Phillips WA. Gene expression profiling of esophageal cancer: Comparative analysis of Barrett's esophagus, adenocarcinoma, and squamous cell carcinoma. Int J Cancer 2007; 120:1914-21. [PMID: 17236199 DOI: 10.1002/ijc.22501] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Esophageal cancer is a particularly aggressive tumor with poor prognosis, however, our current knowledge of the genes and pathways involved in tumorigenesis of the esophagus are limited. To obtain insight into the molecular processes underlying tumorigenesis of the esophagus, we have used cDNA microarrays to compare the gene expression profiles of 128 tissue samples representing the major histological subtypes of esophageal cancer (squamous cell carcinoma and adenocarcinoma (ADC)) as well as Barrett's esophagus (BE), the precursor lesion to ADC, and normal esophageal epithelium. Linear discriminant analysis and unsupervised hierarchical clustering show the separation of samples into 4 distinct groups consistent with their histological subtype. Differentially expressed genes were identified between each of the tissue types. Comparison of gene ontologies and gene expression profiles identified gene profiles specific to esophageal cancer, as well as BE. "Esophageal cancer clusters," representing proliferation, immune response, and extracellular matrix genes were identified, as well as digestion, hydrolase, and transcription factor clusters specific to the columnar phenotype observed during BE and esophageal ADC. These clusters provide valuable insight into the molecular and functional differences between normal esophageal epithelium, BE, and the 2 histologically distinct forms of esophageal cancers. Our thorough, unbiased analysis provides a rich source of data for further studies into the molecular basis of tumorigenesis of the esophagus, as well as identification of potential biomarkers for early detection of progression.
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Affiliation(s)
- Danielle M Greenawalt
- Division of Surgical Oncology, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Vic, Australia
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Chattopadhyay I, Kapur S, Purkayastha J, Phukan R, Kataki A, Mahanta J, Saxena S. Gene expression profile of esophageal cancer in North East India by cDNA microarray analysis. World J Gastroenterol 2007; 13:1438-44. [PMID: 17457978 PMCID: PMC4146931 DOI: 10.3748/wjg.v13.i9.1438] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2006] [Revised: 12/29/2006] [Accepted: 01/26/2007] [Indexed: 02/07/2023] Open
Abstract
AIM To identify alterations in genes and molecular functional pathways in esophageal cancer in a high incidence region of India where there is a widespread use of tobacco and betel quid with fermented areca nuts. METHODS Total RNA was isolated from tumor and matched normal tissue of 16 patients with esophageal squamous cell carcinoma. Pooled tumor tissue RNA was labeled with Cy3-dUTP and pooled normal tissue RNA was labeled with Cy5-dUTP by direct labeling method. The labeled probes were hybridized with human 10K cDNA chip and expression profiles were analyzed by Genespring GX V 7.3 (Silicon Genetics). RESULTS Nine hundred twenty three genes were differentially expressed. Of these, 611 genes were upregulated and 312 genes were downregulated. Using stringent criteria (P < or = 0.05 and > or = 1.5 fold change), 127 differentially expressed genes (87 upregulated and 40 downregulated) were identified in tumor tissue. On the basis of Gene Ontology, four different molecular functional pathways (MAPK pathway, G-protein coupled receptor family, ion transport activity, and serine or threonine kinase activity) were most significantly upregulated and six different molecular functional pathways (structural constituent of ribosome, endopeptidase inhibitor activity, structural constituent of cytoskeleton, antioxidant activity, acyl group transferase activity, eukaryotic translation elongation factor activity) were most significantly downregulated. CONCLUSION Several genes that showed alterations in our study have also been reported from a high incidence area of esophageal cancer in China. This indicates that molecular profiles of esophageal cancer in these two different geographic locations are highly consistent.
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Affiliation(s)
- Indranil Chattopadhyay
- Institute of Pathology, Indian Council of Medical Research, Safdarjang Hospital Campus, Post Box No. 4909, New Delhi 110029, India
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Jensen EH, McLoughlin JM, Yeatman TJ. Microarrays in gastrointestinal cancer: is personalized prediction of response to chemotherapy at hand? Curr Opin Oncol 2006; 18:374-80. [PMID: 16721134 DOI: 10.1097/01.cco.0000228745.56918.0f] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Molecular profiling has proven to be an invaluable tool in cancer research. Although only in its infancy, microarray technology and gene arrays have led to substantial advances in tumor identification, staging and prediction of response. This review outlines some of the more recent advances in the use of microarrays as a novel means to advance the standard of care for patients with gastrointestinal cancers. RECENT FINDINGS Recent investigations have shown that gene expression profiles can be used to identify, stage, and guide therapeutic intervention in many gastrointestinal cancers. In cases of unknown primary disease, genetic fingerprints can be used to define the origin of the tumor in the majority of cases. Similarly, gene expression has been shown to allow for more accurate staging of patients with a variety of tumor types. Perhaps most exciting is early data that support the potential for microarray to guide therapeutic intervention by providing specific gene fingerprints which correlate with sensitivity to specific chemotherapy, biologic therapy, or other cancer treatments. SUMMARY Gene microarrays have become a powerful resource in cancer investigations. Individualized cancer care based on specific gene profiles is on the horizon for patients with gastrointestinal cancers.
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Affiliation(s)
- Eric H Jensen
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
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Suri A. Cancer testis antigens--their importance in immunotherapy and in the early detection of cancer. Expert Opin Biol Ther 2006; 6:379-89. [PMID: 16548764 DOI: 10.1517/14712598.6.4.379] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The development of successful immunotherapeutic strategies requires the identification and characterisation of immunogenic cancer antigens that will be recognised by the host immune system, leading to tumour rejection. The concept of immunotherapy is based on the assumption that antigenic structures expressed in tumours can be used for therapeutic approaches employing the autologous immune system or by the application of immunotherapeutic reagents. Based on this concept, there is a great need to gain profound knowledge of the actual protein/antigen expression and its distribution pattern within normal tissues and cancerous tissues. Cancer testis (CT) antigens represent a unique class of tumour antigens, which are expressed in a variety of cancerous tissues and are silent in normal tissues, except for the testis. Owing to their restricted gene expression in the testis and various malignancies, CT antigens represent potential defined targets for antigen-based vaccination and antigen-directed immunotherapy to control cancer growth. Moreover, the analysis of humoral and cellular immune responses to CT antigens has proved useful for identifying novel cancer serum biomarkers with potential implications in early diagnosis of cancer.
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Affiliation(s)
- Anil Suri
- National Institute of Immunology, Genes and Proteins Laboratory, Aruna Asaf Ali Marg, New Delhi-110067, India.
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Rana R, Jagadish N, Garg M, Mishra D, Dahiya N, Chaurasiya D, Suri A. Small interference RNA-mediated knockdown of sperm associated antigen 9 having structural homology with c-Jun N-terminal kinase-interacting protein. Biochem Biophys Res Commun 2005; 340:158-64. [PMID: 16356479 PMCID: PMC7092841 DOI: 10.1016/j.bbrc.2005.11.168] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2005] [Accepted: 11/23/2005] [Indexed: 01/21/2023]
Abstract
Recently, we reported a novel testis-specific sperm associated antigen 9 (SPAG9) protein, a new member of the JNK-interacting protein family, having a functional role in sperm-egg fusion [N. Jagadish, R. Rana, R. Selvi, D. Mishra, M. Garg, S. Yadav, J.C. Herr, K. Okumura, A. Hasegawa, K. Koyama, A. Suri, Biochem. J. 389 (2005) 73-82]. NCBI Blast searches revealed SPAG9 nucleotide sequence similarities with ESTs of various cancerous tissues. In the present study, we compared the efficiency of two independent SPAG9 specific small interfering RNA (siRNA) constructs, BS/U6/spag9 and BS/U6/spag9-I, to ablate the SPAG9 expression in mammalian cells. A positive correlation between the ratio of target gene versus siRNA and the suppression of SPAG9 expression was observed. Further, the cotransfection of BS/U6/spag9 with pcDNA-SPAG9 and pFlag-CMV2-JNK-3 resulted in specific suppression of SPAG9 without affecting JNK-3 expression. The present investigation will eventually extend the application of SPAG9 siRNA in in vivo targeting experiments that aim to define the SPAG9 functional genomics in tumor and reproductive biology.
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Affiliation(s)
- Ritu Rana
- Genes and Proteins Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, J.N.U. Campus, New Delhi-110 067, India
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