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Xin S, Wei G. Correlation of vascular endothelial growth factor with survival and pathological characteristics of patients with osteosarcoma: A systematic review and meta-analysis. Eur J Cancer Care (Engl) 2022; 31:e13629. [PMID: 35707976 DOI: 10.1111/ecc.13629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/24/2021] [Accepted: 03/18/2021] [Indexed: 11/03/2022]
Abstract
OBJECTIVE This study aimed to assess the prognostic role of vascular endothelial growth factor (VEGF) expression in osteosarcoma. METHODS Systematic searches of PubMed, Embase, CINAHL, Cochrane Library, ScienceDirect, and Web of Science were conducted. The correlation between VEGF expression and patients' survival was our primary endpoint. The secondary endpoints were the associations between VEGF level and patients' sociodemographic and pathological characteristics. The pooled hazard ratio (HR) or odd ratio (OR) and corresponding 95% confidence intervals (CIs) were obtained to assess the associations between VEGF expression and the target factors. Subgroup and meta-regression analyses were conducted to explore potential factors that associated with VEGF efficacy. RESULTS The combined HR suggested that a positive VEGF status has a negative impact on overall survival (OS) (HR = 2.58; 95% CI, 2.09-3.19; P < 0.0001) and disease-free survival (DFS) (HR = 2.54; 95% CI, 1.84-3.50; P < 0.0001) in patients with osteosarcoma. Meta-regression analysis ruled out the influence of cut-off value, disease stage, histological subtype, disease grade, tumour location, geographic area, publication year, and method of HR acquisition on heterogeneity. Results showed that VEGF expression was closely correlated with tumour staging, chemotherapy response, and metastasis. CONCLUSION Based on the study results, VEGF could serve as an effective biomarker of prognosis in patients with osteosarcoma. Besides, VEGF was related to increased tumour malignancy, which might help guide clinical decision-making regarding therapy and outcomes.
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Affiliation(s)
- Sun Xin
- Orthopedic Oncology, Peking University People's Hospital, Beijing, China
| | - Guo Wei
- Orthopedic Oncology, Peking University People's Hospital, Beijing, China
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2
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Zhao X, Huang Q, Koller M, Linssen MD, Hooghiemstra WTR, de Jongh SJ, van Vugt MATM, Fehrmann RSN, Li E, Nagengast WB. Identification and Validation of Esophageal Squamous Cell Carcinoma Targets for Fluorescence Molecular Endoscopy. Int J Mol Sci 2021; 22:9270. [PMID: 34502178 PMCID: PMC8431213 DOI: 10.3390/ijms22179270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 02/05/2023] Open
Abstract
Dysplasia and intramucosal esophageal squamous cell carcinoma (ESCC) frequently go unnoticed with white-light endoscopy and, therefore, progress to invasive tumors. If suitable targets are available, fluorescence molecular endoscopy might be promising to improve early detection. Microarray expression data of patient-derived normal esophagus (n = 120) and ESCC samples (n = 118) were analyzed by functional genomic mRNA (FGmRNA) profiling to predict target upregulation on protein levels. The predicted top 60 upregulated genes were prioritized based on literature and immunohistochemistry (IHC) validation to select the most promising targets for fluorescent imaging. By IHC, GLUT1 showed significantly higher expression in ESCC tissue (30 patients) compared to the normal esophagus adjacent to the tumor (27 patients) (p < 0.001). Ex vivo imaging of GLUT1 with the 2-DG 800CW tracer showed that the mean fluorescence intensity in ESCC (n = 17) and high-grade dysplasia (HGD, n = 13) is higher (p < 0.05) compared to that in low-grade dysplasia (LGD) (n = 7) and to the normal esophagus adjacent to the tumor (n = 5). The sensitivity and specificity of 2-DG 800CW to detect HGD and ESCC is 80% and 83%, respectively (ROC = 0.85). We identified and validated GLUT1 as a promising molecular imaging target and demonstrated that fluorescent imaging after topical application of 2-DG 800CW can differentiate HGD and ESCC from LGD and normal esophagus.
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Affiliation(s)
- Xiaojuan Zhao
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (X.Z.); (M.A.T.M.v.V.); (R.S.N.F.)
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (M.D.L.); (W.T.R.H.); (S.J.d.J.)
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China; (Q.H.); (E.L.)
| | - Qingfeng Huang
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China; (Q.H.); (E.L.)
| | - Marjory Koller
- Department of Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands;
| | - Matthijs D. Linssen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (M.D.L.); (W.T.R.H.); (S.J.d.J.)
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Wouter T. R. Hooghiemstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (M.D.L.); (W.T.R.H.); (S.J.d.J.)
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
| | - Steven J. de Jongh
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (M.D.L.); (W.T.R.H.); (S.J.d.J.)
| | - Marcel A. T. M. van Vugt
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (X.Z.); (M.A.T.M.v.V.); (R.S.N.F.)
| | - Rudolf S. N. Fehrmann
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (X.Z.); (M.A.T.M.v.V.); (R.S.N.F.)
| | - Enmin Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China; (Q.H.); (E.L.)
| | - Wouter B. Nagengast
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (M.D.L.); (W.T.R.H.); (S.J.d.J.)
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Kim GC, Lee CG, Verma R, Rudra D, Kim T, Kang K, Nam JH, Kim Y, Im SH, Kwon HK. ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes. Front Oncol 2020; 10:642. [PMID: 32477936 PMCID: PMC7239993 DOI: 10.3389/fonc.2020.00642] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 04/06/2020] [Indexed: 01/18/2023] Open
Abstract
ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1high BRCA patients showed better prognosis and longer survival compared to ETS1low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.
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Affiliation(s)
- Gi-Cheon Kim
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea.,Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - Choong-Gu Lee
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, South Korea
| | - Ravi Verma
- Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, South Korea
| | - Dipayan Rudra
- Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, South Korea
| | - Taemook Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Keunsoo Kang
- Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, South Korea
| | - Jong Hee Nam
- Department of Pathology, Chonnam National University Medical School, Gwangju, South Korea
| | - Young Kim
- Department of Oral Pathology, School of Dentistry, Chonnam National University, Gwangju, South Korea
| | - Sin-Hyeog Im
- Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, South Korea.,Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
| | - Ho-Keun Kwon
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea.,Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
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Chen X, Lv Z, Zhang C, Wang X, Zhao Y, Wang X, Zheng Y. Retracted Article: Panax notoginseng saponins regulate VEGF to suppress esophageal squamous cell carcinoma progression via DVL3-mediated Wnt/β-catenin signaling. RSC Adv 2020; 10:3256-3265. [PMID: 35497711 PMCID: PMC9048998 DOI: 10.1039/c9ra07830d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022] Open
Abstract
PNS regulate VEGF expression to suppress ESCC progression via the DVL3-mediated Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Xiaoqi Chen
- Department of Gastroenterology
- The First Affiliated Hospital of Henan University of CM
- Zhengzhou
- China
| | - Zhuan Lv
- Medical Administration
- The First Affiliated Hospital of Henan University of CM
- China
| | - Chuanlei Zhang
- Department of Gastroenterology
- The First Affiliated Hospital of Henan University of CM
- Zhengzhou
- China
| | - Xinting Wang
- Department of Gastroenterology
- The First Affiliated Hospital of Henan University of CM
- Zhengzhou
- China
| | | | - Xiao Wang
- Department of Gastroenterology
- The First Affiliated Hospital of Henan University of CM
- Zhengzhou
- China
| | - Yuling Zheng
- Guoyitang
- The First Affiliated Hospital of Henan University of CM
- Zhengzhou
- China
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Hu YY, Du XY, Zhan AL, Zhou L, Jiang Q, Niu YM, Shen M. Vascular endothelial growth factor polymorphisms are associated with osteosarcoma susceptibility. Oncotarget 2018; 7:47711-47719. [PMID: 27351225 PMCID: PMC5216973 DOI: 10.18632/oncotarget.10278] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 06/09/2016] [Indexed: 11/25/2022] Open
Abstract
Polymorphisms in the vascular endothelial growth factor (VEGF) gene may contribute to osteosarcoma risk, but the results of previous studies have been inconsistent and inconclusive. We conducted a meta-analysis to assess this association more accurately. Relevant studies were collected systemically from three online English databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations of three VEGF gene polymorphisms (+936C/T, '634 G/C, +1612 G/A) with osteosarcoma risk. Seven case-control studies involving 1,350 cases and 1,706 controls were selected for the meta-analysis. The pooled OR indicated that the VEGF +936C/T polymorphism was associated with increased risk of osteosarcoma in a Chinese population (T vs. C: OR = 1.26, 95% CI = 1.12–1.42, P < 0.01; TT vs. CC: OR = 1.70, 95% CI = 1.29–2.24, P < 0.01; CT + TT vs. CC: OR = 1.23, 95% CI = 1.06–1.44, P < 0.01; TT vs. CC + CT: OR = 1.61, 95% CI = 1.23–2.10, P < 0.01). A significant association was also found between the −634 G/C polymorphism and osteosarcoma risk (C vs. G: OR = 0.81, 95% CI = 0.69-0.96, P = 0.01; CC vs. GG: OR = 0.66, 95% CI = 0.48–0.90, P < 0.01; GC + CC vs. GG: OR = 0.80, 95% CI = 0.67–0.96, P = 0.02; CC vs. GG + GC: OR = 0.72, 95% CI = 0.60–0.86, P < 0.01). In sum, our meta-analysis suggests VEGF polymorphisms are associated with osteosarcoma susceptibility in the Chinese population. However, further studies that include different ethnicities and larger populations are needed.
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Affiliation(s)
- Yuan-Yuan Hu
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Xin-Ya Du
- Department of Stomatology, People's Hospital of New District Longhua Shenzhen, Shenzhen 518109, China
| | - Ai-Ling Zhan
- Department of Anesthesiology, Central Hospital of Shanghai Songjiang District, Shanghai 201600, China
| | - Lan Zhou
- Department of Neurology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Qian Jiang
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Yu-Ming Niu
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China.,Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Ming Shen
- Jiangsu Key Laboratory of Oral Diseases, Department of Dental Implant, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, China
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Wang Y, Zhang C, Zhu H, Tang J, Zhang S, Luo J, Sun X. CD90 positive cells exhibit aggressive radioresistance in esophageal squamous cell carcinoma. J Thorac Dis 2017; 9:610-620. [PMID: 28449469 PMCID: PMC5394075 DOI: 10.21037/jtd.2017.03.28] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 01/20/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) are widely abundant and considered to be an important factor in therapy resistance. They are also promising potential targets for conquering tumors. We explored the effects of radiation on stem cell-like tumor cells via the candidate marker CD90 to provide new ideas for the comprehensive treatment of esophageal squamous cell carcinoma (ESCC). METHODS We constructed CD90 overexpression ESCC cells by lentiviral transfection and observed differences of toxicity, proliferation, clone number, apoptosis, migration, invasion, and in vivo tumor formation after irradiation. RESULTS We found that the population of CD90 positive cells showed CSC-like characteristics, including increased tumorigenicity and migration in ESCC cells. We discovered that these capacities were strengthened to varying degrees in remaining cells after irradiation. Further exploration revealed that the genes of ETS-1 and its downstream target MMPs changed significantly, which are correlated with the epithelial mesenchymal transition (EMT). These effects lead to enhanced tumor growth and resistance to radiation. CONCLUSIONS We show that CD90 overexpressing ESCC cells exhibit CSC-like characteristics and radiation resistance. From a clinical perspective, ESCC patients with tumors that have high CD90 expression, which inhibits apoptosis, could exhibit more local invasion as well as distant metastasis, indicating a poorer prognosis. Research on the mechanism of CD90 may provide a new perspective to therapeutic strategies for patients with ESCC.
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Affiliation(s)
- Yuandong Wang
- Department of Radiation Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Chi Zhang
- Department of Radiation Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Hongcheng Zhu
- Department of Radiation Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Junwei Tang
- Liver Transplantation Center, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Shu Zhang
- Department of Radiation Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Jinhua Luo
- Department of Thoracic Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Xinchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
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Wang R, Ma Y, Yu D, Zhao J, Ma P. miR-377 functions as a tumor suppressor in human clear cell renal cell carcinoma by targeting ETS1. Biomed Pharmacother 2015; 70:64-71. [DOI: 10.1016/j.biopha.2015.01.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 01/04/2015] [Indexed: 12/12/2022] Open
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Li C, Wang Z, Chen Y, Zhou M, Zhang H, Chen R, Shi F, Wang C, Rui Z. Transcriptional silencing of ETS-1 abrogates epithelial-mesenchymal transition resulting in reduced motility of pancreatic cancer cells. Oncol Rep 2014; 33:559-65. [PMID: 25421630 PMCID: PMC4306275 DOI: 10.3892/or.2014.3613] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 10/30/2014] [Indexed: 11/23/2022] Open
Abstract
v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1) plays crucial roles in a spectrum of malignancies. ETS-1 has gained attention in cancer research for its importance in cell migration, invasion and proliferation. In the present study, we focused on the effect of ETS-1 on epithelial-mesenchymal transition (EMT), which is characterized by reduced E-cadherin expression and increased N-cadherin expression. We found that ETS-1 mRNA expression was positively correlated with N-cadherin and negatively correlated with E-cadherin mRNA expression in five pancreatic cancer cell lines. To elucidate the functionality of ETS-1 on EMT in pancreatic cancer cells, we constructed a green fluorescent protein (GFP)-expressing plasmid carrying ETS-1 short hairpin RNA (shRNA), and transfected Panc-1 cells with the plasmid. We detected reduced N-cadherin and vascular endothelial growth factor yet higher E-cadherin expression in the ETS-1-silenced cells compared with the control group. In addition, we observed reduced cell migration and increased adhesion in these cells. Our data showed that ETS-1 actively functioned as a regulator of EMT in Panc-1 cells, and provide additional evidence supporting a fundamental role for ETS-1 in metastatic pancreatic cancer cells. These results suggest that analysis of ETS-1 expression levels may provide an avenue for evaluating prognosis in pancreatic cancer.
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Affiliation(s)
- Chunyan Li
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhonghan Wang
- Department of Internal Medicine, Nanjing Government Hospital, Nanjing, Jiangsu 210009, P.R. China
| | - Yan Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Min Zhou
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Haijun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Rong Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Fangfang Shi
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Cailian Wang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zongdao Rui
- Department of General Surgery, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
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Cytokines association with clinical and pathological changes in esophageal squamous cell carcinoma. DISEASE MARKERS 2014; 35:883-93. [PMID: 24427776 PMCID: PMC3877595 DOI: 10.1155/2013/302862] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Carcinogenic transformation of cells in esophageal squamous cell carcinoma (ESCC) is characterized on molecular level by, among other things, changes in protein expression. Among all proteins related to inflammation, cytokines may be implicated as possible biological markers of esophageal cancer. These biomarkers, near imaging techniques, may be helpful in diagnosis and monitoring therapy in ESCC patients. This review demonstrates findings of researches on dysregulation of cytokines in ESCC and their clinical and pathological implications. Articles on cytokines were selected according to the following criteria: (i) the study was performed at protein level, (ii) the differences in cytokines expression or concentration were detected in tissues or serum from ESCC patients, (iii) the alterations of cytokines levels were detected by: immunohistochemistry (IHC), western blot (WB) and enzyme-linked immunosorbent assay (ELISA). Members of VEGF family seem to play an essential role as potential markers in ESCC. The results of all cytokines researches are promising but further studies are necessary to establish the biological significance of these peptydes in ESCC, their potential usefulness for early diagnosis, pre- and postoperative prognosis and monitoring of the respond to chemo- and radiotherapy of cancer patients.
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Liu Y, Liu Y, Zhang H, Sun C, Zhao Q, Di C, Li H, Gan L, Wang Y. Effects of carbon-ion beam irradiation on the angiogenic response in lung adenocarcinoma A549 cells. Cell Biol Int 2014; 38:1304-10. [PMID: 24942319 DOI: 10.1002/cbin.10327] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 05/17/2014] [Indexed: 11/06/2022]
Abstract
Radiotherapy has been focused mainly on killing cancer cells, and little attention has been paid to the process supporting tumor growth and metastasis, including the process of angiogenesis. To investigate the effects of carbon-ion irradiation on angiogenesis in lung cancer cells, we examined the expression of vascular endothelial growth factor and basic fibroblast growth factor in the tumor conditioned medium (TCM) of A549 cells exposed to carbon-ion or X-ray irradiation, as well as endothelial cell growth, invasion, and tube formation induced by TCM. No changes in vascular endothelial growth factor secretion were detected in the TCM of A549 cells exposed to carbon-ion irradiation at 2 or 4 Gy, whereas 1 Gy of irradiation significantly decreased vascular endothelial growth factor and basic fibroblast growth factor levels. Carbon-ion irradiation at 1 Gy inhibited endothelial cell invasion and tube formation. The TCM from A549 cells irradiated with X-ray promoted angiogenesis, whereas the TCM of A549 cells exposed to carbon-ion irradiation at 2 or 4 Gy had no effect. These findings suggest that carbon-ion irradiation at 1 Gy significantly suppressed the process of angiogenesis in vitro by inhibiting endothelial cell invasion and tube formation, which are related to vascular endothelial growth factor and basic fibroblast growth factor production.
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Affiliation(s)
- Yuanyuan Liu
- Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou, 730000, China
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Tang KH, Dai YD, Tong M, Chan YP, Kwan PS, Fu L, Qin YR, Tsao SW, Lung HL, Lung ML, Tong DK, Law S, Chan KW, Ma S, Guan XY. A CD90(+) tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer. Cancer Res 2013; 73:2322-32. [PMID: 23382045 DOI: 10.1158/0008-5472.can-12-2991] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Tumor-initiating cells (TIC), also known as cancer stem cells, are regarded widely as a specific subpopulation of cells needed for cancer initiation and progression. TICs have yet to be identified in esophageal tumors that have an increasing incidence in developed countries. Here, we report a CD90(+) cell population found in esophageal squamous cell carcinoma (ESCC), which is endowed with stem cell-like properties and high tumorigenic and metastatic potential. mRNA profiling of these cells suggested pathways through which they drive tumor growth and metastasis, with deregulation of an Ets-1/MMP signaling pathway and epithelial-mesenchymal transition figuring prominently. These cells possessed higher self-renewal activity and were sufficient for tumor growth, differentiation, metastasis, and chemotherapeutic resistance. CD90(+) TICs were isolated and characterized from ESCC clinical specimens as well as ESCC cell lines. In freshly resected clinical specimens, they represented a rare cell population, the levels of which correlated with strong family histories and lymph node metastasis. Our results prompt further study of this CD90(+) population of esophageal TICs as potential therapeutic targets.
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MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/secondary
- Cell Adhesion
- Cell Differentiation
- Cell Movement
- Cell Proliferation
- Disease Progression
- Epithelial-Mesenchymal Transition
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Female
- Flow Cytometry
- Gene Expression Profiling
- Humans
- Immunoenzyme Techniques
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/secondary
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/secondary
- Lymphatic Metastasis
- Male
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Middle Aged
- Neoplasm Staging
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- RNA, Messenger/genetics
- RNA, Small Interfering/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Thy-1 Antigens/chemistry
- Thy-1 Antigens/genetics
- Thy-1 Antigens/metabolism
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Affiliation(s)
- Kwan Ho Tang
- Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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Wu BL, Luo LW, Li CQ, Xie JJ, Du ZP, Wu JY, Zhang PX, Xu LY, Li EM. Comprehensive bioinformation analysis of the mRNA profile of fascin knockdown in esophageal squamous cell carcinoma. Asian Pac J Cancer Prev 2013; 14:7221-7. [PMID: 24460279 DOI: 10.7314/apjcp.2013.14.12.7221] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Fascin, an actin-bundling protein forming actin bundles including filopodia and stress fibers, is overexpressed in multiple human epithelial cancers including esophageal squamous cell carcinoma (ESCC). Previously we conducted a microarray experiment to analyze fascin knockdown by RNAi in ESCC. METHOD In this study, the differentially expressed genes from mRNA expression profilomg of fascin knockdown were analyzed by multiple bioinformatics methods for a comprehensive understanding of the role of fascin. RESULTS Gene Ontology enrichment found terms associated with cytoskeleton organization, including cell adhesion, actin filament binding and actin cytoskeleton, which might be related to fascin function. Except GO categories, the differentially expressed genes were annotated by 45 functional categories from the Functional Annotation Chart of DAVID. Subpathway analysis showed thirty-nine pathways were disturbed by the differentially expressed genes, providing more detailed information than traditional pathway enrichment analysis. Two subpathways derivated from regulation of the actin cytoskeleton were shown. Promoter analysis results indicated distinguishing sequence patterns and transcription factors in response to the co-expression of downregulated or upregulated differentially expressed genes. MNB1A, c-ETS, GATA2 and Prrx2 potentially regulate the transcription of the downregulated gene set, while Arnt-Ahr, ZNF42, Ubx and TCF11-MafG might co-regulate the upregulated genes. CONCLUSIONS This multiple bioinformatic analysis helps provide a comprehensive understanding of the roles of fascin after its knockdown in ESCC.
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Affiliation(s)
- Bing-Li Wu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Guangzhou, China E-mail : ,
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Li SY. Molecular targets for prediction of prognosis and treatment response in esophageal squamous cell carcinoma. Shijie Huaren Xiaohua Zazhi 2012; 20:3488-3493. [DOI: 10.11569/wcjd.v20.i35.3488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, molecular targets for prediction of prognosis and chemotherapy efficacy in esophageal squamous cell carcinoma (ESCC) have been increasingly identified, which involve up-regulation of growth signals, down-regulation of inhibitory growth signals, death avoidance, limitless replicative potential, continuous eternal angiogenesis, invasion, and metastasis. Typical molecular targets include mutant p53, vascular endothelial growth factor, epidermal growth factor receptor, and Ki-67. The clinical value of currently available molecular targets in prediction of prognosis and treatment response in ESCC needs to be further evaluated.
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14
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Chen M, Cai E, Huang J, Yu P, Li K. Prognostic value of vascular endothelial growth factor expression in patients with esophageal cancer: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012; 21:1126-34. [PMID: 22564870 DOI: 10.1158/1055-9965.epi-12-0020] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND VEGF is a prime mediator of tumorigenesis and metastasis. Various studies assessing the prognostic value of VEGF in patients with esophageal cancer remain controversial. This study aims to comprehensively and quantitatively summarize the evidence on the suitability of VEGF to predict patients' survival. METHODS Searches were applied to PubMed and EMBASE until December 31, 2011, without language restrictions. Studies were assessed for quality using REMARK (Reporting recommendations for tumor MARKer prognostic studies). Data were collected comparing overall survival in patients with high VEGF level with those with low level. We conducted a systematic review of 31 studies (n = 2,387 patients) and completed a meta-analysis of 30 studies (n = 2,345 patients) that correlated VEGF levels with overall survival. Data were synthesized with HRs. RESULTS The estimated risk of death was 1.82-fold greater in patients with high VEGF expression [95% confidence interval (CI), 1.58-2.08]. The heterogeneity was not significant (P = 0.130) between studies. High VEGF expression was associated with worse survival in esophageal squamous cell carcinoma (HR, 1.81; 95% CI, 1.57-2.10) and there was no significance in between-study heterogeneity (P = 0.185). Data collected were not sufficient to determine the prognostic value of VEGF in patients with esophageal adenocarcinoma. CONCLUSIONS In this meta-analysis, elevated VEGF expression was associated with poor survival in patients with esophageal cancer but not esophageal adenocarcinoma. IMPACT These results support further investigation of VEGF expression for predicting poor survival in patients with esophageal carcinoma and may have implications for treatments directed at inhibiting VEGF-mediated angiogenesis.
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Affiliation(s)
- Meilan Chen
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
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15
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Cyclooxygenase isoenzyme-2 and vascular endothelial growth factor are associated with poor prognosis in esophageal adenocarcinoma. J Gastrointest Surg 2012; 16:956-66. [PMID: 22258871 PMCID: PMC3324693 DOI: 10.1007/s11605-011-1814-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 12/28/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cyclooxygenase isoenzyme-2 (COX-2) and vascular endothelial growth factor (VEGF) contribute to angiogenesis and are overexpressed in various malignancies. The aim of the study was to evaluate expression, prognostic value and correlation between COX-2 and VEGF expression in esophageal adenocarcinoma (EAC). METHODS Surgical specimens of 154 patients with EAC were used to construct a tissue micro array (TMA). TMA sections were immunohistochemically stained for COX-2 and VEGF and scored on intensity of staining. RESULTS Estimated 5-year cancer specific survival was 37%. High COX-2 and VEGF expression was observed in 39 (26.5%) and in 77 (53.8%) tumors, respectively. Both markers were associated with poor cancer specific survival (p = .022 and p = .004, respectively, log rank). No significant correlation was found between VEGF and COX-2 expression (r = 063; p = .455). In multivariate analysis, high COX-2 expression (HR 1.65; 95% CI 1.04-2.61; p = .034) was associated with overall survival. In patients with T3 tumors, COX-2 expression was an independent prognostic factor for cancer specific survival (HR 1.81 95% CI 1.10-2.95; p = .019). CONCLUSIONS This is the first study that evaluated the prognostic value and correlation of COX-2 and VEGF expression in a large and homogenous population of patients with EAC. No correlation between COX-2 and VEGF expression was found. Both markers were expressed in EAC and were associated with poor prognosis. The findings support the use of COX-2 and VEGF inhibitors in future clinical studies.
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16
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Yoon MS, Nam TK, Lee JS, Cho SH, Song JY, Ahn SJ, Chung IJ, Jeong JU, Chung WK, Nah BS. VEGF as a predictor for response to definitive chemoradiotherapy and COX-2 as a prognosticator for survival in esophageal squamous cell carcinoma. J Korean Med Sci 2011; 26:513-20. [PMID: 21468258 PMCID: PMC3069570 DOI: 10.3346/jkms.2011.26.4.513] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Accepted: 02/17/2011] [Indexed: 12/14/2022] Open
Abstract
We investigated the patterns of pretreatment expression of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) by immunohistochemical staining and determined their correlation with treatment response and survival in 44 patients with esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). The definitive CCRT consisted of a median dose of 54 Gy (range: 40.0-68.4 Gy) and two cycles of concurrent administration of mostly 5-fluorouracil + cisplatinum. High expression of EGFR, VEGF, and COX-2 was found in 79.5%, 31.8%, and 38.6%, respectively. The Cox regression analysis for overall survival (OS) showed that both the treatment response and COX-2 expression were significant. The 3-yr OS rates of patients that achieved a complete response and those that did not were 46.7% and 5.3%, respectively (P = 0.006). The logistic regression analysis for treatment response with various parameters showed that only a high expression of VEGF was significantly associated with a complete response. Unlike other well-known studies, higher expression of VEGF was significantly correlated with a complete response to CCRT in this study. However, higher expression of COX-2 was significantly associated with shorter survival. These results suggest that VEGF might be a predictive factor for treatment response and COX-2 a prognostic factor for OS in patients with ESCC after definitive CCRT.
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Affiliation(s)
- Mee Sun Yoon
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
| | - Taek-Keun Nam
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
| | - Ji-Shin Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
| | - Sang-Hee Cho
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Ju-Young Song
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
| | - Sung-Ja Ahn
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
| | - Ik-Joo Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jae-Uk Jeong
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
| | - Woong-Ki Chung
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
| | - Byung-Sik Nah
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
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Verschoor ML, Wilson LA, Singh G. Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer. Can J Physiol Pharmacol 2011; 88:204-19. [PMID: 20393586 DOI: 10.1139/y09-135] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The mitochondria are unique cellular organelles that contain their own genome and, in conjunction with the nucleus, are able to transcribe and translate genes encoding components of the electron transport chain (ETC). To do so, the mitochondria must communicate with the nucleus via the production of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which are produced as a byproduct of aerobic respiration within the mitochondria. Mitochondrial signaling is proposed to be altered in cancer cells, where the mitochondria are frequently found to harbor mutations within their genome and display altered functional characteristics leading to increased glycolysis. As signaling molecules, ROS oxidize and inhibit MAPK phosphatases resulting in enhanced proliferation and survival, an effect particularly advantageous to cancer cells. In terms of transcriptional regulation, ROS affect the phosphorylation, activation, oxidation, and DNA binding of transcription factors such as AP-1, NF-kappaB, p53, and HIF-1alpha, leading to changes in target gene expression. Increased ROS production by defective cancer cell mitochondria also results in the upregulation of the transcription factor Ets-1, a factor that has been increasingly associated with aggressive cancers.
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Affiliation(s)
- Meghan L Verschoor
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
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18
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Abstract
Carcinogenesis is a multi-step process which could be prevented by phytochemicals. Phytochemicals from dietary plants and other plant sources such as herbs are becoming increasingly important sources of anticancer drugs or compounds for cancer chemoprevention or adjuvant chemotherapy. Phytochemicals can prevent cancer initiation, promotion, and progression by exerting anti-inflammatory and anti-oxidative stress effects which are mediated by integrated Nrf2, NF-kappaB, and AP-1 signaling pathways. In addition, phytochemicals from herbal medicinal plants and/or some dietary plants developed in recent years have been shown to induce apoptosis in cancer cells and inhibition of tumor growth in vivo. In advanced tumors, a series of changes involving critical signaling molecules that would drive tumor cells undergoing epithelial-mesenchymal transition and becoming invasive. In this review, we will discuss the potential molecular targets and signaling pathways that mediate tumor onset and metastasis. In addition, we will shed light on some of the phytochemicals that are capable of targeting these signaling pathways which would make them potentially applicable to cancer chemoprevention, treatment and control of cancer progression.
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The role of ets factors in tumor angiogenesis. JOURNAL OF ONCOLOGY 2010; 2010:767384. [PMID: 20454645 PMCID: PMC2863161 DOI: 10.1155/2010/767384] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Revised: 02/06/2010] [Accepted: 03/02/2010] [Indexed: 12/14/2022]
Abstract
Angiogenesis is a critical component of tumor growth. A number of growth factors, including VEGF, FGF, and HGF, have been implicated as angiogenic growth factors that promote tumor angiogenesis in different types of cancer. Ets-1 is the prototypic member of the Ets transcription factor family. Ets-1 is known to be a downstream mediator of angiogenic growth factors. Expression of Ets-1 in a variety of different tumors is associated with increased angiogenesis. A role for other selected members of the Ets transcription factor family has also been shown to be important for the development of tumor angiogenesis. Because Ets factors also express a number of other important genes involved in cell growth, they contribute not only to tumor growth, but to disease progression. Targeting Ets factors in mouse tumor models through the use of dominant-negative Ets proteins or membrane permeable peptides directed at competitively inhibiting the DNA binding domain has now demonstrated the therapeutic potential of inhibiting selected Ets transcription factors to limit tumor growth and disease progression.
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20
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Nagarajan P, Parikh N, Garrett-Sinha LA, Sinha S. Ets1 induces dysplastic changes when expressed in terminally-differentiating squamous epidermal cells. PLoS One 2009; 4:e4179. [PMID: 19142229 PMCID: PMC2615206 DOI: 10.1371/journal.pone.0004179] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2008] [Accepted: 11/28/2008] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Ets1 is an oncogene that functions as a transcription factor and regulates the activity of many genes potentially important for tumor initiation and progression. Interestingly, the Ets1 oncogene is over-expressed in many human squamous cell cancers and over-expression is highly correlated with invasion and metastasis. Thus, Ets1 is believed to mainly play a role in later stages of the oncogenic process, but not early events. METHODOLOGY/PRINCIPAL FINDINGS To better define the role of Ets1 in squamous cell carcinogenesis, we generated a transgenic mouse model in which expression of the Ets1 oncogene could be temporally and spatially regulated. Upon Ets1 induction in differentiating cells of stratified squamous epithelium, these mice exhibited dramatic changes in epithelial organization including increased proliferation and blocked terminal differentiation. The phenotype was completely reversed when Ets1 expression was suppressed. In mice where Ets1 expression was re-induced at a later age, the phenotype was more localized and the lesions that developed were more invasive. Many potential Ets1 targets were upregulated in the skin of these mice with the most dramatic being the metalloprotease MMP13, which we demonstrate to be a direct transcriptional target of Ets1. CONCLUSIONS/SIGNIFICANCE Collectively, our data reveal that upregulation of Ets1 can be an early event that promotes pre-neoplastic changes in epidermal tissues via its regulation of key genes driving growth and invasion. Thus, the Ets1 oncogene may be important for oncogenic processes in both early and late stages of tumor development.
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Affiliation(s)
- Priyadharsini Nagarajan
- Department of Biochemistry, State University of New York at Buffalo, Center for Excellence in Bioinformatics and Life Sciences, Buffalo, New York, United States of America
| | - Neha Parikh
- Department of Biochemistry, State University of New York at Buffalo, Center for Excellence in Bioinformatics and Life Sciences, Buffalo, New York, United States of America
| | - Lee Ann Garrett-Sinha
- Department of Biochemistry, State University of New York at Buffalo, Center for Excellence in Bioinformatics and Life Sciences, Buffalo, New York, United States of America
- * E-mail: (LAG-S); (SS)
| | - Satrajit Sinha
- Department of Biochemistry, State University of New York at Buffalo, Center for Excellence in Bioinformatics and Life Sciences, Buffalo, New York, United States of America
- * E-mail: (LAG-S); (SS)
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21
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Saad RS, Lindner JL, Liu Y, Silverman JF. Lymphatic vessel density as prognostic marker in esophageal adenocarcinoma. Am J Clin Pathol 2009; 131:92-8. [PMID: 19095571 DOI: 10.1309/ajcpkwuqsipvg90h] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We studied tumor lymphatic vascular density (LVD) as a predictive marker for the risk of lymph node (LN) metastasis and its relationship to other prognostic parameters and survival in 75 patients with esophageal adenocarcinoma. Samples were immunostained for D2-40, CD31, and vascular endothelial growth factor (VEGF). Microvessels were counted in densely vascular/lymphatic foci (hot spots) at x400 field (0.17 mm2). Intensity of staining for VEGF was scored on a 2-tiered scale. CD31 microvessel counts showed significant correlation with tumor stage and patient survival (P < .01). D2-40 LVD demonstrated a significant correlation with LN metastases, lymphovascular invasion, and tumor stage (r = 0.45, r = 0.47, and r = 0.37, respectively) and with shorter disease-free survival. D2-40 detected lymphovascular invasion in 29 of 75 cases, more than with CD31 (23/75) and H&E (18/75). VEGF was expressed in 48 (64%) of 75 cases and was significantly correlated with lymphovascular invasion, LN metastases, and overall survival. Our study showed that angiogenesis and lymphangiogenesis have important roles in the progression of esophageal adenocarcinoma.
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Affiliation(s)
- Reda S. Saad
- Department of Pathology, Allegheny General Hospital, Sunnybrook Health Sciences Center, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada
- Drexel University College of Medicine, Pittsburgh, PA
| | - Jennifer L. Lindner
- Department of Pathology, Allegheny General Hospital, Sunnybrook Health Sciences Center, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada
| | - Yulin Liu
- Department of Pathology, Allegheny General Hospital, Sunnybrook Health Sciences Center, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada
- Drexel University College of Medicine, Pittsburgh, PA
| | - Jan F. Silverman
- Department of Pathology, Allegheny General Hospital, Sunnybrook Health Sciences Center, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada
- Drexel University College of Medicine, Pittsburgh, PA
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22
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Albini A, Benelli R. The chemoinvasion assay: a method to assess tumor and endothelial cell invasion and its modulation. Nat Protoc 2007; 2:504-11. [PMID: 17406614 DOI: 10.1038/nprot.2006.466] [Citation(s) in RCA: 161] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Invasive and metastatic cells, as well as endothelial cells, must cross basement membranes (BMs) in order to disseminate or to form new blood vessels. The chemoinvasion assay using the reconstituted BM Matrigel in Boyden blind-well chambers is a very rapid, easy, inexpensive and flexible test that can be used to quantify the invasive potential of most cell types; it can be applied to detect the migratory activity associated with matrix degradation and can also be adapted to study the selective degrading activity on different matrix substrates. Transwell inserts can also be used. Once the optimal experimental conditions are empirically determined for specific cellular models, the chemoinvasion assay can be used for the screening of inhibitors of invasiveness and angiogenesis, or to select for invasive cellular populations. This protocol can be completed in 9 h.
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Affiliation(s)
- Adriana Albini
- Polo Scientifico e Tecnologico, IRCCS Multimedica, Milano, Italy.
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23
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McClelland MR, Carskadon SL, Zhao L, White ES, Beer DG, Orringer MB, Pickens A, Chang AC, Arenberg DA. Diversity of the angiogenic phenotype in non-small cell lung cancer. Am J Respir Cell Mol Biol 2006; 36:343-50. [PMID: 17079777 PMCID: PMC1899317 DOI: 10.1165/rcmb.2006-0311oc] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis is crucial for tumor biology. There are many mechanisms by which tumors induce angiogenesis. We hypothesize that each individual tumor develops a unique mechanism to induce angiogenesis, and that activation of a particular angiogenic pathway suppresses the evolution of alternative pathways. We characterized 168 human non-small cell lung cancer (NSCLC) specimens for levels of angiogenic factors (angiogenic CXC chemokines, basic fibroblast growth factor, and vascular endothelial growth factor). We also induced lung tumor formation in A/J mice by injecting the tobacco carcinogen NNK. We dissected individual lung tumors and measured expression of angiogenic factors from three distinct families using real-time PCR. Finally, we controlled the angiogenic milieu using in vivo models to determine the resultant phenotype of the angiogenic factors expressed by NSCLC cells. Human tumors displayed marked variation in the expression of angiogenic factors. Individual mouse tumors, even from within the same mouse, displayed variability in their pattern of expression of angiogenic factors. In a sponge model of angiogenesis using murine lung cancer cells, implanting LLC cells with an angiogenic factor suppressed the expression of other angiogenic factors in implanted sponges. This suppressive effect was not seen in vitro. We conclude that lung cancer tumors evolve a unique and dominant angiogenic phenotype. Once an angiogenic pathway is activated, it may allow for tumor growth to proceed in the absence of a selection pressure to activate a second pathway.
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MESH Headings
- Angiogenic Proteins/genetics
- Angiogenic Proteins/metabolism
- Animals
- Carcinoma, Non-Small-Cell Lung/blood supply
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Chemokines, CXC/genetics
- Chemokines, CXC/metabolism
- Demography
- Female
- Gene Expression Regulation, Neoplastic
- Genes, ras
- Genetic Variation
- Humans
- Lung/blood supply
- Lung/pathology
- Lung Neoplasms/blood supply
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mutation/genetics
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Neovascularization, Pathologic
- Phenotype
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Time Factors
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Marc R McClelland
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA
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Mikami S, Oya M, Mizuno R, Murai M, Mukai M, Okada Y. Expression of Ets-1 in human clear cell renal cell carcinomas: implications for angiogenesis. Cancer Sci 2006; 97:875-82. [PMID: 16856880 PMCID: PMC11158423 DOI: 10.1111/j.1349-7006.2006.00268.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Expression of vascular endothelial growth factor (VEGF) has been reported in renal cell carcinoma (RCC), a highly angiogenic carcinoma. However, little or no information is available on the expression of Ets-1, which is one of the target molecules of VEGF. In the present study, we examined the expression of Ets-1 and VEGF in RCC by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), and correlations between expression and the microvessel density (MVD) were evaluated. Ets-1 was immunolocalized to carcinoma cells and endothelial cells of the microvessels in clear cell RCC, but not in papillary RCC. Immunohistochemical Ets-1 expression and MVD were significantly higher in clear cell RCC than in papillary RCC. Predominant mRNA expression of Ets-1 in clear cell RCC was confirmed by RT-PCR. The expression of Ets-1 correlated directly with MVD in clear cell RCC. Hypoxic treatment upregulated the mRNA expression of Ets-1 and VEGF in cell lines derived from clear cell RCC, suggesting that hypoxia is a key regulator for these molecules. These results demonstrate the expression of Ets-1 in human clear cell RCC and suggest the possibility that Ets-1 is involved in angiogenesis in clear cell RCC.
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Affiliation(s)
- Shuji Mikami
- Division of Diagnostic Pathology, School of Medicine, Keio University Hospital, 35 Shinanomachi, Tokyo, 160-8582, Japan
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25
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Schneider S, Park DJ, Yang D, El-Khoueiry A, Sherrod A, Groshen S, Streeter O, Iqbal S, Danenberg KD, Lenz HJ. Gene expression in tumor-adjacent normal tissue is associated with recurrence in patients with rectal cancer treated with adjuvant chemoradiation. Pharmacogenet Genomics 2006; 16:555-63. [PMID: 16847424 DOI: 10.1097/01.fpc.0000220563.44724.6d] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recurrence is a significant clinical problem for patients with rectal cancer treated with adjuvant chemoradiation. Previous studies have suggested that determining intratumoral gene expression of key genes may be helpful in predicting clinical outcome of patients with gastrointestinal malignancies undergoing chemotherapy. The role of molecular predictors for prediction of recurrence in the setting of adjuvant chemoradiotherapy is not well established. The present study was designed to identify a genetic profile that would be associated with recurrence in patients with rectal cancer treated with adjuvant chemoradiation therapy. A retrospective study with a longitudinal cohort and a cross-sectional cohort of 67 patients with locally advanced rectal cancer who underwent cancer resection, followed by 5-fluorouracil (5-FU) plus pelvic radiation was conducted. Total RNA was extracted from formalin-fixed, paraffin-embedded, laser-captured-microdissected tissue. We determined mRNA levels of genes involved in the 5-FU pathway (thymidylate synthase, dihydropyrimidine dehydrogenase), DNA-repair (excision-repair cross-complementing factor 1, Rad51), angiogenesis/radiation sensitivity [vascular endothelial growth factor (VEGF)] and radio-sensitivity [epidermal growth factor receptor (EGFR)] in tumor tissue and tumor-adjacent normal tissue by quantitative reverse transcriptase-polymerase chain reaction. In univariate analysis, only intratumoral gene expression level of VEGF (P = 0.055) was associated with recurrence, whereas elevated mRNA expression levels of thymidylate synthase (P = 0.008), VEGF (P = 0.023) and EGFR (P = 0.004) in tumor-adjacent normal tissue were significantly associated with recurrence. Multivariate analysis using recursive partitioning indicated that distinct groups of recurrence could be defined by elevated mRNA expression levels of VEGF, EGFR in tumor-adjacent normal tissue, and Rad51 in tumor tissue. These data suggest that the genetic profile of the tumor-adjacent normal tissue may be associated with treatment failure, indicating that tumor microenvironment may be more important in the development of recurrence of rectal tumors than formerly expected.
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Affiliation(s)
- Sylke Schneider
- Department of Dermatology of the Charite, Humboldt-University, Berlin, Germany
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26
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Baillat D, Leprivier G, Régnier D, Vintonenko N, Bègue A, Stéhelin D, Aumercier M. Stromelysin-1 expression is activated in vivo by Ets-1 through palindromic head-to-head Ets binding sites present in the promoter. Oncogene 2006; 25:5764-76. [PMID: 16652151 DOI: 10.1038/sj.onc.1209583] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Regulation of the gene expression of Stromelysin-1 (matrix metalloproteinase-3), a member of the matrix metalloproteinase family, is critical for tissue homeostasis. The Stromelysin-1 promoter is known to be transactivated by Ets proteins through palindromic head-to-head Ets binding sites (EBS), an unusual configuration among metalloproteinase promoters. Patterns of increased co-expression of Stromelysin-1 and Ets-1 genes have been observed in pathological processes such as rheumatoid arthritis, glomerulonephritis and tumor invasion. In this context, we show in a synovial fibroblastic model cell line (HIG-82), which is able to co-express Stromelysin-1 and Ets-1, that the EBS palindrome is essential for the expression of Stromelysin-1. More precisely, using electrophoretic mobility shift assays, DNA affinity purification and chromatin immunoprecipitation, we demonstrate that endogenous Ets-1, but not Ets-2, is present on this palindrome. The use of a dominant-negative form of Ets-1 and the decrease of Ets-1 amount either by fumagillin, an antiangiogenic compound, or by short interfering RNA show that the activation rate of the promoter and the expression of Stromelysin-1 correlate with the level of endogenous Ets-1. Thus, it is the first demonstration, using this cellular model, that endogenously expressed Ets-1 is actually a main activator of the Stromelysin-1 promoter through its effective binding to the EBS palindrome.
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Affiliation(s)
- D Baillat
- CNRS Unité Mixte de Recherche 8526, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille II, Lille Cedex, France
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Hong W, Liu NZ, Zhang Q, Li XM, Ni Z. Expression of E26 transformation-specific-1, matrix metalloproteinases-1 and vascular endothelial growth factor in colorectal carcinoma. Shijie Huaren Xiaohua Zazhi 2005; 13:2441-2445. [DOI: 10.11569/wcjd.v13.i20.2441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of E26 transformation-specific-1 (Ets-1), matrix metalloproteinases-1 (MMP-1) and vascular endothelial growth factor (VEGF) in human colorectal carcinoma, and to explore the role of Ets-1 in the angiogenesis and metastasis of carcinoma.
METHODS: The expression of Ets-1, MMP-1 and VEGF were detected in colorectal carcinoma (n = 61) and normal colon tissues (n = 21) by the immunohistochemical method respectively.
RESULTS: Ets-1, MMP-1 and VEGF were negatively expressed in all normal mucosal tissues. The positive rates of Ets-1, MMP-1 and VEGF expression were 75.4%, 78.7% and 82.0% in colorectal carcinoma respectively. No significant correlation was found between their positive rates and tumor′s size as well as the differentiation (P >0.05). The expression of Ets-1, MMP-1 and VEGF were significantly correlated with Duke's staging (χ2 = 10.718, P <0.01; χ2 = 8.323, P <0.01; χ2 = 6.145, P <0.05), the depth of invasion (χ2 = 7.705, P <0.01; χ2 = 19.101, P <0.01; χ2 = 14.707, P <0.01), lymphatic invasion (χ2 = 9.333, P <0.01; χ2 = 3.965, P <0.05; χ2 = 4.638, P <0.05) and distant metastasis (χ2 = 5.472, P <0.05; χ2 = 4.125, P <0.05; χ2 = 5.034, P <0.05). Ets-1 expression was positively associated with MMP-1 and VEGF level (r = 0.447, P <0.01; r = 0.425, P <0.05).
CONCLUSION: Ets-1 was over-expressed in colorectal carcinoma, and its expression was related to clinical staging, invasion and metastasis. Ets-1 expression was also positively related to MMP-1 and VEGF level. Their expression can become referential indexes to predict the malignant behavior of colorectal carcinoma.
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Wilson LA, Gemin A, Espiritu R, Singh G. ets-1 is transcriptionally up-regulated by H2O2 via an antioxidant response element. FASEB J 2005; 19:2085-7. [PMID: 16234432 DOI: 10.1096/fj.05-4401fje] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Expression of the transcription factor Ets-1 is increasingly associated with the progression of several human cancers. A tumor-derived factor is expected to be involved in the inappropriate up-regulation of ets-1 in tumor and surrounding cells. A link between hydrogen peroxide (H2O2) and increased Ets-1 expression has also been suggested, leading to the proposal that this reactive oxygen species (ROS) may be an important factor in directly regulating the expression of ets-1 in tumor cells. Ets-1 expression in response to H2O2 was examined in an ovarian carcinoma cell model, and the genes promoter region was analyzed in order to identify putative elements involved in redox responsiveness. The up-regulation of Ets-1 by H2O2 was confirmed in the cells tested. Luciferase assays using constructs generated to test the contribution of specific promoter elements indicated that an antioxidant response element (ARE) is primarily involved in the H2O2-mediated induction. Gel shift analysis confirmed the increased binding of an Nrf2 containing protein complex to the ets-1 ARE after H2O2 treatment. This study has delineated a key element involved in the transcriptional regulation of ets-1 under basal and induced conditions. Ets-1 has obvious deleterious effects in many cancer cells, and thus, the identification of this regulatory pathway has provided possible targets for manipulating its expression.
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Affiliation(s)
- Leigh A Wilson
- Juravinski Cancer Center and Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
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Kleespies A, Bruns CJ, Jauch KW. Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies. Oncol Res Treat 2005; 28:281-8. [PMID: 15867486 DOI: 10.1159/000085198] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vascular endothelial growth factors (VEGF)-A, -C and -D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma (EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma (SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and -D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.
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Affiliation(s)
- Axel Kleespies
- Chirurgische Klinik und Poliklinik, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Germany.
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Kleespies A, Guba M, Jauch KW, Bruns CJ. Vascular endothelial growth factor in esophageal cancer. J Surg Oncol 2004; 87:95-104. [PMID: 15282704 DOI: 10.1002/jso.20070] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis of many solid malignancies. The influence of angiogenesis and VEGF expression on progression and recurrence of esophageal cancer has been investigated over the last years. This article reviews the prognostic significance of VEGF expression, microvessel density (MVD), and lymphangiogenic factors in squamous cell carcinoma (SCC), Barrett's dysplasia, and adenocarcinoma (AC) of the esophagus, their predictive value for treatment response to chemo-radiotherapy and new anti-angiogenic treatment strategies.
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Affiliation(s)
- Axel Kleespies
- Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilian-University, Munich, Germany.
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Lü F, Qin ZY, Yang WB, Qi YX, Li YM. A DNA vaccine against extracellular domains 1-3 of flk-1 and its immune preventive and therapeutic effects against H22 tumor cell in vivo. World J Gastroenterol 2004; 10:2039-44. [PMID: 15237430 PMCID: PMC4572329 DOI: 10.3748/wjg.v10.i14.2039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To construct a DNA vaccine against extracellular domains 1-3 of fetal liver kinase-1 (flk-1), and to investigate its preventive and therapeutic effect against H22 cell in vivo.
METHODS: Flk-1 DNA vaccine was produced by cloning extracellular domains 1-3 of flk-1 and by inserting the cloned gene into pcDNA3.1 (+). Fifteen mice were divided into 3 groups and inoculated by vaccine, plasmid and saline respectively to detect specific T lymphocyte response. Thirty Mice were equally divided into preventive group and therapeutic group. Preventive group was further divided into V, P, and S subgroups, namely immunized by vaccine, pcDNA3.1 (+) and saline, respectively, and attacked by H22 cell. Therapeutical group was divided into 3 subgroups of V, P and S, and attacked by H22, then treated with vaccine, pcDNA3.1 (+) and saline, respectively. The tumor size, tumor weight, mice survival time and tumor latency period were compared within these groups. Furthermore, intratumoral microvessel density (MVD) was assessed by immunohistochemistry.
RESULTS: DNA vaccine pcDNA3.1 (+) flk-1-domains 1-3 was successfully constructed and could raise specific CTL activity. In the preventive group and therapeutic group, tumor latency period and survival time were significantly longer in vaccine subgroup than that in P and S subgroups (P < 0.05); the tumor size, weight and MVD were significantly less in vaccine subgroup than that in P and S subgroups (P < 0.05). The survival time of therapeutic vaccine subgroup was significantly shorter than that of preventive vaccine subgroup (P < 0.05); the tumor size, and MVD of therapeutic vaccine subgroup were significantly greater than that of preventive vaccine subgroup (P < 0.05).
CONCLUSION: DNA vaccine against flk-1 domains 1-3 can stimulate potent specific CTL activity; and has distinctive prophylactic effect on tumor H22; and also can inhibit the tumor growth in vivo. This vaccine may be used as an adjuvant therapy because it is less effective on detectable tumor.
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Affiliation(s)
- Fan Lü
- Department of General Surgery, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
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Varghese HJ, Mackenzie LT, Groom AC, Ellis CG, Ryan A, MacDonald IC, Chambers AF. In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model. Angiogenesis 2004; 7:157-64. [PMID: 15516836 DOI: 10.1007/s10456-004-1941-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of approximately 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.
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Affiliation(s)
- Hemanth J Varghese
- Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
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Abstract
The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of Ets1 is controlled by kinases and transcription factors. Some transcription factors, such as AML-1, regulate Ets1 by targeting its autoinhibitory module. Others, such as Pax-5, alter Ets1 DNA binding properties. Ets1 harbors two phosphorylation sites, threonine-38 and an array of serines within the exon VII domain. Phosphorylation of threonine-38 by ERK1/2 activates Ets1, whereas phosphorylation of the exon VII domain by CaMKII or MLCK inhibits Ets1 DNA binding activity. Ets1 is expressed by numerous cell types. In haemotopoietic cells, it contributes to the regulation of cellular differentiation. In a variety of other cells, including endothelial cells, vascular smooth muscle cells and epithelial cancer cells, Ets1 promotes invasive behavior. Regulation of MMP1, MMP3, MMP9 and uPA as well as of VEGF and VEGF receptor gene expression has been ascribed to Ets1. In tumors, Ets1 expression is indicative of poorer prognosis.
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Affiliation(s)
- Jürgen Dittmer
- Universität Halle-Wittenberg Universitätsklinik und Poliklinik für Gynäkologie Magdeburger Str, 24 06097 Halle, Saale, Germany.
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