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Responses to the Tepotinib in Gastric Cancers with MET Amplification or MET Exon 14 Skipping Mutations and High Expression of Both PD-L1 and CD44. Cancers (Basel) 2022; 14:cancers14143444. [PMID: 35884507 PMCID: PMC9318186 DOI: 10.3390/cancers14143444] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/30/2022] [Accepted: 07/13/2022] [Indexed: 02/01/2023] Open
Abstract
Both MET exon 14 skipping mutation (METex14SM) and high copy-number variation (CNV) lead to enhanced carcinogenesis; additionally, programmed-death ligand 1 (PD-L1) is often upregulated in cancers. In this study, we characterized the expression of MET (including METex14SM), PD-L1, and CD44 in human gastric cancer (GC) cells as well as the differential susceptibility of these cells to tepotinib. Tepotinib treatments inhibited the growth of five GC cells in a dose-dependent manner with a concomitant induction of cell death. Tepotinib treatments also significantly reduced the expression of phospho-MET, total MET, c-Myc, VEGFR2, and Snail protein in SNU620, MKN45, and Hs746T cells. Notably, tepotinib significantly reduced the expression of CD44 and PD-L1 in METex14SM Hs746T cells. By contrast, tepotinib was only slightly active against SNU638 and KATO III cells. Migration was reduced to a greater extent in the tepotinib-treated group than in the control group. Tepotinib may have therapeutic effects on c-MET-amplified GC, a high expression of both PD-L1 and CD44, and METex14SM. Clinical studies are needed to confirm these therapeutic effects.
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Heydari R, Abdollahpour-Alitappeh M, Shekari F, Meyfour A. Emerging Role of Extracellular Vesicles in Biomarking the Gastrointestinal Diseases. Expert Rev Mol Diagn 2021; 21:939-962. [PMID: 34308738 DOI: 10.1080/14737159.2021.1954909] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Extracellular vesicles (EVs) play an important role in cell-cell communication and regulation of various cellular functions under physiological and pathophysiological conditions through transferring their cargo to recipient cells. Molecular constituents of EVs are a fingerprinting profile of secreting cells which can be used as promising prognostic, diagnostic, and drug-response biomarkers in clinical settings. AREAS COVERED The present study provides a brief introduction about the biology of EVs and reviews methodologies used for EV isolation and characterization as well as high-throughput strategies to analyze EV contents. Furthermore, this review highlights the importance and unique role of EVs in the development and progression of gastrointestinal (GI) diseases, especially GI cancers, and then discusses their potential use, particularly those isolated from body fluids, in diagnosis and prognosis of GI diseases. EXPERT OPINION In-depth analysis of EV content can lead to the identification of new potential biomarkers for early diagnosis and prognosis prediction of GI diseases. The use of a more targeted approach by establishing more reproducible and standardized methods to decrease variations and obtain desired EV population as well as revisiting large pools of identified biomarkers and their evaluation in larger patient cohorts can result in the introduction of more reliable biomarkers in clinic.
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Affiliation(s)
- Raheleh Heydari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Clinical significance of endoscopic ultrasonography in diagnosing invasion depth of early gastric cancer prior to endoscopic submucosal dissection. Gastric Cancer 2021; 24:145-155. [PMID: 32572791 DOI: 10.1007/s10120-020-01100-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Endoscopic ultrasonography is a reliable diagnostic modality for determining indications of endoscopic submucosal dissection for early gastric cancer. We aimed to clarify the clinical significance of endoscopic ultrasonography in the invasion depth diagnosis of early gastric cancer. METHODS We retrospectively assessed 1598 consecutive patients with 2001 early gastric cancers who underwent EUS before ESD or surgery between October 2010 and April 2019 at our institution. Lesions were classified according to endoscopic ultrasonography-determined invasion depth as EUS-M/SM1 (lesions confined to sonographic layers 1 and 2 or lesions with changes in sonographic layer 3; depth, < 1 mm) and EUS-SM2 (lesions with changes in sonographic layer 3; depth, ≥ 1 mm). We evaluated the invasion depth determination accuracy of endoscopic ultrasonography and analyzed the clinicopathological features of misdiagnosed early gastric cancer cases. RESULTS The invasion depth determination accuracy was as follows: EUS-M/SM1: pathological T1a/T1b1 early gastric cancer, 97%; EUS-SM2: pathological T1b2 early gastric cancer, 79%. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 95%, 98%, 69%, 97%, and 79%, respectively. In EUS-M/SM1 early gastric cancer, tumor size of ≥ 15 mm, presence of ulceration, and undifferentiated histological type were significantly associated with endoscopic ultrasonography accuracy. In EUS-SM2 early gastric cancer, tumor size of ≥ 30 mm was significantly associated with endoscopic ultrasonography accuracy. CONCLUSIONS Endoscopic ultrasonography is a useful modality in accurately determining the invasion depth of early gastric cancer before endoscopic submucosal dissection.
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Zhang YY, Luo LM, Wang YX, Zhu N, Zhao TJ, Qin L. Total saponins from Lilium lancifolium: a promising alternative to inhibit the growth of gastric carcinoma cells. J Cancer 2020; 11:4261-4273. [PMID: 32368309 PMCID: PMC7196269 DOI: 10.7150/jca.42285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Bulbus Lilii, as a medicinal and edible plant, has anti-inflammatory, anti-oxidative and immunopotentiating pharmacological activities, which seems to be therapeutic on cancer prevention. The purpose of this study was to investigate the effects of total saponins from Lilium lancifolium (TSLL) on proliferation, apoptosis and migration of human gastric carcinoma cells lines SGC-7901 and HGC-27 and its underlying mechanism. The results showed that TSLL inhibited the proliferation of gastric carcinoma cells by suppressing the level of proliferating cell nuclear antigen (PCNA) and increased p21 level. TSLL induced cells apoptosis by up-regulating expression of pro-apoptotic protein Bax and down-regulating anti-apoptotic protein Bcl-2 expression. Meanwhile, TSLL remarkably inhibited cell migration and invasion, decreased matrix metalloproteinase-2 (MMP-2) expression and increased tissue inhibitor of metalloproteinases-1 (TIMP-1) expression. Notably, TSLL had stronger anti-cancer effect on undifferentiated HGC-27 cells than differentiated SGC-7901 cells. Accordingly, TSLL might be a promising candidate to prevent and suppress the growth of gastric carcinoma cells.
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Affiliation(s)
- Yin-Yu Zhang
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Lin-Ming Luo
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Yu-Xiang Wang
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Neng Zhu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Tan-Jun Zhao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Li Qin
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Factors Affecting the Accuracy of Endoscopic Ultrasonography in the Diagnosis of Early Gastric Cancer Invasion Depth: A Meta-analysis. Gastroenterol Res Pract 2019; 2019:8241381. [PMID: 31933632 PMCID: PMC6942824 DOI: 10.1155/2019/8241381] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/02/2019] [Accepted: 11/25/2019] [Indexed: 12/15/2022] Open
Abstract
Background Endoscopic ultrasonography (EUS) is the first imaging modality for investigating the depth of invasion in early gastric cancer (EGC). However, there is presently no consensus on the accuracy of EUS in diagnosing the invasion depth of EGC. Aim This study is aimed at systematically evaluating the accuracy of EUS in diagnosing the invasion depth of EGC and its affecting factors. Methods The literatures were identified by searching PubMed, SpringerLink, Cochrane Library, Web of Science, Nature, and Karger knowledge databases. Two researchers extracted the data from the literature and reconstructed these in 2 × 2 tables. The Meta-DiSc software was used to evaluate the overall sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic advantage ratio, and 95% confidence interval (CI). The SROC was drawn, and the area under the curve (AUC) was calculated to evaluate the diagnostic value. Results A total of 17 articles were selected, which included 4525 cases of lesions. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic dominance ratio, and 95% CI of EUS for diagnosing EGC was 0.87 (95% CI: 0.86-0.88), 0.67 (95% CI: 0.65-0.70), 2.90 (95% CI: 2.25-3.75), 0.17 (95% CI: 0.13-0.23), and 18.25 (95% CI: 12.61-26.39), respectively. The overall overstaging rate of mucosa/submucosa 1 (M/SM1) and SM by EUS was 13.31% and 32.8%, respectively, while the overall understaging rate of SM was 29.7%. The total misdiagnosis rates for EUS were as follows: 30.4% for lesions ≥ 2 cm and 20.9% for lesions < 2 cm, 27.7% for ulcerative lesions and 21.4% for nonulcerative lesions, and 22% for differentiated lesions and 26.9% for undifferentiated lesions. Conclusion EUS has a moderate diagnostic value for the depth of invasion of EGC. The shape, size, and differentiation of lesions might be the main factors that affect the accuracy of EUS in diagnosing EGC.
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Liu H, Li PW, Yang WQ, Mi H, Pan JL, Huang YC, Hou ZK, Hou QK, Luo Q, Liu FB. Identification of non-invasive biomarkers for chronic atrophic gastritis from serum exosomal microRNAs. BMC Cancer 2019; 19:129. [PMID: 30736753 PMCID: PMC6368711 DOI: 10.1186/s12885-019-5328-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 01/29/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Serum exosomal microRNAs (miRNAs) have been suggested as novel biomarkers for various diseases, especially gastric cancer (GC). But circulating biomarkers for Chronic atrophic gastritis (CAG) which is defined as precancrerous lesions of GC remain largely elusive. To investigate serum exosomal miRNAs that are differently expressed in CAG patients and Chronic nonatrophic gastritis (CNAG) may be helpful for its diagnosis and therapy. METHODS Patients were recruited according to the diagnosis and exclusioncriteria. RNA was extracted from serum exosomes of 30 CAG and 30 CNAG patients. The miRNA expression profiles were analyzed by next generation sequencing and were validated by qRT-PCR. Receiver operating characteristic (ROC) analysis has been used to evaluate the diagnostic value. RESULTS 30 CAG patients and 30 CNAG patients were recruited in our study. sRNA-seq results showed that hsa-miR-3591-3p, - 122-3p, and - 122-5p of the top 10 miRNAs (hsa-miR-148a-3p, - 122-3p, - 486-3p, -451a, - 122-5p, - 3591-3p, - 486-5p, -151a-3p, -92a-3p, -320a) were significantly upregulated in exosomes from CAG patients versus those from CNAG patients, but hsa-miR-451a, -151a-3p, and -92a-3p were significantly downregulated. Furthermore, qRT-PCR analysis confirmed that hsa-miR-122-5p and hsa-miR-122-3p were significantly upregulated in CAG samples, but hsa-miR-122-3p hadnot a steable expression. ROC curves showed that the AUC for hsa-miR-122-5p was 0.67 (95% CI 0.52-0.82, SE 62%, SP 86%). A sum of the four miRNAs (panel 1, hsa-miR-122-5p, -451a, -151a-3p, and -92a-3p) did not significantly improve the diagnostic potential (AUC 0.63, 95% CI 0.47 to 0.78). Correlation analysis showed that the expression of hsa-miR-122-5p differed significantly between patients based on atrophic (Moderate atrophic vs. Absent, P value was 0.036.) and IM (compare moderate-severe, absent and mild P values were 0.001 and 0.014, respectively). However, there were no differences between groups based on age, gender, dysplasia, or chronic or active inflammation. CONCLUSION These results suggested that hsa-miR-122-5p in serum exosomes might serve as a potential biomarker for CAG diagnosis. TRIAL REGISTRATION Chinese Clinical Trial Registy ( ChiCTR-IOR-16008027 , Date of Registration:2016-03-01).
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Affiliation(s)
- Hong Liu
- The First Affiliated Hospital of Guangdong Pharmaceutical University, No.19 Nonglinxia Road, Guangzhou, 510080 Guangdong Province China
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Pei-wu Li
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Wei-qin Yang
- The Eight Affiliated Hospital, Sun Yat-sen University, No.3025 Shennanzhong Road, Shenzhen, 518033 Guangdong Province China
| | - Hong Mi
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Jing-lin Pan
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Yuan-cheng Huang
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Zheng-kun Hou
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Qiu-ke Hou
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Qi Luo
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
| | - Feng-bin Liu
- Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16 Jichang Road, Guangzhou, 510405 Guangdong Province China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, No.12 Jichang Road, Guangzhou, 510405 Guangdong Province China
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Diagnostic, Predictive, Prognostic, and Therapeutic Molecular Biomarkers in Third Millennium: A Breakthrough in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7869802. [PMID: 29094049 PMCID: PMC5637861 DOI: 10.1155/2017/7869802] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
Introduction Gastric cancer is the fifth most common cancer and the third cause of cancer death. The clinical outcomes of the patients are still not encouraging with a low rate of 5 years' survival. Often the disease is diagnosed at advanced stages and this obviously negatively affects patients outcomes. A deep understanding of molecular basis of gastric cancer can lead to the identification of diagnostic, predictive, prognostic, and therapeutic biomarkers. Main Body This paper aims to give a global view on the molecular classification and mechanisms involved in the development of the tumour and on the biomarkers for gastric cancer. We discuss the role of E-cadherin, HER2, fibroblast growth factor receptor (FGFR), MET, human epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), mammalian target of rapamycin (mTOR), microsatellite instability (MSI), PD-L1, and TP53. We have also considered in this manuscript new emerging biomarkers as matrix metalloproteases (MMPs), microRNAs, and long noncoding RNAs (lncRNAs). Conclusions Identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers will have a huge impact on patients outcomes as they will allow early detection of tumours and also guide the choice of a targeted therapy based on specific molecular features of the cancer.
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Kim SJ, Choi CW, Kang DH, Kim HW, Park SB, Nam HS, Shin DH. Factors associated with the efficacy of miniprobe endoscopic ultrasonography after conventional endoscopy for the prediction of invasion depth of early gastric cancer. Scand J Gastroenterol 2017; 52:864-869. [PMID: 28434266 DOI: 10.1080/00365521.2017.1315167] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study aimed to compare the accuracy of conventional endoscopy (CE) and endoscopic ultrasonography (EUS) to predict tumor invasion depth and to determine factors associated with higher accuracy of additional miniprobe EUS after CE. METHODS Between May 2009 and February 2015, 273 lesions in 266 patients were subjected to miniprobe EUS after CE and curative treatment for well-to-moderately differentiated early gastric cancer (EGC). We reviewed preoperative CE and EUS findings and compared them to the pathologic findings. RESULTS The accuracy of CE and EUS to estimate the invasion depth of EGCs was 78.8% (215/273) and 83.9% (229/273) (p = .124), respectively. Using multivariate analysis, irregular depressed surface (odds ratio [OR] 8.11; 95% confidence interval [CI]: 2.79-23.53), fold change (OR 7.22; 95% CI: 2.33-22.38), size >2 cm (OR 2.72; 95% CI: 1.15-6.42) and ulcer scar (OR 2.64; 95% CI: 1.07-6.49) were associated with the higher accuracy of EUS than that of CE. CONCLUSIONS Routine assessment using miniprobe EUS did not increase the accuracy of predicting invasion depth, compared to CE. However, EUS could be helpful in the treatment decision-making process for EGCs with lesions having irregular surfaces, fold change, size >2 cm, or ulcer scar.
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Affiliation(s)
- Su Jin Kim
- a Department of Internal Medicine and Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
| | - Cheol Woong Choi
- a Department of Internal Medicine and Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
| | - Dae Hwan Kang
- a Department of Internal Medicine and Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
| | - Hyung Wook Kim
- a Department of Internal Medicine and Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
| | - Su Bum Park
- a Department of Internal Medicine and Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
| | - Hyeong Seok Nam
- a Department of Internal Medicine and Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
| | - Dong Hoon Shin
- b Department of Pathology, Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Korea
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Yang B, Luo T, Zhang M, Lu Z, Xue X, Fang G. The novel long noncoding RNA RP11-357H14.17 acts as an oncogene by promoting cell proliferation and invasion in diffuse-type gastric cancer. Onco Targets Ther 2017; 10:2635-2643. [PMID: 28572735 PMCID: PMC5442875 DOI: 10.2147/ott.s134121] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Current evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in human cancers. The present study aims to assess differentially expressed lncRNAs related to diffuse-type gastric carcinoma (DGC). Next-generation RNA sequencing was carried out to detect aberrantly expressed lncRNAs in DGC. Real-time polymerase chain reaction (RT-PCR) was performed to evaluate RP11–357H14.17 gene expression levels in DGC cell lines/tissues comparatively with normal gastric epithelial cell lines and adjacent normal tissues. The associations of RP11–357H14.17 expression levels with the clinicopathological features were also analyzed. The regulatory effects of RP11–357H14.17 on the biological behaviors of DGC cells were evaluated by MTT, colony formation assays, flow cytometry for apoptosis, wound healing assay, and transwell migration and invasion assays. RP11–357H14.17 expression was remarkably increased in DGC tissues and cell lines compared with normal gastric epithelial cells and adjacent normal tissues. High levels of RP11–357H14.17 were associated with increased tumor size, deeper depth of invasion, lymphatic metastasis, and advanced pathological stage. Further experiments demonstrated that the DGC cells MGC-803 transfected with si-RP11–357H14.17 showed reduced cell proliferation, migration, invasion, enhanced G1 phase arrest and cell apoptosis. These findings suggest that the novel lncRNA RP11–357H14.17 is associated with poor prognosis, and may serve as a potential prognostic biomarker and target for new antineoplastic therapies in human DGC.
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Affiliation(s)
| | | | - Meijing Zhang
- Department of Oncology, Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China
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Peng L, Xie YF, Wang CG, Wu HG, Liu M, Wang YD, Ma FQ, Chang XR, Yang ZB. MOXIBUSTION ALLEVIATES GASTRIC PRECANCEROUS LESIONS IN RATS BY PROMOTING CELL APOPTOSIS AND INHIBITING PROLIFERATION-RELATED ONCOGENES. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES 2017; 14:148-160. [PMID: 28573231 PMCID: PMC5446438 DOI: 10.21010/ajtcam.v14i2.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Background: It is well known that gastric mucosa dysplasia and intestinal metaplasia are gastric precancerous lesions (GPL). Moxibustion treatment of Liangmen (ST21) and Zusanli (ST36) alleviated the inflammatory response and dysplasia of gastric mucosa in our previous study. The purpose of this study was to further examine the underlying mechanism of moxibustion treatment of ST21 and ST36 on GPL. Materials and Methods: Sixty SD rats were divided into five groups and rats with GPL were treated with either moxibustion (ST), moxibustion (Sham), or vitacoenzyme. B-cell lymphoma 2 (bcl-2), tumor protein p53 (P53) and cellular Myc (C-MYC), which are related to cell apoptosis, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), argyrophilic nucleolar organizer region proteins (Ag-NORs), which are associated with cell proliferation, and cell signaling proteins, nuclear factor kappa B (NF-κB), epidermal growth factor receptor (EGFR) and phosphorylated extracellular signal regulated kinase (p-ERK), were measured after moxibustion treatment. Results: Compared with Control group, gastric mucosa in GPL group showed abnormal mucosal proliferation and pathological mitotic figure, the mRNA expression of bcl-2, P53 and C-MYC increased significantly (P < 0.01), the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-κβ as well as EGFR/ERK signaling proteins also increased significantly (P < 0.01). Moxibustion treatment decreased gastric mucosal proliferation and pathological mitotic figure, down-regulated the mRNA expression of bcl-2, P53, C-MYC (P < 0.01), decreased the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-κβ as well as EGFR/ERK signaling proteins significantly (P < 0.01). But moxibustion treatment of Sham didn’t show the same effect on GPL. Conclusion: Moxibustion treatment inhibited cell apoptosis and reduced gastric mucosa dysplasia by inhibiting the expression of bcl-2, P53, C-MYC and decreased the activity of NF-κβ as well as EGFR/ERK signaling proteins.
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Affiliation(s)
- Li Peng
- Medical College, Xiamen University, Xiamen 361102 PRC
| | - Yu-Feng Xie
- Acupuncture and Moxibustion Department, Shenzhen 2 hospital of Traditional Chinese Medicine (Futian hospital of Traditional Chinese Medicine), Shenzhen 518000 PRC
| | | | - Huan-Gan Wu
- Research Institute of Acupuncture and Moxibustion, Shanghai University of Traditional Chinese Medicine, Shanghai 200030 PRC
| | - Mi Liu
- Acupuncture and Moxibustion College, Hunan University of Traditional Chinese Medicine, Changsha 330004 PRC
| | - Ya-Dong Wang
- Medical College, Xiamen University, Xiamen 361102 PRC
| | - Fu-Qiang Ma
- Medical College, Xiamen University, Xiamen 361102 PRC
| | - Xiao-Rong Chang
- Acupuncture and Moxibustion College, Hunan University of Traditional Chinese Medicine, Changsha 330004 PRC.,Zong-bao Yang: corresponding author, Medical College, Xiamen University, Xiamen 361102, China
| | - Zong-Bao Yang
- Medical College, Xiamen University, Xiamen 361102 PRC.,Zong-bao Yang: corresponding author, Medical College, Xiamen University, Xiamen 361102, China
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Konishi H, Asano N, Imatani A, Kimura O, Kondo Y, Jin X, Kanno T, Hatta W, Ara N, Asanuma K, Koike T, Shimosegawa T. Notch1 directly induced CD133 expression in human diffuse type gastric cancers. Oncotarget 2016; 7:56598-56607. [PMID: 27489358 PMCID: PMC5302937 DOI: 10.18632/oncotarget.10967] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 07/19/2016] [Indexed: 01/19/2023] Open
Abstract
CD133 is considered as a stem-like cell marker in some cancers including gastric cancers, and Notch1 signaling is known to play an important role in the maintenance and differentiation of stem-like cells. We aimed to investigate whether Notch1 signaling contributes to the carcinogenesis of gastric cancers and CD133 induction. CD133 expression was detected in 51.4% of diffuse type gastric cancers while it was not detected in intestinal type gastric cancers. Similarly, only poorly-differentiated gastric cancer cell lines expressed CD133 and activated-Notch1. Inhibiting Notch1 signaling resulted in decreased CD133 expression, side population cells, cell proliferation and anchorage independent cell growth. Chromatin immunoprecipitation suggested that this Notch1 dependent regulation of CD133 was caused by direct binding of activated-Notch1 to the RBP-Jκ binding site in the 5' promoter region of CD133 gene. In addition, knocking down RBP-Jκ reduced CD133 induction in activated-Notch1 transfected cells. These findings suggested that Notch1 signaling plays an important role in the maintenance of the cancer stem-like phenotype in diffuse type gastric cancer through an RBP-Jκ dependent pathway and that inhibiting Notch1 signaling could be an effective therapy against CD133 positive diffuse type gastric cancers.
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Affiliation(s)
- Hidetomo Konishi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Akira Imatani
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Osamu Kimura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Yutaka Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Xiaoyi Jin
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Takeshi Kanno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Waku Hatta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Nobuyuki Ara
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Kiyotaka Asanuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tomoyuki Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan
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Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:441-78. [PMID: 27573785 DOI: 10.1007/978-3-319-41388-4_22] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.
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14
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Tang XD, Zhou LY, Zhang ST, Xu YQ, Cui QC, Li L, Lu JJ, Li P, Lu F, Wang FY, Wang P, Bian LQ, Bian ZX. Randomized double-blind clinical trial of Moluodan (摩罗丹) for the treatment of chronic atrophic gastritis with dysplasia. Chin J Integr Med 2015; 22:9-18. [DOI: 10.1007/s11655-015-2114-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Indexed: 01/06/2023]
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15
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Hirahashi M, Koga Y, Kumagai R, Aishima S, Taguchi K, Oda Y. Induced nitric oxide synthetase and peroxiredoxin expression in intramucosal poorly differentiated gastric cancer of young patients. Pathol Int 2014; 64:155-63. [PMID: 24750185 DOI: 10.1111/pin.12152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Accepted: 02/27/2014] [Indexed: 12/21/2022]
Abstract
To investigate the relationship between oxidative stress and gastric carcinogenesis of poorly differentiated adenocarcinoma in young patients, we analyzed the surgically resected specimens of 22 young patients (21-30 years) and 29 older patients (41-72 years) with intramucosal gastric cancer of the poorly differentiated type. We used immunohistochemical staining to evaluate the expression of 8-hydroxydeoxyguanosine (8OHdG), induced nitric oxide synthetase (iNOS), and antioxidant enzymes (thioredoxin [TRX] and peroxiredoxin [PRDX1, 2 and 3]). We assessed these proteins in the cancer, noncancerous gastric foveolar epithelium and noncancerous mucosal neck. In both the young and older patient groups, the 8OHdG and TRX expressions were gradually increased in cancer cells compared with the noncancerous foveolar epithelial cells and the noncancerous mucosal neck cells (P < 0.001). Although the iNOS and PRDXs expressions were increased in the noncancerous mucosal neck cells compared with the noncancerous foveolar epithelial cells, regardless of age (P < 0.001), the iNOS and PRDX2 expression in the cancer cells were significantly reduced in the young patients compared with the older patients (P < 0.001, P < 0.05). In conclusion, the reduced expression of iNOS or PRDX2 may play an important role in the carcinogenesis of gastric cancer associated with Helicobacter pylori-induced chronic active gastritis in young patients.
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Affiliation(s)
- Minako Hirahashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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16
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Wu JX, Zhao YY, Wu X, An HX. Clinicopathological and prognostic significance of CD24 overexpression in patients with gastric cancer: a meta-analysis. PLoS One 2014; 9:e114746. [PMID: 25503963 PMCID: PMC4264770 DOI: 10.1371/journal.pone.0114746] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 11/13/2014] [Indexed: 01/29/2023] Open
Abstract
Objective The prognostic significance of CD24 expression for survival in patients with gastric cancer remains controversial. We conducted a meta-analysis to investigate the impact of CD24 expression on clinicopathological features and survival outcomes in gastric cancer. Methods A comprehensive literature search of the electronic databases PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI; up to April 8, 2014) was performed for relevant studies using multiple search strategies. Correlations between CD24 expression and clinicopathological features and overall survival (OS) were analyzed. Results A total of 1,041 patients with gastric cancer from 9 studies were included. The pooled odds ratios (ORs) indicated CD24 expression was associated with tumor depth (OR = 0.45, 95% confidence interval [CI] = 0.32–0.63; P<0.00001), status of lymph nodes (OR = 0.40, 95% CI = 0.25–0.64; P = 0.0001) and tumor node metastasis (TNM) stage (OR = 0.56, 95% CI = 0.41–0.77; P = 0.0003). The pooled hazard ratio (HR) for OS showed overexpression of CD24 reduced OS in gastric cancer (HR = 1.99, 95% CI = 1.29–3.07, P = 0.002). Whereas, combined ORs showed that CD24 expression had no correlation with tumor differentiation or Lauren classifications. Conclusion CD24 overexpression in patients with gastric cancer indicated worse survival outcomes and was associated with common clinicopathological poor prognostic factors.
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Affiliation(s)
- Jing-Xun Wu
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Yuan-Yuan Zhao
- State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xuan Wu
- Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Han-Xiang An
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- * E-mail:
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17
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Wei X, Zhang E, Wang C, Gu D, Shen L, Wang M, Xu Z, Gong W, Tang C, Gao J, Chen J, Zhang Z. A MAP3k1 SNP predicts survival of gastric cancer in a Chinese population. PLoS One 2014; 9:e96083. [PMID: 24759887 PMCID: PMC3997500 DOI: 10.1371/journal.pone.0096083] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 04/03/2014] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES Genome-wide association studies (GWAS) have demonstrated that the single nucleotide polymorphism (SNP) MAP3K1 rs889312 is a genetic susceptibility marker significantly associated with a risk of hormone-related tumors such as breast cancer. Considering steroid hormone-mediated signaling pathways have an important role in the progression of gastric cancer, we hypothesized that MAP3K1 rs889312 may be associated with survival outcomes in gastric cancer. The purpose of this study was to test this hypothesis. METHODS We genotyped MAP3K1 rs889312 using TaqMan in 884 gastric cancer patients who received subtotal or total gastrectomy. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between MAP3K1 rs889312 genotypes and survival outcomes of gastric cancer. RESULTS Our findings reveal that the rs889312 heterozygous AC genotype was significantly associated with an increased rate of mortality among patients with diffuse-type gastric cancer (log-rank P = 0.028 for AC versus AA/CC, hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 1.03-1.69), compared to those carrying the homozygous variant genotypes (AA/CC). Additionally, univariate and multivariate Cox regression analysis demonstrate that rs889312 polymorphism was an independent risk factor for poor survival in these patients. CONCLUSIONS In conclusion, we demonstrate that MAP3K1 rs889312 is closely correlated with outcome among diffuse-type gastric cancer. This raises the possibility for rs889312 polymorphisms to be used as an independent indicator for predicting the prognosis of diffuse-type gastric cancer within the Chinese population.
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Affiliation(s)
- Xiaowei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Enke Zhang
- Central Laboratory, Shanxi People’s Hospital, Xi’an, Shanxi Province, China
| | - Chun Wang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Dongying Gu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lili Shen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China
- Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zhi Xu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Weida Gong
- Department of General Surgery, Yixing Tumor Hospital, Yixing, Jiangsu Province, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jinglong Gao
- Central Laboratory, Shanxi People’s Hospital, Xi’an, Shanxi Province, China
| | - Jinfei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
- * E-mail: (JC); (ZZ)
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China
- Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China
- * E-mail: (JC); (ZZ)
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18
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Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R. Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors. Cancer Sci 2014; 105:528-36. [PMID: 24612061 PMCID: PMC4317844 DOI: 10.1111/cas.12387] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 02/18/2014] [Accepted: 02/20/2014] [Indexed: 01/25/2023] Open
Abstract
Diffuse-type gastric carcinomas (DGC) exhibit more aggressive progression and poorer prognosis than intestinal-type and other gastric carcinomas. To identify potential therapeutic targets, we examined protein tyrosine phosphorylation in a panel of DGC and other gastric cancer cell lines. Protein tyrosine phosphorylation was significantly enhanced or altered in DGC cell lines compared with that in other gastric cancer cell lines. Affinity purification and mass spectrometry analysis of tyrosine-phosphorylated proteins identified Met as a protein that is preferentially expressed and phosphorylated in DGC cell lines. Unexpectedly, Met inhibitors blocked cell growth, Met downstream signaling and peritoneal dissemination in vivo in only a subset of cell lines that exhibited remarkable overexpression of Met. Likewise, only cell lines with overexpression of fibroblast growth factor receptor 2 (FGFR2) or phosphorylation of FRS2 were sensitive to an FGFR2 inhibitor. A Src inhibitor saracatinib impaired growth in cell lines that are insensitive to both Met and FGFR2 inhibitors. Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells. Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors. These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.
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Affiliation(s)
- Hideki Yamaguchi
- Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
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Liu YJ, Shen D, Yin X, Gavine P, Zhang T, Su X, Zhan P, Xu Y, Lv J, Qian J, Liu C, Sun Y, Qian Z, Zhang J, Gu Y, Ni X. HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma. Br J Cancer 2014; 110:1169-78. [PMID: 24518603 PMCID: PMC3950883 DOI: 10.1038/bjc.2014.61] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Revised: 12/24/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Background: Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval
of trastuzumab, targeted therapies are emerging as promising treatment options for the
disease. This study aimed to explore the molecular segmentation of several known
therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and
fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or
investigational kits and scoring criteria. Knowledge of how these markers are segmented
in the same cohort of GC patients could improve future clinical trial designs. Methods: Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of
HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations
between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2
alterations were further tested in a panel of GC cell lines and the patient-derived GC
xenograft (PDGCX) model using the targeted inhibitors. Results: Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23
(13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity
for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET
was found in 1 GC patient, and amplification of the two genes was found in different
tumour cells. Our study in a panel of GC cell lines showed that in most cell lines,
amplification or high expression of a particular molecular marker was mutually exclusive
and in vitro sensitivity to the targeted agents lapatinib, PD173074 and
crizotinib was only observed in cell lines with the corresponding high expression of the
drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to
crizotinib but not to lapatinib or PD173074. Conclusions: Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations
(gene amplification and overexpression) occur in three largely distinct molecular
segments in GC. A significant proportion of HER2-negative patients may potentially
benefit from MET- or FGFR2-targeted therapies.
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Affiliation(s)
- Y J Liu
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - D Shen
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200127, China
| | - X Yin
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - P Gavine
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - T Zhang
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - X Su
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - P Zhan
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - Y Xu
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - J Lv
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - J Qian
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - C Liu
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - Y Sun
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - Z Qian
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - J Zhang
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - Y Gu
- Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China
| | - X Ni
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200127, China
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Li Y, Sun Z, Zhu Z, Zhang J, Sun X, Xu H. PBX3 is overexpressed in gastric cancer and regulates cell proliferation. Tumour Biol 2013; 35:4363-8. [PMID: 24375258 DOI: 10.1007/s13277-013-1573-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 12/17/2013] [Indexed: 12/12/2022] Open
Abstract
The pre-leukemia transcription factor 3 (PBX3) is a member of the PBX family of transcription factors, which is known to increase DNA-binding/transcriptional activity of HOX proteins and regulate genes involved in development. Recently, PBX3 was reported to be involved in a variety of cancers, while its implication in gastric cancer is unclear. This study aimed to investigate its clinical significance and biological function in gastric cancer. PBX3 expression was analyzed in 90 gastric cancer specimens using immunohistochemistry. PBX3 was overexpressed in 30 cases (33.33%). Importantly, PBX3 overexpression positively correlated with advanced invasion depth (p = 0.0017), Clinical stage (p = 0.0127) and grade of tumor differentiation (p = 0.0158). PBX3 was also overexpressed in gastric cancer cell lines. Plasmid transfection was performed in AGS and SGC-7901 gastric cancer cell line with low endogenous PBX3 expression. MTT and colony formation assay were carried out to assess the role of PBX3 in proliferation. PBX3 overexpression in gastric cancer cell lines accelerated cell proliferation rate and colony formation ability, with upregulation of PCNA expression. In addition, matrigel invasion assay showed that PBX3 transfection also increased cell-invading ability. These results validate the role of PBX3 as a clinically relevant oncoprotein and establish PBX3 as a promising therapeutic target of gastric cancer.
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Affiliation(s)
- Yanke Li
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, People's Republic of China
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21
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Kim JY, Shin NR, Kim A, Lee HJ, Park WY, Kim JY, Lee CH, Huh GY, Park DY. Microsatellite instability status in gastric cancer: a reappraisal of its clinical significance and relationship with mucin phenotypes. KOREAN JOURNAL OF PATHOLOGY 2013; 47:28-35. [PMID: 23483099 PMCID: PMC3589606 DOI: 10.4132/koreanjpathol.2013.47.1.28] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 12/27/2012] [Accepted: 01/04/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Gastric cancers with microsatellite instabilities (MSI) have been reported to be associated with favorable prognosis. However, the significance of the effect of MSI on the clinicopathological features, as well as its association with mucin phenotype, remains unclear. METHODS MSI status was assessed in 414 cases of gastric cancer using polymerase chain reaction analysis of five microsatellite loci, as recommended by National Cancer Institution criteria. The expression of mucins (MUC5AC, MUC6, MUC2, and CD10) was assessed. RESULTS Out of 414 total cases of gastric cancer, 380 (91.7%), 11 (2.7%), and 23 (5.6%) were microsatellite stable (MSS), low-level MSI (MSI-L), and high-level MSI (MSI-H), respectively. Compared to MSS/MSI-L, MSI-H gastric cancers were associated with older age (p=0.010), tumor size (p=0.014), excavated gross (p=0.042), intestinal type (p=0.028), aggressive behaviors (increase of T stage [p=0.009]), perineural invasion [p=0.022], and lymphovascular emboli [p=0.027]). MSI-H gastric cancers were associated with tumor necrosis (p=0.041), tumor-infiltrating lymphocytes (≥2/high power field, p<0.001), expanding growth patterns (p=0.038), gastric predominant mucin phenotypes (p=0.028), and MUC6 expression (p=0.016). Tumor necrosis (≥10% of mass, p=0.031), tumor-infiltrating lymphocytes (p<0.001), intestinal type (p=0.014), and gastric mucin phenotypes (p=0.020) could represent independent features associated with MSI-H gastric cancers. MSI-H intestinal type gastric cancers had a tendency for poor prognosis in univariate analysis (p=0.054) but no association in Cox multivariate analysis (p=0.197). CONCLUSIONS Our data suggest that MSI-H gastric cancers exhibit distinct aggressive biologic behaviors and a gastric mucin phenotype. This contradicts previous reports that describe MSI-H gastric cancer as being associated with favorable prognosis.
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Affiliation(s)
- Joo-Yeun Kim
- Department of Pathology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
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22
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Kasuga A, Yamamoto Y, Fujisaki J, Okada K, Omae M, Ishiyama A, Hirasawa T, Chino A, Tsuchida T, Igarashi M, Hoshino E, Yamamoto N, Kawaguchi M, Fujita R. Clinical characterization of gastric lesions initially diagnosed as low-grade adenomas on forceps biopsy. Dig Endosc 2012; 24:331-8. [PMID: 22925285 DOI: 10.1111/j.1443-1661.2012.01238.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM The aim of this study was to elucidate characteristics of gastric lesions that are initially diagnosed as low-grade adenomas and to establish appropriate treatment. METHODS We retrospectively reviewed 231 lesions initially diagnosed as gastric adenomas. All forceps biopsy samples were histologically diagnosed as category 3 low-grade adenomas according to the revised Vienna Classification. All patients underwent endoscopic resection with endoscopic findings and post-resection diagnoses evaluated subsequently. RESULTS Sixty-three lesions were initially diagnosed as depressed adenomas, and 168 lesions were diagnosed as protruding adenomas. The depressed lesions were significantly smaller (11.6 ± 5.0 mm) than the protruding lesions (17.0 ± 10.8 mm) (P < 0.001). Diagnoses reclassified to category 4 mucosal high-grade neoplasia (i.e. high-grade adenoma, adenocarcinoma in adenoma and adenocarcinoma) were more frequent among depressed lesions (52.4%) than among protruding lesions (31.0%) (P = 0.004). Multivariate analysis of all 231 lesions showed that lesion size larger than 20 mm (P < 0.001) and depressed appearance (including central depression) (P < 0.001) were significant independent factors suggesting cancer. For the 168 protruding lesions, lesion size larger than 20 mm (P < 0.001) and central depression (P < 0.001) were significant independent factors suggesting cancer. For the 63 depressed lesions, lesion size larger than 15 mm (P = 0.016) and a moth-eaten appearance (P = 0.017) were significant independent factors in the pre-treatment diagnosis of cancer. CONCLUSIONS Adenocarcinoma lesions were often found in depressed lesions and protruding lesions with central depression. Endoscopic resection for total biopsy is recommended, even if forceps biopsy indicates low-grade adenoma, as pre-treatment biopsy may be inadequate for an accurate histological diagnosis.
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Affiliation(s)
- Akiyoshi Kasuga
- Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.
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Gonçalves AR, Carneiro AJV, Martins I, de Faria PAS, Ferreira MA, de Mello ELR, Fogaça HS, Elia CCS, de Souza HSP. Prognostic significance of p53 protein expression in early gastric cancer. Pathol Oncol Res 2011; 17:349-355. [PMID: 21116760 DOI: 10.1007/s12253-010-9333-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Accepted: 10/28/2010] [Indexed: 01/11/2023]
Abstract
Mutations of the p53 tumor suppressor gene have been associated with abnormalities in cell cycle regulation, DNA repair and synthesis, apoptosis, and it has been implicated in the prognosis of advanced gastric cancer. The aim of this study was to evaluate the occurrence of p53 gene mutation and its possible prognostic implications in early gastric cancer. In a retrospective study, we studied 80 patients with early gastric cancer treated surgically between 1982 and 2001. Mutation of p53 gene was investigated in surgical gastric specimens by immunohistochemistry, and results were analyzed in relation to gender, age, macroscopic appearance, size and location of tumor, presence of lymph nodes, Lauren's histological type, degree of differentiation, and the 5-year survival. The expression of p53 was more frequent among the intestinal type (p = 0.003), the differentiated (p = 0.007), and the macroscopically elevated tumors (p = 0.038). Nevertheless, the isolated expression of p53 was not associated with the 5-year survival, or with the frequency of lymph node involvement. The degree of differentiation was detected as an independent factor related to the outcome of patients (0.044). Significantly shorter survival time was found in p53-negative compared with p53-positive patients, when considering the degree of differentiation of tumors, as assessed by Cox regression analysis (0.049). The association of p53 with the intestinal type, the degree of differentiation and morphological characteristics, may reflect the involvement of chronic inflammatory process underlying early gastric cancer. In this population sample, the expression of p53 alone has no prognostic value for early gastric cancer. However, the significant difference in p53 expression between subgroups of degree of differentiation of tumors can influence post-operative outcome of patients and may be related to possible distinct etiopathogenic subtypes.
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Affiliation(s)
- Andrea Rodrigues Gonçalves
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Abstract
INTRODUCTION Inhibitors targeting oncogenic kinases, especially receptor tyrosine kinases (RTKs), are being vigorously developed, and some have been demonstrated to be effective in clinical settings. The amplification of certain RTKs (ErbB2, c-Met and FGFR2) is associated with gastric cancer progression, but the only recently approved inhibitor is trastuzumab, ErbB2-targeting antibody. Other well-known oncogenic kinases (PI3K and RAF) are also activated in a small portion of gastric cancers. Drugs targeting these kinases are promising and should be approved in an appropriate and expeditious way. AREAS COVERED This article reviews novel inhibitors emerging in the field of advanced gastric cancer, based on basic research concerning altered oncogenes and the clinical trials of drugs targeting these oncogenes. EXPERT OPINION Promising inhibitors of gastric cancer may be found in not only new investigative agents but also agents currently being used against other malignancies. The appropriate design for clinical trials of molecularly targeted therapeutic agents is also important. Targeted therapies tailored to individual genomic profiles would provide a more personalized treatment for advanced gastric cancer.
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Affiliation(s)
- Yoshinari Asaoka
- The University of Tokyo, Graduate School of Medicine, Department of Gastroenterology, Japan.
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Watanabe H. Intestinal metaplasia -the effect of Acid on the gastric mucosa and gastric carcinogenesis-. J Toxicol Pathol 2010; 23:115-23. [PMID: 22272022 PMCID: PMC3234614 DOI: 10.1293/tox.23.115] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Accepted: 06/02/2010] [Indexed: 12/25/2022] Open
Abstract
This review concerns stem cells and their relation to intestinal metaplasia. When
gastric regions of mice, Mongolian gerbils or several strains of rats were
irradiated with a total dose of 20 Gy of X-rays given in two fractions,
intestinal metaplasia was only induced in rats. In addition, it was greatly
influenced by rat strain and sex. Alkaline phosphatase (ALP) positive
metaplastic foci were increased by administration of ranitidine (H2
receptor antagonist), crude stomach antigens or subtotal resection of the fundus
and decreased by cysteamine (gastric acid secretion stimulator), histamine or
removal of the submandibular glands. Recent studies have shown that
Cdx2 transgenic mice with gastric achlorhydria develop
intestinal metaplasia and that in men and animals, Helicobacterpylori (H. pyrlori) infection can cause intestinal metaplasias
that are reversible on eradication. Our results combined with findings for
H. pylori infection or eradication and transgenic mice
suggest that an elevation in the pH of the gastric juice due to disappearance of
parietal cells is one of the principal factors for development of reversible
intestinal metaplasia. When different organs were transplanted into the stomach
or duodenum, they were found to transdifferentiate into gastric or duodenal
mucosae, respectively. Organ-specific stem cells in normal non-liver tissues
(heart, kidney, brain and skin) also differentiate into hepatocytes when
transplanted into an injured liver. Therefore, stem cells have a multipotential
ability, transdifferentiating into different organs when transplanted into
different environments. Finally, intestinal metaplasia has been found to
possibly increase sensitivity to the induction of tumors by colon carcinogens of
the 1,2-dimethylhydrazine (DMH), azoxymethane (AOM) or
2-amino-1-methyl-6-phenylimidazo[4.5-b]pyridine (PhIP) type. This carcinogenic
process, however, may be relatively minor compared with the main gastric
carcinogenesis process induced by N-methy1-N’-nitro-N-nitrosoguanidine (MMNG) or
N-methylnitrosourea (MNU), which is not affected by the presence of intestinal
metaplasia. The protocol used in these experiments may provide a new approach to
help distinguish between developmental events associated with intestinal
metaplasia and gastric tumors.
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Affiliation(s)
- Hiromitsu Watanabe
- Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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Okada K, Fujisaki J, Kasuga A, Omae M, Yoshimoto K, Hirasawa T, Ishiyama A, Yamamoto Y, Tsuchida T, Hoshino E, Igarashi M, Takahashi H. Endoscopic ultrasonography is valuable for identifying early gastric cancers meeting expanded-indication criteria for endoscopic submucosal dissection. Surg Endosc 2010; 25:841-8. [PMID: 20734082 DOI: 10.1007/s00464-010-1279-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2009] [Accepted: 07/19/2010] [Indexed: 12/29/2022]
Abstract
BACKGROUND Endoscopic ultrasonography (EUS) has become a reliable method for predicting the invasion depth of early gastric cancer (EGC). This study evaluated the accuracy of EUS in identifying lesions meeting expanded-indication criteria for endoscopic submucosal dissection (ESD) and analyzed clinicopathologic factors influencing the diagnostic accuracy of EUS in assessing tumor invasion depth. METHODS This study investigated 542 EGCs of 515 patients who underwent EUS pretreatment. The pretreatment EUS-determined diagnosis was compared with the final histopathologic evaluation of resected specimens, and the impact of various clinicopathologic parameters on diagnostic accuracy was analyzed. RESULTS The diagnostic accuracy of EUS in identifying lesions meeting expanded-indication criteria for ESD was 87.8% (259/295) for differentiated adenocarcinoma (D-type) 30 mm in diameter or smaller, 43.5% (10/23) for D-type tumor larger than 30 mm in diameter, and 75% (42/56) for undifferentiated adenocarcinoma (UD-type) 20 mm in diameter or smaller. Using multivariate analysis, the diagnostic accuracy of EUS in predicting tumor invasion depth was determined to be decreased significantly by ulcerous change and large tumor size (diameter, ≥30 mm). CONCLUSION For patients with EGC, D-type lesions 30 mm in diameter or smaller and UD-type lesions 20 mm in diameter or smaller can be diagnosed with high accuracy by EUS, but larger D-type lesions (diameter, >30 mm) should be considered carefully in terms of EUS-based treatment decisions. Findings of ulceration and large tumors are associated with incorrect diagnosis of tumor invasion depth by EUS.
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Affiliation(s)
- Kazuhisa Okada
- Ariake Hospital of Japanese Foundation for Cancer Research,Tokyo, Japan
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Kubota E, Kataoka H, Aoyama M, Mizoshita T, Mori Y, Shimura T, Tanaka M, Sasaki M, Takahashi S, Asai K, Joh T. Role of ES cell-expressed Ras (ERas) in tumorigenicity of gastric cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:955-63. [PMID: 20566745 DOI: 10.2353/ajpath.2010.091056] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
ERas, a unique member of the Ras family, was initially found only in embryonic stem (ES) cells, where it plays a crucial role in the transformation of transplanted ES cells to teratomas. ERas is involved in ES cell survival, and unlike other Ras family members, is constitutively active without any mutations. The aim of this study was to investigate the expression and role of ERas in human gastric cancer. To test whether ERas played a significant role in human cancer cells, we examined its expression and function in gastric cancer. ERas was expressed in gastric cancer cell lines at different levels. Induction of ERas expression activated the phosphatidylinositol 3 kinase (PI3K)/Akt axis and then enhanced anchorage-independent growth and ERas knockdown by siRNA suppressed cell invasion. Immunohistochemical analyses revealed that ERas was expressed in 38.7% (55/142) of human gastric carcinoma tissues, and its expression was significantly associated with metastasis to the liver (P < 0.0001) and lymph nodes (P < 0.05). ERas up-regulated transcription regulatory factors including ZFHX1A, ZFHX1B, and TCF3, which repress E-cadherin. These data suggest that ERas is activated in a significant population of gastric cancer, where it may play a crucial role in gastric cancer cell survival and metastases to liver via down-regulation of E-cadherin.
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Affiliation(s)
- Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Zhang J, Zhan N, Dong WG. Altered expression of selenium-binding protein 1 in gastric carcinoma and precursor lesions. Med Oncol 2010; 28:951-7. [PMID: 20480265 DOI: 10.1007/s12032-010-9564-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 05/04/2010] [Indexed: 10/19/2022]
Abstract
Selenium-binding protein 1 (SBP1) has been shown to be greatly reduced in various human cancers. The purpose of this study was to evaluate the expression of SBP1 in precursor lesions and gastric carcinoma (GC) and to discuss the specific role of SBP1 in gastric carcinogenesis. Using tissue microarray (TMA) technology and immunohistochemical (IHC) survey, SBP1 expressions were evaluated based on a semi-quantitative scoring system developed for this study in 25 paired of GC and corresponding nonneoplastic epithelia tissues, 21 gastric ulcer, 13 gastric polyp, 19 chronic atrophic gastritis, 20 intestinal metaplasia, and 16 dysplasia tissues. We found abundant expression of SBP1 in most precursor lesions in addition to the nonneoplastic epithelia tissues. However, the expression of SBP1 was severely suppressed in most of the GC tissues (P=0.000). Although no statistical differences were found between the expressions of SBP1 in gastric tissues with different levels of intestinal metaplasia or dysplasia (P>0.05), the reduction in SBP1 seems to be correlated with clinical stage of GC (P=0.044). Thus, SBP1 can be supposed as a diagnosis marker of GC. The suppression of SBP1 may be a late event in gastric carcinogenesis.
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Affiliation(s)
- Jin Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 9 # Ziyang Road, 430060, Wuhan, Hubei Province, China
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Asaoka Y, Tada M, Ikenoue T, Seto M, Imai M, Miyabayashi K, Yamamoto K, Yamamoto S, Kudo Y, Mohri D, Isomura Y, Ijichi H, Tateishi K, Kanai F, Ogawa S, Omata M, Koike K. Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion. Biochem Biophys Res Commun 2010; 394:1042-6. [PMID: 20331976 DOI: 10.1016/j.bbrc.2010.03.120] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 03/18/2010] [Indexed: 10/19/2022]
Abstract
Receptor tyrosine kinases (RTKs) are involved in oncogenesis and disease progression for many cancers. Inhibitors targeting them are vigorously developed and some of them are tested in the clinical setting. Amplifications of certain RTKs (c-Met, FGFR2 and ErbB2) have been associated with human gastric cancer progression. According to our genome-wide scans of genetic lesions in 34 gastric cancer cell lines using high-density single-nucleotide polymorphism genotyping microarrays, we confirmed that the c-met locus was amplified in four gastric cancer cell lines (Hs746T, MKN45, NUGC4 and SNU5). It was reported that somatic mutation is occasionally detected in tumor samples of a certain type of cancer with gene amplification. Previous reports showed gastric cancers harbored mutations of FGFR2 and ErbB2, but c-Met oncogenic mutation had not yet been reported. We performed mutational analysis of the cytoplasmic domains of c-Met using the genome DNA of the gastric cancer cell lines, and found that Hs746T cells had a splice site mutation of exon 14. By cDNA sequencing and Western blotting, we showed that the mutation caused juxtamembrane domain deletion. Previously, this mutation had been detected only in lung cancer specimens and this deletion resulted in the loss of Cbl E3-ligase binding causing decreased ubiquitination and delayed down-regulation. In conclusion, four gastric cancer cell lines harbored amplification of c-met locus, and among them, Hs746T had a putative oncogenic mutation with amplification. This information will be useful for screening of inhibitors targeting gastric cancer with c-Met aberration.
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Affiliation(s)
- Yoshinari Asaoka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Kim JH, Shin HS, Lee SH, Lee I, Lee YS, Park JC, Kim YJ, Chung JB, Lee YC. Contrasting activity of Hedgehog and Wnt pathways according to gastric cancer cell differentiation: relevance of crosstalk mechanisms. Cancer Sci 2010; 101:328-35. [PMID: 19930158 PMCID: PMC11158279 DOI: 10.1111/j.1349-7006.2009.01395.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Gastric cancer displays different biological behaviors according to histological differentiation. The different biological behavior might involve the activation of distinct signaling pathways necessary for the growth and survival of cancer cells in gastric cancer. We investigated the differentiation-related signal interaction between Hedgehog and Wnt pathways in gastric cancer cells. Differentiation of gastric cancer cells was induced by sodium butyrate. The sonic Hedgehog (SHH) signal expressions were increased during cellular differentiation. In contrast, the expression of Wnt signaling was decreased during differentiation. Ectopic expression of glioma-associated oncogene-1 (GLI1) increased the level of secreted frizzled related protein-1 (SFRP1) transcript, whereas inhibition of GLI1 reduced the level of SFRP1 transcript. ChIP assay showed that GLI1 induced the transcriptional regulation of SFRP1 gene expression. Ectopic expression of GLI1 decreased the nuclear beta-catenin staining, but the inhibition of GLI1 induced the reversal of nuclear beta-catenin overexpression. Ectopic expression of beta-catenin also decreased the expression of GLI1 in the butyrate treated cancer cells. SHH and GLI1 immunoexpression was greater in well differentiated gastric cancer tissues compared to poorly differentiated tissues, and nuclear beta-catenin immunoexpression was lower in well differentiated compared to poorly differentiated tissues. The SHH and Wnt pathways are differentially involved according to gastric cancer cell differentiation.
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Affiliation(s)
- Jie-Hyun Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Kameda C, Nakamura M, Tanaka H, Yamasaki A, Kubo M, Tanaka M, Onishi H, Katano M. Oestrogen receptor-alpha contributes to the regulation of the hedgehog signalling pathway in ERalpha-positive gastric cancer. Br J Cancer 2010; 102:738-47. [PMID: 20087349 PMCID: PMC2837575 DOI: 10.1038/sj.bjc.6605517] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Oestrogen receptor-alpha (ERalpha) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERalpha-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. METHODS We used 17-beta-oestradiol (E2) as a stimulator against the ERalpha pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERalpha (ERalpha siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERalpha-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. RESULTS In ERalpha-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-beta-Oestradiol-induced cell proliferation was suppressed by ICI, ERalpha siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERalpha siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERalpha and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERalpha and Hh pathways. CONCLUSION Our data indicate that activation of the ERalpha pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERalpha-positive gastric cancer.
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Affiliation(s)
- C Kameda
- Department of Cancer Therapy and Research, Kyushu University, Fukuoka, Japan
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Yashima K, Sasaki S, Koda M, Kawaguchi K, Harada K, Murawaki Y. Premalignant lesions in gastric cancer. Clin J Gastroenterol 2009; 3:6-12. [PMID: 26189899 DOI: 10.1007/s12328-009-0130-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 11/18/2009] [Indexed: 12/27/2022]
Abstract
Despite a plateau in incidence, gastric cancer is one of the most common cancers worldwide and causes considerable morbidity and mortality. Premalignant gastric lesions are well known risk factors for the development of intestinal-type gastric adenocarcinomas. In this multistep model of gastric carcinogenesis, Helicobacter pylori causes chronic active inflammation of the gastric mucosa, which slowly progresses through the premalignant stages of atrophic gastritis, intestinal metaplasia, and adenoma/dysplasia to gastric carcinoma. This progression is paralleled by a stepwise accumulation of multiple genetic and epigenetic abnormalities. Detection, treatment, and molecular analyses of premalignant lesions may thus provide a basis for gastric cancer prevention. This review describes an overview of current knowledge on premalignant gastric lesions. It also reviews the issue of surveillance of patients with premalignant lesions in order to improve the survival of patients with gastric cancer.
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Affiliation(s)
- Kazuo Yashima
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan.
| | - Shuji Sasaki
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Masaharu Koda
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Yoshikazu Murawaki
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
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Jiang XY, Qian LP, Zheng XJ, Xia YY, Jiang YB, Sun DY. Interventional effect of Ginkgo biloba extract on the progression of gastric precancerous lesions in rats. J Dig Dis 2009; 10:293-9. [PMID: 19906108 DOI: 10.1111/j.1751-2980.2009.00398.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the effect of Ginkgo biloba extract on gastric precancerous lesions in rats. METHODS 80 4-week-old Wistar rats were randomly divided into four groups: a control group, a model group, a low and a high dose Ginkgo biloba extract intervention group; 20 in each group. Gastric precancerous lesions were induced by giving them 100 mg/L N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) solution to drink ad libitum for 20 weeks. In addition to the MNNG, the intervention groups were lavaged with Ginkgo biloba extract (0.5 mg/kg/d in the low dose group, 1.5 mg/kg/d in the high dose group) for 20 weeks. Starting from week 21 all the rats were fed with normal rat chow and tap water. At the end of week 30 the rats were killed. The histopathological changes of their gastric mucosa, ISA, NGI, the serum and gastric mucosal SOD/MDA and the expressions of oncogenes were studied. RESULTS The incidence of mild to severe intestinal metaplasia and dysplasia were significantly lower in the intervention groups than those in the model group (P < 0.01). The ISA and NGI in the intervention groups were significantly lower than those in the model group (P < 0.01). In the intervention groups the activity of SOD was increased and the concentration of MDA was decreased (P < 0.01). Expressions of Bcl-2, c-myc and FasL decreased in the intervention groups, whereas the expression of Fas increased. When compared with the model group, the differences were statistically significant (P < 0.01, P < 0.05, respectively). CONCLUSION Ginkgo biloba extract can increase anti-oxidative activity and inhibit the progression of gastric precancerous lesions via the regulation of cell proliferation and apoptosis.
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Affiliation(s)
- Xiao Yun Jiang
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
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Yashiro M, Inoue T, Nishioka N, Matsuoka T, Boland CR, Hirakawa K. Allelic imbalance at p53 and microsatellite instability are predictive markers for resistance to chemotherapy in gastric carcinoma. Ann Surg Oncol 2009; 16:2926-35. [PMID: 19597886 DOI: 10.1245/s10434-009-0590-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 06/09/2009] [Accepted: 06/11/2009] [Indexed: 12/20/2022]
Abstract
BACKGROUND Combined treatment with 5-fluorouracil and cisplatin (FP chemotherapy) is an effective neoadjuvant regimen for gastric carcinoma. However, it is ineffective in half of all patients. This study tests the hypothesis that genetic markers might identify those patients with gastric cancer who would respond to neoadjuvant FP chemotherapy. MATERIALS AND METHODS A total of 23 patients with gastric carcinoma were treated with neoadjuvant chemotherapy. Pretreatment biopsy specimens before neoadjuvant chemotherapy were obtained from 15 of 23 patients, and resected tumors were obtained from all 23. Genetic studies were performed to detect allelic imbalance (AI), microsatellite instability (MSI), and K-ras mutation. RESULTS A clinical response was observed in 13 of 23 patients. Kaplan-Meier survival curve showed that clinical responder group had a significantly higher likelihood of overall survival (P = 0.0165), compared with nonresponder group. In 23 resection specimens, 10 of 23 tumors presented AI at the p53 locus and/or MSI; 8 of the 10 tumors were nonresponders, while 12 of 13 tumors without p53 AI or MSI were responders (P = 0.0007). In 15 pretreatment biopsy specimens, 8 tumors had p53 AI and/or MSI; 7 of the 8 tumors were nonresponders, while 6 of 7 tumors without p53 AI or MSI were responders to preoperative chemotherapy (P = 0.008). Tumors with AI at the p53 locus and/or MSI were significantly more resistant to neoadjuvant chemotherapy. No relationship was found between K-ras mutations and responses. CONCLUSIONS Analysis for p53 AI and MSI might represent a clinically useful approach to predicting the response to neoadjuvant FP chemotherapy in gastric carcinoma.
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Affiliation(s)
- Masakazu Yashiro
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Usefulness of endoscopic ultrasonography in determining the depth of invasion and indication for endoscopic treatment of early gastric cancer. J Clin Gastroenterol 2009; 43:318-22. [PMID: 19077733 DOI: 10.1097/mcg.0b013e3181775966] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Endoscopic ultrasonography (EUS) is a useful method for visualizing features of gastric cancer. However, a previously reported classification system tended to result in overstaging. We investigated the usefulness of EUS for evaluation of the depth of gastric cancer invasion and indications for endoscopic treatment. METHODS Accuracy of EUS for determining the depth of invasion and incidences of a positive basal margin were assessed in 235 patients who underwent endoscopic treatment or surgery for gastric cancer. The EUS-determined depth of invasion was classified as follows: EUS-M (lesion confined to sonographic layers 1 and 2); EUS-M/SM border (lesion with changes in sonographic layer 3 but no deeper than 1 mm); EUS-SM (lesion with changes in sonographic layer 3 deeper than 1 mm); or EUS-AD (lesion with changes in sonographic layer 4 or 5). RESULTS Accuracy of EUS for determining the depth of invasion was as follows: EUS-M, 99% were M and SM1 lesions; EUS-M/SM border, 87% were M and SM1 lesions; EUS-SM, 91% were SM2 lesions; EUS-AD, 100% were muscularis propria or deeper lesions. There was no EUS-M or EUS-M/SM border lesion for which endoscopic treatment resulted in a positive basal margin. CONCLUSIONS EUS is useful for accurately determining the depth of invasion of gastric cancer. When there are no endoscopically determined ulcerous changes, endoscopic treatment should be considered for EUS-M and EUS-M/SM border lesions, and EUS-SM lesions should be treated surgically.
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Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. Br J Cancer 2008; 100:389-98. [PMID: 19107131 PMCID: PMC2634717 DOI: 10.1038/sj.bjc.6604846] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We previously reported hedgehog (Hh) signal activation in the mucus-secreting pit cell of the stomach and in diffuse-type gastric cancer (GC). Epithelial–mesenchymal transition (EMT) is known to be involved in tumour malignancy. However, little is known about whether and how both signallings cooperatively act in diffuse-type GC. By microarray and reverse transcription–PCR, we investigated the expression of those Hh and EMT signalling molecules in pit cells and in diffuse-type GCs. How both signallings act cooperatively in those cells was also investigated by the treatment of an Hh-signal inhibitor and siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human GC cell lines. Pit cells and diffuse-type GCs co-expressed many Hh and EMT signalling genes. Mesenchymal-related genes (WNT5A, CDH2, PDGFRB, EDNRA, ROBO1, ROR2, and MEF2C) were found to be activated by an EMT regulator, SIP1/ZFHX1B/ZEB2, which was a target of a primary transcriptional regulator GLI1 in Hh signal. Furthermore, we identified two cancer-specific Hh targets, ELK1 and MSX2, which have an essential role in GC cell growth. These findings suggest that the gastric pit cell exhibits mesenchymal-like gene expression, and that diffuse-type GC maintains expression through the Hh–EMT pathway. Our proposed extensive Hh–EMT signal pathway has the potential to an understanding of diffuse-type GC and to the development of new drugs.
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Carinci F, Arcelli D, Lo Muzio L, Francioso F, Valentini D, Evangelisti R, Volinia S, D'Angelo A, Meroni G, Zollo M, Pastore A, Ionna F, Mastrangelo F, Conti P, Tetè S. Molecular classification of nodal metastasis in primary larynx squamous cell carcinoma. Transl Res 2007; 150:233-45. [PMID: 17900511 DOI: 10.1016/j.trsl.2007.03.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2006] [Revised: 03/12/2007] [Accepted: 03/13/2007] [Indexed: 11/25/2022]
Abstract
Classification and prognosis of larynx squamous cell carcinoma (LSCC) depends on clinical and histopathological examination. Currently, expression profiling harbors the potential to investigate, classify, and better manage cancer. Gene expression profiles of 22 primary LSCCs were analyzed by microarrays containing 19,200 cDNAs. GOAL functionally classified differentially expressed genes, and a novel "in silico" procedure identified physical gene clusters differentially transcribed. A signature of 158 genes differentiated tumors with nodal metastasis. A novel statistical method allowed categorization of metastatic tumors into 2 distinct subgroups of differential gene expression patterns. Among genes correlated to nodal metastatic progression, we verified in vitro that NM23-H3 reduced cell motility and TRIM8 were a growth suppressor. Six chromosomal regions were specifically downregulated in metastatic tumors. This large-scale gene expression analysis in LSCC provides information on changes in genomic activity associated with lymphonodal metastasis and identifies molecules that might prove useful as novel therapeutic targets.
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MESH Headings
- Biomarkers, Tumor/genetics
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/secondary
- Carrier Proteins/genetics
- Cell Line, Tumor
- Cluster Analysis
- DNA, Complementary/genetics
- Disease Progression
- Down-Regulation/genetics
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Genes, Neoplasm
- Humans
- Laryngeal Neoplasms/genetics
- Laryngeal Neoplasms/metabolism
- Laryngeal Neoplasms/pathology
- Lymphatic Metastasis
- Male
- NM23 Nucleoside Diphosphate Kinases/genetics
- Neoplasm Staging
- Nerve Tissue Proteins/genetics
- Oligonucleotide Array Sequence Analysis/methods
- Prognosis
- RNA, Neoplasm/isolation & purification
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Suppressor Proteins/genetics
- Up-Regulation/genetics
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Affiliation(s)
- Francesco Carinci
- Department of Maxillofacial Surgery, University of Ferrara, Ferrara, Italy
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38
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Chou YY, Jeng YM, Lee TT, Hu FC, Kao HL, Lin WC, Lai PL, Hu RH, Yuan RH. Cytoplasmic CD24 expression is a novel prognostic factor in diffuse-type gastric adenocarcinoma. Ann Surg Oncol 2007; 14:2748-58. [PMID: 17680316 DOI: 10.1245/s10434-007-9501-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2007] [Revised: 05/28/2007] [Accepted: 05/28/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND CD24, a mucin like cell surface adhesion molecule and a ligand for P-selectin, has been reported as a prognostic factor in a variety of human cancers. However, the role of CD24 in gastric adenocarcinoma remains largely unknown. METHODS The expression pattern of CD24 in 103 gastric adenocarcinomas (31 diffuse type, 60 intestinal type, and 12 mixed type) was analyzed by immunohistochemistry. RESULTS Cytoplasmic CD24 expression occurred in 50% of the gastric adenocarcinoma patients and was associated with high-stage tumor (Stage III-IV, P = .023), serosal invasion (SI, P = .010), lymphovascular invasion (LVI, P = .039), and lower 10-year survival (P = .0238). The CD24 staining pattern was different in intestinal and diffuse-type gastric adenocarcinomas. However, the tumor thrombi in lymphovascular spaces exhibited strong cytoplasmic CD24 expression in both types. Further analysis showed that cytoplasmic CD24 expression was, in fact, correlated with high-stage tumor, SI, LVI, and lower 10-year survival significantly (P = .020, P = .007, P = .018, P = .0285, respectively) in diffuse-type gastric adenocarcinoma. Moreover, multivariate analysis showed that cytoplasmic CD24 expression was an independent risk factor of SI and LVI respectively (P = .0083 and P = .0019), and thus it contributed to high-stage tumor and poor patient survival in diffuse- or mixed-type gastric adenocarcinoma. CONCLUSIONS Cytoplasmic expression of CD24 was associated with invasiveness and poorer prognosis and can serve as a novel target for prognostic prediction and adjuvant treatment of patients with diffuse-type gastric adenocarcinoma after tumor resection.
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Affiliation(s)
- Yuh-Yu Chou
- Department of Pathology and Laboratory Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, 95 Wen-Chang Road, Taipei, Taiwan
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39
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Tari A, Kitadai Y, Sumii M, Sasaki A, Tani H, Tanaka S, Chayama K. Basis of decreased risk of gastric cancer in severe atrophic gastritis with eradication of Helicobacter pylori. Dig Dis Sci 2007; 52:232-9. [PMID: 17151803 DOI: 10.1007/s10620-006-9411-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2005] [Accepted: 04/30/2006] [Indexed: 12/27/2022]
Abstract
Helicobacter pylori infection induces chronic gastritis and lowers gastric juice ascorbic acid concentrations. We investigated how H. pylori eradication affected multiple variables that could prevent or delay development of new or occult gastric cancer in patients with early gastric cancer treated by endoscopic mucosal resection. Gastric juice pH, nitrite concentrations, and total vitamin C concentrations, serum concentrations of vitamin C and specific H. pylori antibody, and intensity of neutrophil infiltration in gastric mucosa were determined before and after successful H. pylori eradication. Successful eradication increased acid output and ascorbic acid secretion into gastric juice, accompanied by disappearance of polymorphonuclear infiltration from the surface epithelium and decreased gastric juice nitrite concentrations. Our data suggest that H. pylori eradication decreases the nitrosation rate as the ratio of vitamin C to nitrite increases. This decreases reactive oxygen species and nitric oxide, eliminating their damaging effect on DNA and reducing cell turnover.
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Affiliation(s)
- Akira Tari
- Department of Internal Medicine, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, 1-9-6 Senda-machi, Hiroshima, 730-8619, Japan.
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40
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Leyden J, Murray D, Moss A, Arumuguma M, Doyle E, McEntee G, O'Keane C, Doran P, MacMathuna P. Net1 and Myeov: computationally identified mediators of gastric cancer. Br J Cancer 2006; 94:1204-12. [PMID: 16552434 PMCID: PMC2361249 DOI: 10.1038/sj.bjc.6603054] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Gastric adenocarcinoma (GA) is a significant cause of mortality worldwide. The molecular mechanisms of GA remain poorly characterised. Our aim was to characterise the functional activity of the computationally identified genes, NET 1 and MYEOV in GA. Digital Differential Display was used to identify genes altered expression in GA-derived EST libraries. mRNA levels of a subset of genes were quantitated by qPCR in a panel of cell lines and tumour tissue. The effect of pro- and anti-inflammatory stimuli on gene expression was investigated. Cell proliferation and invasion were measured using in an in-vitro GA model following inhibition of expression using siRNA. In all, 23 genes not previously reported in association with GA were identified. Two genes, Net1 and Myeov, were selected for further analysis and increased expression was detected in GA tissue compared to paired normal tissue using quantitative PCR. siRNA-mediated downregulation of Net1 and Myeov resulted in decreased proliferation and invasion of gastric cancer cells in vitro. These functional studies highlight a putative role for NET1 and Myeov in the development and progression of gastric cancer. These genes may provide important targets for intervention in GA, evidenced by their role in promoting invasion and proliferation, key phenotypic hallmarks of cancer cells.
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Affiliation(s)
- J Leyden
- Gastrointestinal Unit, Mater Misericordiae University Hospital, University College Dublin, Ireland
| | - D Murray
- Genome Resource Unit, Department of Medicine and Therapeutics, Mater Misericordiae University Hospital, University College Dublin, Dublin 7, Ireland
| | - A Moss
- Gastrointestinal Unit, Mater Misericordiae University Hospital, University College Dublin, Ireland
| | - M Arumuguma
- Department of Surgery, Mater Misericordiae University Hospital, University College Dublin, Ireland
| | - E Doyle
- Department of Pathology, Mater Misericordiae University Hospital, University College Dublin, Ireland
| | - G McEntee
- Department of Surgery, Mater Misericordiae University Hospital, University College Dublin, Ireland
| | - C O'Keane
- Department of Pathology, Mater Misericordiae University Hospital, University College Dublin, Ireland
| | - P Doran
- Genome Resource Unit, Department of Medicine and Therapeutics, Mater Misericordiae University Hospital, University College Dublin, Dublin 7, Ireland
- Genome Resource Unit, Department of Medicine and Therapeutics, Mater Misericordiae University Hospital, University College Dublin, Dublin 7, Ireland. E-mail:
| | - P MacMathuna
- Gastrointestinal Unit, Mater Misericordiae University Hospital, University College Dublin, Ireland
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41
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Paju A, Stenman UH. Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci 2006; 43:103-42. [PMID: 16517420 DOI: 10.1080/10408360500523852] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Trypsinogens and PSTI/TATI/SPINK1 are expressed, usually together, at high levels by the pancreas but also by many other normal and malignant tissues. The present review describes studies on the expression and putative functions of trypsinogens and PSTI/TATI/SPINK1 in the human body. The clinical aspects are discussed, including the correlations between expression of trypsinogens and PSTI/TATI/SPINK1 in tissues, serum, and urine of patients with pancreatitis or cancer and clinicopathological characteristics, i.e., the roles of trypsinogens and PSTI/TATI/SPINK1 in spontaneous and hereditary pancreatitis, tumor progression, and prognosis.
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Affiliation(s)
- Annukka Paju
- Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland
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42
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Fukaya M, Isohata N, Ohta H, Aoyagi K, Ochiya T, Saeki N, Yanagihara K, Nakanishi Y, Taniguchi H, Sakamoto H, Shimoda T, Nimura Y, Yoshida T, Sasaki H. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology 2006; 131:14-29. [PMID: 16831586 DOI: 10.1053/j.gastro.2006.05.008] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2005] [Accepted: 03/16/2006] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Sonic hedgehog (SHH) and Indian hedgehog (IHH) have cell-specific actions in some organs. Only SHH has been shown to regulate parietal cell differentiation. This study examined whether SHH, 2 other ligands IHH and Desert hedgehog, and receptors or downstream targets are expressed in normal gastric epithelium or in intestinal and diffuse-type gastric cancers. The effects of a Hedgehog (Hh) inhibitor, cyclopamine, were assessed in primary gastric epithelium cultures and gastric cancer cell lines. METHODS Reverse-transcription polymerase chain reaction and immunostaining compared expression and localization of Hh signaling molecules and phenotypic markers of pit, neck, and gland cells in situ and in cultured cells treated with cyclopamine. Bromodeoxyuridine staining assessed the effects of cyclopamine on proliferation. RESULTS Hh signaling molecules were expressed differentially in pit, neck, and gland cells. IHH co-expressed with most downstream targets in the pit. IHH, SHH, Patched (PTCH), Smoothened (SMO), and downstream targets were expressed more frequently and highly in the diffuse as compared with intestinal type cancers. In diffuse cancers, IHH was expressed in cells with an epithelial phenotype and SHH in cells with a mesenchymal phenotype. Cyclopamine reduced the number of cells with a pit phenotype but not a gland phenotype in primary cultures. Cyclopamine had particularly potent effects of inhibiting the growth of cell lines that expressed high levels of SMO. CONCLUSIONS Expression of IHH and downstream targets correlates with pit cells. IHH and SMO may be useful biomarkers of diffuse cancers that may show growth inhibition with Hh antagonists such as cyclopamine.
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Affiliation(s)
- Masahide Fukaya
- Genetics Division, National Cancer Center Research Institute, Tsukiji, Tokyo, Japan
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43
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Vauhkonen M, Vauhkonen H, Sajantila A, Sipponen P. Differences in genomic instability between intestinal- and diffuse-type gastric cancer. Gastric Cancer 2006; 8:238-44. [PMID: 16328598 DOI: 10.1007/s10120-005-0346-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2004] [Accepted: 07/19/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND Microsatellite instability (MSI) and loss of heterozygosity (LOH) are lesions in the genome found with different frequencies in gastric carcinomas (GCAs). Despite a great body of studies, no systematic approach to the detailed classification of MSI and LOH in the two major types of GCA has been published. METHODS Thirty-seven advanced GCAs, 25 intestinal-type (IGCAs) and 12 diffuse-type (DGCAs), were assayed with 15 autosomal tetranucleotide markers on 14 chromosomal arms. The observed frequencies and types of microsatellite alterations allowed stratification into subgroups, i.e., high- and low-grade MSI (MSI-H, MSI-L) or microsatellite-stable (MSS), and high- or low-grade, or non-detectable LOH (LOH-H, LOH-L, LOH-N). RESULTS Collectively, the markers detected MSI-H tumors with sensitivity equal to that of BAT-26 (a single marker highly specific for MSI-H). Likewise, the markers detected LOH at chromosomal arms 5q, 18q, and 21q with a sensitivity equal to markers used previously. Seven (19%) MSI-H and six (16%) LOH-H tumors were found, with a significant association (P = 0.027) with IGCA: 92% of MSI-H and LOH-H occurred in IGCA patients only. Conversely, in DGCA, a significantly higher prevalence of a stable (LOH-N/MSS) phenotype was found as compared with IGCA (75.1% vs 28.0%; P = 0.035). The MSI-L phenotype was found in 57.9% of non-MSI-H IGCA tumors and was associated significantly (P = 0.015) with LOH-H. CONCLUSION A clear difference in genomic instability between IGCA and DGCA was found. In IGCA, the MSI and LOH pathways were more commonly involved, whereas in DGCA, a stable phenotype was predominant. As a novel finding, MSI-L as a true phenomenon and its association with LOH was observed in IGCA.
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Affiliation(s)
- Matti Vauhkonen
- Department of Medicine, HUCH, Jorvi Hospital, Turuntie 150, 02740 Espoo, Finland
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44
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Kim HS, Lee JS, Freund JN, Min KW, Lee JS, Kim W, Juhng SW, Park CS. CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions. J Gastroenterol Hepatol 2006; 21:438-42. [PMID: 16509871 DOI: 10.1111/j.1440-1746.2005.03933.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recent studies have demonstrated that CDX-2 is expressed in the intestinal metaplasia of the stomach and intestinal-type gastric cancer. To address the role of CDX-2 in carcinogenesis of gastric carcinomas of intestinal type, the expression of CDX-2 in gastric carcinoma and precursor lesions were examined using immunohistochemistry. METHODS A total of 160 specimens diagnosed as gastric carcinomas or non-invasive neoplasia from 158 patients were analyzed for CDX-2 expression by immunochemical methods. Patients were classified into histopathologic subgroups according to the Padova international classification: 60 cases of low-grade non-invasive neoplasia, 55 cases of high grade, and 45 cases of invasive intestinal-type adenocarcinoma. The CDX-2 expression in non-neoplastic gastric mucosa including intestinal metaplasia was also evaluated in the areas included in the histologic sections. RESULTS The CDX-2 expression was localized in the epithelial cell nuclei in the area of intestinal metaplasia with or without dysplasia and carcinoma, consistent with its role as a transcriptional regulator. No CDX-2 reactivity was noted in the normal mucosa in all cases. The CDX-2 expression was detected in 73.3% of low-grade cases, 85.5% of high-grade cases and 91.1% of intestinal-type adenocarcinoma cases. In the gastric mucosa with intestinal metaplasia, 89.7% of the samples were positive. The CDX-2-expressing cells in intestinal metaplasia were more prevalent than in dysplasia and carcinoma. Expression of CDX-2 showed a statistically significant positive correlation with increasing grade of dysplasia and carcinoma. CONCLUSIONS These findings suggest that CDX-2 expression in stomach cancer may be a marker of the progression of gastric carcinogenesis, and that its activation may represent an early event.
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Affiliation(s)
- Hyung-Seok Kim
- Department of Pathology, Seonam University, College of Medicine, Korea
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45
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Mini R, Annibale B, Lahner E, Bernardini G, Figura N, Santucci A. Western blotting of total lysate of Helicobacter pylori in cases of atrophic body gastritis. Clin Chem 2006; 52:220-226. [PMID: 16306089 DOI: 10.1373/clinchem.2005.054627] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Atrophic body gastritis is considered the first important step in the histogenesis of gastric carcinoma, a multistep process starting from chronic gastritis and progressing through chronic atrophic gastritis, intestinal metaplasia, and dysplasia. Helicobacter pylori is involved in the induction of atrophic body gastritis, but documentation of H. pylori infection is difficult because of the progressive disappearance of the bacterium. Our study aimed to detect past H. pylori infection in patients with atrophic body gastritis. METHODS We used Western blot analyses of whole bacterial protein lysate of 2 different strains to probe sera from 143 patients. All sera were analyzed by ELISA (Bio-Rad), and results of gastric histology were available for all patients. RESULTS Among 111 patient sera previously classified as negative for H. pylori infection by ELISA, 106 (95.5%) were positive when assayed by immunoblotting. CONCLUSIONS Commercial diagnostic reagent sets may fail to detect H. pylori infection. Western blotting of whole bacterial protein extracts could provide the basis of a noninvasive serology tool able to assess previous infection with H. pylori in patients with atrophic body gastritis.
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Affiliation(s)
- Roberta Mini
- Dipartimento di Biologia Molecolare, Policlinico Le Scotte, Università degli Studi di Siena, Siena, Italy
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Luebke T, Baldus SE, Grass G, Bollschweiler E, Thiele J, Dienes HP, Hoelscher AH, Moenig SP. Histological grading in gastric cancer by Ming classification: correlation with histopathological subtypes, metastasis, and prognosis. World J Surg 2006; 29:1422-7; discussion 1428. [PMID: 16222448 DOI: 10.1007/s00268-005-7795-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The aim of this prospective study was to analyze Ming's classification in correlation with other currently used classification systems of gastric cancer. In addition, we wanted to define the prognostic significance of the Ming classification system. The present study analyzed material of 117 patients with gastric carcinoma who underwent D2-gastrectomy with curative intent. All specimens were categorized according to International Union Against Cancer (UICC) classification, World Health Organization (WHO) classification, Borrmann classification, Laurén classification, Goseki classification, Ming classification, and tumor differentiation. For analysis of correlation between the classification systems, the correlation coefficient according to Spearman was calculated. The survival curves have been calculated according to the Kaplan-Meier method. According to the Ming classification, 38.5% of the carcinomas exhibited an expanding growth pattern, and 61.5% of specimens showed an infiltrating growth pattern. The subtypes according to the Ming and Laurén classification correlated significantly (P < 0.001). WHO classification (P < 0.001), tumor differentiation (P < 0.001), and Goseki classification (P < 0.001), as well as the macroscopic classification of Borrmann (P < 0.001) and the pT and pN categories of the UICC classification exhibited a highly significant correlation with the Ming classification (P < 0.001 and 0.001, respectively). Median overall survival was 31.3 months. In Kaplan-Meier analysis, the 3-year survival rates were lower in the infiltrative tumor type when compared to the expansive tumor type according to Ming (P = 0.0847). In multivariate analysis, only the UICC system presented as an independent prognostic factor in multivariate analysis (P < 0.001). This study shows that the Ming classification correlates significantly with the currently used classification systems for gastric cancer and with the UICC staging system, especially, the pT and pN category. The 3-year survival rates were lower in the infiltrative tumor type than in the expansive tumor type according to Ming. However, the Ming classification is not an independent prognostic factor.
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Affiliation(s)
- Thomas Luebke
- Department of Visceral and Vascular Surgery, University of Cologne, Joseph-Stelzmann-Strasse 9, Cologne 50931, Germany
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Abstract
Several attempts to classify gastric cancer (GCA) have been made over the past decades. Most successful, and widely used, is the classification by Laurén, which distinguishes, by microscopical morphology alone, two main cancer pathogeneses, diffuse (DGCA) and intestinal (IGCA) subtypes, which appear clearly as dissimilar clinical and epidemiological entities. Here we review the main differences in epidemiology, histopathology, and molecular pathology of the two main subtypes of gastric carcinomas based on Laurén classification. In clinical practice, however, clinical staging, particularly in predicting the survival, still remains superior to all classifications of gastric cancer independent of cancer type. The existence of local precursor lesions or conditions of IGCA tumours, i.e. Helicobacter pylori gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), adenoma, dysplasia, and intramucosal neoplasia, is firmly established. The links of DGCA with intestinal-type epithelium, AG or IM are poor, or do not exist. So far, H. pylori gastritis is the only universal precursor condition for DGCA. It implies that AG and achlorhydria are of minor significance and infrequent in the development of DGCA but are important steps in that of IGCA. Despite an increasing body of data, the overall view on molecular pathology of GCA remains fragmentary. No consistent differences in the molecular pathology of GCA subtypes to meet the Laurén classification have been established. With the exception of TP53, no gene mutation occurring regularly in both histological types of GCA has been reported. Chromosomal aberrations and loss of heterozygosity seem to be non-specific and do not follow any consistent route in the progression of GCA. Microsatellite instability is more commonly found in IGCA than in DGCA. The present epigenetic data suggest that most of the decrease (or loss) of gene expression may be explained by promoter hypermethylation which is more often found in IGCA. In DGCA specific genes such as CDH1 are more often hypermethylated. Compared with GCA, in premalignant condition lesions gene mutations and chromosomal aberrations are infrequent. Epigenetic dysregulation might also represent a major mechanism for altered gene expression in premalignant stages in gastric carcinogenesis.
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Affiliation(s)
- Matti Vauhkonen
- Department of Medicine, Helsinki University Central Hospital (HUCH), Jorvi Hospital, Espoo, Finland
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48
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Leedham SJ, Schier S, Thliveris AT, Halberg RB, Newton MA, Wright NA. From gene mutations to tumours--stem cells in gastrointestinal carcinogenesis. Cell Prolif 2005; 38:387-405. [PMID: 16300652 PMCID: PMC6496903 DOI: 10.1111/j.1365-2184.2005.00359.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2005] [Accepted: 09/02/2005] [Indexed: 12/18/2022] Open
Abstract
Stem cells share many properties with malignant cells, such as the ability to self-renew and proliferate. Cancer is believed to be a disease of stem cells. The gastrointestinal tract has high cancer prevalence partly because of rapid epithelial cell turnover and exposure to dietary toxins. The molecular pathways of carcinogenesis differ according to the tissue. Work on hereditary cancer syndromes including familial adenomatous polyposis (FAP) has led to advances in our understanding of the events that occur in tumour development from a gastrointestinal stem cell. The initial mutation involved in the adenoma-carcinoma sequence is in the 'gatekeeper' tumour-suppressor gene adenomatous polyposis coli (APC). Somatic hits in this gene are non-random in FAP, with the type of mutation selected for by the position of the germline mutation. In the stomach, a metaplasia-dysplasia sequence occurs and is often related to Helicobacter pylori infection. Clonal expansion of mutated cells occurs by niche succession. Further expansion of the aberrant clone then occurs by the longitudinal division of crypts into two daughter units--crypt fission. Two theories seek to explain the early development of adenomas--the 'top down' and 'bottom up' hypotheses. Initial studies suggested that colorectal tumours were monoclonal; however, later work on chimeric mice and a sex chromosome mixoploid patient with FAP suggested that up to 76% of early adenomas were polyclonal. Introduction of a homozygous resistance allele has reduced tumour multiplicity in the mouse and has been used to rule out random collision of polyps as the cause of these observations. It is likely that short-range interaction between adjacent initiated crypts is responsible for polyclonality.
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Affiliation(s)
- S J Leedham
- Histopathology Unit, Cancer Research UK, London, UK.
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49
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Rubio CA, Jónasson J, Nesi G, Mandai K, Pisano R, King A, Owen D. Extensive intestinal metaplasia in gastric carcinoma and in other lesions requiring surgery: a study of 3,421 gastrectomy specimens from dwellers of the Atlantic and Pacific basins. J Clin Pathol 2005; 58:1271-7. [PMID: 16311346 PMCID: PMC1770798 DOI: 10.1136/jcp.2005.029587] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2005] [Indexed: 01/22/2023]
Abstract
BACKGROUND Extensive intestinal metaplasia (EIM) has been reported in gastrectomies from patients dwelling in the Pacific and Atlantic basins. AIMS To compare all the results in an attempt to explain the findings. METHOD All sections from 3,421 gastrectomies were reviewed at various hospitals: 1946 in the Atlantic and 1475 in the Pacific basin. Sections with EIM showed IM encompassing one or more entire low power field (>or=5 mm in length/section) in one or more section. RESULTS In the Atlantic basin, EIM was present in 18.8% (153 of 814) of specimens with intestinal carcinoma (IC) and in 10.3% (65 of 630) of those with diffuse carcinoma (DC). In the Pacific basin, EIM was found in 62.9% (412 of 655) of gastrectomies with IC and in 33.3% (160 of 481) of those with DC. The numbers of specimens with EIM were significantly higher in the Pacific than in the Atlantic basin for both carcinoma phenotypes, particularly among elderly patients (>or=60 years). CONCLUSIONS The proportion of gastrectomies with EIM was higher among populations at a higher gastric cancer risk than in those with a lower cancer risk. EIM was mostly associated with IC rather than DC or with miscellaneous gastric diseases (841 control gastrectomies) in both basins. The proportion of gastrectomies with EIM was significantly higher in Vancouver than in New York and in Santiago de Chile than in Buenos Aires, even though these populations reside at approximately the same geographical latitude, but in different basins. Environmental factors seem to accelerate the evolution of EIM.
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Affiliation(s)
- C A Rubio
- Department of Pathology, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden.
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50
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Yoshida S, Tanaka S, Kunihiro K, Mitsuoka Y, Hara M, Kitadai Y, Hata J, Yoshihara M, Haruma K, Hayakawa N, Chayama K. Diagnostic ability of high-frequency ultrasound probe sonography in staging early gastric cancer, especially for submucosal invasion. ABDOMINAL IMAGING 2005; 30:518-523. [PMID: 15688103 DOI: 10.1007/s00261-004-0287-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2004] [Accepted: 10/21/2004] [Indexed: 01/25/2023]
Abstract
BACKGROUND Advances in gastrointestinal endoscopy have resulted in endoscopic mucosal resection becoming the main therapy for many early gastric cancers confined to the mucosa and, in some cases, of minimal submucosal invasion. Thus, preoperative determination of the depth of the cancer is important. We compared the results of high-frequency ultrasound probe sonography with those of histologic study to clarify the usefulness of identifying of submucosal invasion and determining the depth of early gastric cancer. METHODS Subjects were 295 patients diagnosed with early gastric cancer who had undergone endoscopic mucosal or surgical resection. High-frequency ultrasound probe sonographic findings were compared with histologic findings. RESULTS The muscularis mucosae was visualized in 63% of cases of early gastric cancer. By construction on receiver operator characteristics curve, we determined that submucosal invasive cancer could be diagnosed by high-frequency ultrasound probe sonography to a depth of about 600 microm. There was no case in which invasion deeper than 1000 microm was diagnosed as a hypoechoic area limited to the mucosal layer or a fan-shaped hypoechoic area in the submucosal layer. The depth of early gastric cancer was accurately determined in 90% of cases. CONCLUSIONS High-frequency ultrasound probe is a useful tool for accurately determining the depth of invasion of early gastric cancer when its limitations are understood.
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Affiliation(s)
- S Yoshida
- Department of Endoscopy, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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