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Singh V, Pant T, Kumar Y, Bhatnagar S. Novel potent heterocyclic Grb2-SH2 domain antagonists as potential anti-proliferative agents. Biochem Biophys Res Commun 2025; 760:151680. [PMID: 40157294 DOI: 10.1016/j.bbrc.2025.151680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/03/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
Growth factor receptor-bound protein 2 (Grb2) plays a critical role in proliferative diseases by binding phosphotyrosine residues on target proteins leading to activation of key pathways. The phosphotyrosyl motif of Focal Adhesion Kinase (FAK) has been utilized as a pharmacophore to identify small molecules that disrupt its interaction with the Grb2 Src Homology 2 (SH2) domain. In this study, we report the hit-to-lead optimization of 11,12,479 synthesizable analogs of previously identified Grb2-SH2 antagonists via virtual screening using AutoDock Vina v1.2.0. ADMET predictions were performed using SwissADME and pkCSM. Molecular dynamics (MD) simulations were conducted using AMBER v18. The Grb2-SH2 domain was cloned, expressed as a GST fusion protein, and purified for in vitro analysis. Binding interactions of the top compounds were assessed using SPR spectroscopy and competitive ELISA. Five heterocyclic molecules with novel scaffolds demonstrated favorable AutoDock binding affinities, stable binding in MD simulations, and promising ADMET profiles. MMPBSA calculations indicated the strongest binding energy for DO71_2. Per residue decomposition confirmed the maximum contribution of charged pocket residues to the binding energy. SPR determined KD values in the nanomolar range, >50-fold better than the phosphorylated peptide substrate. KD value of the peptide substrate was similar to previously reported values. DO71_2 showed the best KD value (9.4 nM) in consonance with the in silico prediction. ELISA confirmed concentration-dependent, specific binding of all the five compounds to Grb2-SH2. Our findings highlight the potential of these non-peptidic, non-phosphorous-based Grb2-SH2 antagonists as therapeutic agents for proliferative diseases like cancer and cardiac hypertrophy.
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Affiliation(s)
- Vasundhara Singh
- Computational and Structural Biology Laboratory, Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India
| | - Tarun Pant
- Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India
| | - Yatender Kumar
- Mammalian Cell Culture Laboratory, Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India.
| | - Sonika Bhatnagar
- Computational and Structural Biology Laboratory, Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India.
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Huang SKH, Bueno PRP, Garcia PJB, Lee MJ, De Castro-Cruz KA, Leron RB, Tsai PW. Antioxidant, Anti-Inflammatory and Antiproliferative Effects of Osmanthus fragrans (Thunb.) Lour. Flower Extracts. PLANTS (BASEL, SWITZERLAND) 2023; 12:3168. [PMID: 37687413 PMCID: PMC10489841 DOI: 10.3390/plants12173168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/01/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023]
Abstract
Osmanthus fragrans (Thunb.) Lour. flowers (OF-F) have been traditionally consumed as a functional food and utilized as folk medicine. This study evaluated the antioxidant, anti-inflammatory and cytotoxic effects of OF-F extracts on prostate cancer cells (DU-145) and determined possible protein-ligand interactions of its compounds in silico. The crude OF-F extracts-water (W) and ethanol (E) were tested for phytochemical screening, antioxidant, anti-inflammatory, and anti-cancer. Network and molecular docking analyses of chemical markers were executed to establish their application for anticancer drug development. OF-F-E possessed higher total polyphenols (233.360 ± 3.613 g/kg) and tannin (93.350 ± 1.003 g/kg) contents than OF-F-W. In addition, OF-F-E extract demonstrated effective DPPH scavenging activity (IC50 = 0.173 ± 0.004 kg/L) and contained a high FRAP value (830.620 ± 6.843 g Trolox/kg). In cell culture experiments, OF-F-E significantly reduced NO levels and inhibited cell proliferation of RAW-264.7 and DU-145 cell lines, respectively. Network analysis revealed O. fragrans (Thunb.) Lour. metabolites could affect thirteen molecular functions and thirteen biological processes in four cellular components. These metabolites inhibited key proteins of DU-145 prostate cancer using molecular docking with rutin owning the highest binding affinity with PIKR31 and AR. Hence, this study offered a new rationale for O. fragrans (Thunb.) Lour. metabolites as a medicinal herb for anticancer drug development.
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Affiliation(s)
- Steven Kuan-Hua Huang
- Department of Medical Science Industries, College of Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan; (S.K.-H.H.); (M.-J.L.)
- Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan 711, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Paolo Robert P. Bueno
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Metro Manila 1000, Philippines;
- School of Medicine, The Manila Times College of Subic, Zambales 2222, Philippines
- Department of Chemistry, College of Science, Adamson University, Metro Manila 1000, Philippines
| | - Patrick Jay B. Garcia
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Metro Manila 1002, Philippines; (P.J.B.G.); (K.A.D.C.-C.); (R.B.L.)
- School of Graduate Studies, Mapúa University, Metro Manila 1002, Philippines
| | - Mon-Juan Lee
- Department of Medical Science Industries, College of Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan; (S.K.-H.H.); (M.-J.L.)
| | - Kathlia A. De Castro-Cruz
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Metro Manila 1002, Philippines; (P.J.B.G.); (K.A.D.C.-C.); (R.B.L.)
| | - Rhoda B. Leron
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Metro Manila 1002, Philippines; (P.J.B.G.); (K.A.D.C.-C.); (R.B.L.)
| | - Po-Wei Tsai
- Department of Medical Science Industries, College of Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan; (S.K.-H.H.); (M.-J.L.)
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Bufano M, Puxeddu M, Nalli M, La Regina G, Toto A, Liberati FR, Paone A, Cutruzzolà F, Masci D, Bigogno C, Dondio G, Silvestri R, Gianni S, Coluccia A. Targeting the Grb2 cSH3 domain: Design, synthesis and biological evaluation of the first series of modulators. Bioorg Chem 2023; 138:106607. [PMID: 37210829 DOI: 10.1016/j.bioorg.2023.106607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/23/2023]
Abstract
Growth factor receptor bound protein 2 (Grb2) is an adaptor protein featured by a nSH3-SH2-cSH3 domains. Grb2 finely regulates important cellular pathways such as growth, proliferation and metabolism and a minor lapse of this tight control may totally change the entire pathway to the oncogenic. Indeed, Grb2 is found overexpressed in many tumours type. Consequently, Grb2 is an attractive therapeutic target for the development of new anticancer drug. Herein, we reported the synthesis and the biological evaluation of a series of Grb2 inhibitors, developed starting from a hit-compound already reported by this research unit. The newly synthesized compounds were evaluated by kinetic binding experiments, and the most promising derivatives were assayed in a short panel of cancer cells. Five of the newly synthesized derivatives proved to be able to bind the targeted protein with valuable inhibitory concentration in one-digit micromolar concentration. The most active compound of this series, derivative 12, showed an inhibitory concentration of about 6 μM for glioblastoma and ovarian cancer cells, and an IC50 of 1.67 for lung cancer cell. For derivative 12, the metabolic stability and the ROS production was also evaluated. The biological data together with the docking studies led to rationalize an early structure activity relationship.
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Affiliation(s)
- Marianna Bufano
- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Michela Puxeddu
- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Marianna Nalli
- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Giuseppe La Regina
- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Angelo Toto
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Francesca Romana Liberati
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Alessio Paone
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Francesca Cutruzzolà
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Chiara Bigogno
- Aphad SrL, Via della Resistenza 65, 20090 Buccinasco, Italy
| | - Giulio Dondio
- Aphad SrL, Via della Resistenza 65, 20090 Buccinasco, Italy
| | - Romano Silvestri
- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Stefano Gianni
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Antonio Coluccia
- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
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Stainthorp AK, Lin CC, Wang D, Medhi R, Ahmed Z, Suen KM, Miska EA, Whitehouse A, Ladbury JE. Regulation of microRNA expression by the adaptor protein GRB2. Sci Rep 2023; 13:9784. [PMID: 37328606 PMCID: PMC10276003 DOI: 10.1038/s41598-023-36996-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/14/2023] [Indexed: 06/18/2023] Open
Abstract
Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.
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Affiliation(s)
- Amy K Stainthorp
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Chi-Chuan Lin
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Dapeng Wang
- LeedsOmics, University of Leeds, Leeds, LS2 9JT, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
- National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK
| | - Ragini Medhi
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Zamal Ahmed
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kin Man Suen
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Eric A Miska
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - John E Ladbury
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
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Tang Y, Cao J, Peng R, Mao X, Su B, Tang H, Tu D, Zhou J, Jiang G, Jin S, Wang Q, Zhang C, Liu R, Zhang C, Bai D. Screening and Verification of Key Ubiquitination Genes Related to Immune Infiltration in Stage III/IV Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:765-781. [PMID: 37250505 PMCID: PMC10216869 DOI: 10.2147/jhc.s407536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/08/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them. Methods A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein-protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments. Results GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage. Conclusion A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.
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Affiliation(s)
- Yuhong Tang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Jun Cao
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Rui Peng
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Xingkang Mao
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Bingbing Su
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Hao Tang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Daoyuan Tu
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Guoqing Jiang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Shengjie Jin
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Qian Wang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Chen Zhang
- The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Renjie Liu
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China
| | - Dousheng Bai
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China
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B. AV, Behera MK, Patne SCU, Shukla SK, Dixit VK. Clinicopathological Significance and Prognostic Role of Her2neu Protein Expression in Patients with Carcinoma Stomach: A Prospective Study from Northern India. South Asian J Cancer 2023; 12:135-140. [PMID: 37969677 PMCID: PMC10635765 DOI: 10.1055/s-0042-1759601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023] Open
Abstract
Manas Kumar BeheraBackground and Aims Gastric cancer is the third most common cause of cancer-related mortality worldwide after lungs and colorectum. Although controversial, Her2neu overexpression by immunohistochemistry is usually associated with poor prognosis in patients with carcinoma stomach. We conducted a prospective study to evaluate the prognostic role of Her2neu and its correlation with clinical, pathologic type, and stage of the disease. Methods A prospective study was performed on paraffin blocks of 111 gastric cancer specimens (88 patients were biopsy specimens and 23 were gastrectomy specimens). The paraffin blocks were processed for Her2neu receptor immunohistochemical staining and fluorescence in situ hybridization, and scoring was done. Results Her2neu overexpression was detected in 30 out of 111 (27%) patients. The mean age was 57.68 ± 12.82 years, with males constituting two-thirds of total patients. Tobacco addiction was found in 44% of the patients and smoking in 33% of the patients. Her2neu expression was similar in Lauren's intestinal and diffuse histologic type; however, proximal gastric tumors overexpressed Her2neu as compared with distal tumors. Her2neu 2+ or 3 + (odds ratio: 2.52, 95% CI: 1.61-3.95, p = 0.001) was the only independent predictor of survival in gastric cancer patients. Kaplan-Meir survival analysis showed that the survival of gastric cancer patients with Her2neu overexpression (Her2neu 2+ or 3 + ) was significantly lower than that of those with Her2neu nonexpression ( p = 0.001). Conclusion Her2neu positivity was a significant predictor of mortality in patients with carcinoma stomach, and Her2neu overexpression was associated with a lower overall survival rate compared with Her2neu nonexpression.
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Affiliation(s)
| | - Manas Kumar Behera
- Department of Hepatology, Srirama Chandra Bhanja (SCB) Medical College, Bhubaneswar, Odisha, India
| | - Shashikant C. U. Patne
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sunit Kumar Shukla
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Vinod Kumar Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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Zhao J, Han Z, Xu C, Li L, Pei H, Song Y, Wang Z, Tang B. Separation and single-cell analysis for free gastric cancer cells in ascites and peritoneal lavages based on microfluidic chips. EBioMedicine 2023; 90:104522. [PMID: 36933411 PMCID: PMC10034419 DOI: 10.1016/j.ebiom.2023.104522] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 02/13/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUNDS Detecting free cancer cells from ascites and peritoneal lavages is crucial for diagnosing gastric cancer (GC). However, traditional methods are limited for early-stage diagnosis due to their low sensitivity. METHODS A label-free, rapid, and high-throughput technique was developed for separating cancer cells from ascites and peritoneal lavages using an integrated microfluidic device, taking advantage of dean flow fractionation and deterministic lateral displacement. Afterward, separated cells were analyzed using a microfluidic single-cell trapping array chip (SCTA-chip). In situ immunofluorescence for EpCAM, YAP-1, HER-2, CD45 molecular expressions, and Wright-Giemsa staining were performed for cells in SCTA-chips. At last, YAP1 and HER-2 expression in tissues was analyzed by immunohistochemistry. FINDINGS Through integrated microfluidic device, cancer cells were successfully separated from simulated peritoneal lavages containing 1/10,000 cancer cells with recovery rate of 84.8% and purity of 72.4%. Afterward, cancer cells were isolated from 12 patients' ascites samples. Cytological examinations showed cancer cells were efficiently enriched with background cells excluded. Afterwards, separated cells from ascites were analyzed by SCTA-chips, and recognized as cancer cells through EpCAM+/CD45- expression and Wright-Giemsa staining. Interestingly, 8 out of 12 ascites samples showed HER-2+ cancer cells. At last, the results through a serial expression analysis showed that YAP1 and HER-2 have discordant expression during metastasis. INTERPRETATION Microfluidic Chips developed in our study could not only rapidly detect label-free free GC cells in ascites and peritoneal lavages with high-throughput, they could also analyze ascites cancer cells at the single-cell level, improving peritoneal metastasis diagnosis and investigation of therapeutic targets. FUNDING This research was supported by National Natural Science Foundation of China (22134004, U1908207, 91859111); Natural Science Foundation of Shandong Province of China (ZR2019JQ06); Taishan Scholars Program of Shandong Province tsqn (201909077); Local Science and Technology Development Fund Guided by the Central Government (YDZX20203700002568); Applied Basic Research Program of Liaoning Province (2022020284-JH2/1013).
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Affiliation(s)
- Junhua Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, Liaoning, 110001, PR China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China; Institute of Health Sciences, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China
| | - Zhaojun Han
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Chang Xu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Lu Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China.
| | - Haimeng Pei
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, Liaoning, 110001, PR China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China; Institute of Health Sciences, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, Liaoning, 110001, PR China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China; Institute of Health Sciences, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China.
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China.
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Liu Y, Shi Y, Han R, Liu C, Qin X, Li P, Gu R. Signaling pathways of oxidative stress response: the potential therapeutic targets in gastric cancer. Front Immunol 2023; 14:1139589. [PMID: 37143652 PMCID: PMC10151477 DOI: 10.3389/fimmu.2023.1139589] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 03/20/2023] [Indexed: 05/06/2023] Open
Abstract
Gastric cancer is one of the top causes of cancer-related death globally. Although novel treatment strategies have been developed, attempts to eradicate gastric cancer have been proven insufficient. Oxidative stress is continually produced and continually present in the human body. Increasing evidences show that oxidative stress contributes significantly to the development of gastric cancer, either through initiation, promotion, and progression of cancer cells or causing cell death. As a result, the purpose of this article is to review the role of oxidative stress response and the subsequent signaling pathways as well as potential oxidative stress-related therapeutic targets in gastric cancer. Understanding the pathophysiology of gastric cancer and developing new therapies for gastric cancer depends on more researches focusing on the potential contributors to oxidative stress and gastric carcinogenesis.
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Affiliation(s)
- Yingying Liu
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Yu Shi
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ruiqin Han
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chaoge Liu
- Department of Oromaxillofacial - Head and Neck Surgery, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, China
| | - Xiaogang Qin
- Traditional Chinese Medicine Hospital of Tongzhou District, Nantong, Jiangsu, China
- *Correspondence: Renjun Gu, ; Pengfei Li, ; Xiaogang Qin,
| | - Pengfei Li
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Renjun Gu, ; Pengfei Li, ; Xiaogang Qin,
| | - Renjun Gu
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Renjun Gu, ; Pengfei Li, ; Xiaogang Qin,
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9
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Seiler C, Stainthorp AK, Ketchen S, Jones CM, Marks K, Quirke P, Ladbury JE. The Grb2 splice variant, Grb3-3, is a negative regulator of RAS activation. Commun Biol 2022; 5:1029. [PMID: 36171279 PMCID: PMC9519967 DOI: 10.1038/s42003-022-03985-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/13/2022] [Indexed: 11/24/2022] Open
Abstract
Activation of RAS is crucial in driving cellular outcomes including proliferation, differentiation, migration and apoptosis via the MAPK pathway. This is initiated on recruitment of Grb2, as part of a Grb2-Sos complex, to an up-regulated receptor tyrosine kinase (RTK), enabling subsequent interaction of Sos with the plasma membrane-localised RAS. Aberrant regulation at this convergence point for RTKs in MAPK signalling is a key driver of multiple cancers. Splicing of the GRB2 gene produces a deletion variant, Grb3-3, that is incapable of binding to RTKs. We show that, despite maintaining the ability to bind to Sos, the Grb3-3-Sos complex remains in the cytoplasm, unable to engage with RAS. Competition between Grb2 and Grb3-3 for binding to C-terminal proline-rich sequences on Sos modulates MAPK signalling. Additionally, we demonstrate that splicing is regulated by heterogenous nuclear riboproteins C1/C2, and that normal and malignant colon tissue show differential Grb3-3 expression.
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Affiliation(s)
- Caroline Seiler
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
| | - Amy K Stainthorp
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
| | - Sophie Ketchen
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
| | - Christopher M Jones
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
- Radiotherapy Research Group, Faculty of Medicine & Health, University of Leeds, Leeds, UK
- Leeds Cancer Centre, The Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Kate Marks
- University of Leeds School of Medicine, Leeds Institute of Medical Research, Pathology and Data Analytics, University of Leeds, Leeds, UK
| | - Philip Quirke
- University of Leeds School of Medicine, Leeds Institute of Medical Research, Pathology and Data Analytics, University of Leeds, Leeds, UK
| | - John E Ladbury
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
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10
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Sun J, Li X, Chen P, Gao Y. From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer. J Inflamm Res 2022; 15:4061-4085. [PMID: 35873388 PMCID: PMC9304417 DOI: 10.2147/jir.s368138] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022] Open
Abstract
Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.
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Affiliation(s)
- Jiangang Sun
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xiaojing Li
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Peng Chen
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
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11
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Wu J, Li L, Qin J, Yan Z, Chen S, Jin T, Xu J. Case Report: Durable Clinical Response to Third-Line Pyrotinib After Resistance to Trastuzumab in a Gastric Cancer Patient. Front Oncol 2022; 11:780577. [PMID: 35155188 PMCID: PMC8829539 DOI: 10.3389/fonc.2021.780577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/13/2021] [Indexed: 12/15/2022] Open
Abstract
Background Trastuzumab plus chemotherapy remains the standard first-line treatment strategy for HER2-positive gastric cancer (GC). Trastuzumab resistance, on the other hand, remains a significant issue. There are a few effective anti-HER2 agents for patients who develop resistance to trastuzumab. Case Presentation A 49-year-old female was diagnosed with stage IV GC with liver and lung metastasis in July 2017. She underwent gastrostomy, and the immunohistochemistry (IHC) result of postoperative tissue demonstrated HER2 (3+). She received first-line treatment of trastuzumab (440 mg), oxaliplatin (200 mg), and S-1 (40 mg). After treatment for 6 months, the patient achieved complete response (CR) with PFS up to 21 months. After progression, she subsequently received trastuzumab (440 mg) plus oxaliplatin (200 mg) as second-line treatment. However, the patient developed resistance to trastuzumab after 12 months of treatment. She started to receive third-line treatment of irinotecan (200 mg d1) and capecitabine (60 mg bid) plus pyrotinib (400 mg/day). After 2 months of treatment, the tumor is evaluated as partial response with PFS of 12 months. Conclusions We presented a patient with HER2-positive GC who benefited from the pyrotinib-based treatment after two lines of trastuzumab-based therapies failed. Further research is required to validate such conclusions.
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Affiliation(s)
- Junyi Wu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lei Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jun Qin
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhengqing Yan
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Shiqing Chen
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Tao Jin
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Junming Xu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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12
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He K, Chen C, Xia L, Si L, Pan X, Sun Z, Wang Y, Jiang Y, Shi Y, Zhou B, Wang S, Han J, Shen B, Zhou G, Lu J, Wang X. Deep muscularis propria tumor invasion without lymph node metastasis as a unique subclassification of stage IB gastric cancer: a retrospective study. BMC Gastroenterol 2022; 22:30. [PMID: 35062873 PMCID: PMC8783482 DOI: 10.1186/s12876-021-02090-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 12/22/2021] [Indexed: 12/26/2022] Open
Abstract
Background The prognosis difference based on the depth of tumor muscularis propria invasion in gastric cancer (GC) was still debated, and therapy strategy for stage IB GC patient required further investigation. Methods A total of 380 patients with pT2 GC after radical surgery were retrospectively analyzed, including 185 in superficial muscularis propria (sMP) group and 195 in deep muscularis propria (dMP) group. Results The overall survival (OS) was significantly better for patients in sMP group than for patients in dMP group (P = 0.007). In multivariate analysis, depth of tumor invasion, pN stage, age, primary location, positive expression of p53, elevated maximal LDH, elevated initial CA19-9 and AFP level were independent prognostic factors for OS. The sMP group had a significantly better OS than dMP group (P = 0.014) in pN0 stage. After further stratification, the survival outcomes were not significantly different between deep muscularis propria tumor invasion without lymph node metastasis (dMPN0) group (stage IB) and superficial muscularis propria tumor invasion with stage 1–2 lymph node metastasis (sMPN1–2) group (stage II) (P = 0.100). Patients with adjuvant chemotherapy had a statistically better survival than those without in dMPN0 group (P = 0.045) and dMPN0 patients with adjuvant chemotherapy had better OS than sMPN1–2 patients (P = 0.015). In addition, greater postoperative survival could be observed in sMPN0 patients than dMPN0 patients in p53-positive group (P = 0.002), and similar OS could be seen between dMPN0 patients with p53-positive and T2N1–2 patients (P = 0.872). Conclusion As a unique subclassification of stage IB GC, appropriate adjuvant chemotherapy should be considered for patients with dMPN0 stage. In addition, positive expression of p53, elevated LDH could be potential factors in identifying the different prognoses for stage IB GC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-02090-z.
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13
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Wang S, Chen Y, Zhang H, Liang Z, Bu J. The Value of Predicting Human Epidermal Growth Factor Receptor 2 Status in Adenocarcinoma of the Esophagogastric Junction on CT-Based Radiomics Nomogram. Front Oncol 2021; 11:707686. [PMID: 34722254 PMCID: PMC8552039 DOI: 10.3389/fonc.2021.707686] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 09/29/2021] [Indexed: 01/08/2023] Open
Abstract
Purpose We developed and validated a CT-based radiomics nomogram to predict HER2 status in patients with adenocarcinoma of esophagogastric junction (AEG). Method A total of 101 patients with HER2-positive (n=46) and HER2-negative (n=55) esophagogastric junction adenocarcinoma (AEG) were retrospectively analyzed. They were then randomly divided into a training cohort (n=70) and a verification cohort (n=31). The radiomics features were obtained from the portal phase of the CT enhanced scan. We used the least absolute shrinkage and selection operator (LASSO) logistic regression method to select the best radiomics features in the training cohort, combined them linearly, and used the radiomics signature formula to calculate the radiomics score (Rad-score) of each AEG patient. A multivariable logistic regression method was applied to develop a prediction model that incorporated the radiomics signature and independent risk predictors. The prediction performance of the nomogram was evaluated using the training and validation cohorts. Result In the training (P<0.001) and verification groups (P<0.001), the radiomics signature combined with seven radiomics features was significantly correlated with HER2 status. The nomogram composed of CT-reported T stage and radiomics signature showed very good predictive performance for HER2 status. The area under the curve (AUC) of the training cohort was 0.946 (95% CI: 0.919–0.973), and that of the validation group was 0.903 (95% CI: 0.847–0.959). The calibration curve of the radiomics nomogram showed a good degree of calibration. Decision-curve analysis revealed that the radiomics nomogram was useful. Conclusion The nomogram CT-based radiomics signature combined with CT-reported T stage can better predict the HER2 status of AEG before surgery. It can be used as a non-invasive prediction tool for HER2 status and is expected to guide clinical treatment decisions in clinical practice, and it can assist in the formulation of individualized treatment plans.
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Affiliation(s)
- Shuxing Wang
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Yiqing Chen
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Han Zhang
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Zhiping Liang
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Jun Bu
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
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14
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Li H, Zhang X, Xu Z, Li L, Liu W, Dai Z, Zhao Z, Xiao L, Li H, Hu C. Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors. Antib Ther 2021; 4:175-184. [PMID: 34532642 DOI: 10.1093/abt/tbab017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/30/2022] Open
Abstract
Background ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. Methods We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. Results MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE. Conclusion MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).
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Affiliation(s)
- Hu Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Xiao Zhang
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhenyi Xu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Lingrui Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Wenchao Liu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhenyu Dai
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhongrun Zhao
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Lili Xiao
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Hongfeng Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Chaohong Hu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
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15
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Iwata T, Sedukhina AS, Kubota M, Oonuma S, Maeda I, Yoshiike M, Usuba W, Minagawa K, Hames E, Meguro R, Cho S, Chien SHH, Urabe S, Pae S, Palanisamy K, Kumai T, Yudo K, Kikuchi E, Sato K. A new bioinformatics approach identifies overexpression of GRB2 as a poor prognostic biomarker for prostate cancer. Sci Rep 2021; 11:5696. [PMID: 33707553 PMCID: PMC7952695 DOI: 10.1038/s41598-021-85086-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 02/19/2021] [Indexed: 11/16/2022] Open
Abstract
A subset of prostate cancer displays a poor clinical outcome. Therefore, identifying this poor prognostic subset within clinically aggressive groups (defined as a Gleason score (GS) ≧8) and developing effective treatments are essential if we are to improve prostate cancer survival. Here, we performed a bioinformatics analysis of a TCGA dataset (GS ≧8) to identify pathways upregulated in a prostate cancer cohort with short survival. When conducting bioinformatics analyses, the definition of factors such as “overexpression” and “shorter survival” is vital, as poor definition may lead to mis-estimations. To eliminate this possibility, we defined an expression cutoff value using an algorithm calculated by a Cox regression model, and the hazard ratio for each gene was set so as to identify genes whose expression levels were associated with shorter survival. Next, genes associated with shorter survival were entered into pathway analysis to identify pathways that were altered in a shorter survival cohort. We identified pathways involving upregulation of GRB2. Overexpression of GRB2 was linked to shorter survival in the TCGA dataset, a finding validated by histological examination of biopsy samples taken from the patients for diagnostic purposes. Thus, GRB2 is a novel biomarker that predicts shorter survival of patients with aggressive prostate cancer (GS ≧8).
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Affiliation(s)
- Teppei Iwata
- Department of Frontier Medicine, Institute of Medical Science, Graduate School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan.,Department of Urology, School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Anna S Sedukhina
- Department of Frontier Medicine, Institute of Medical Science, Graduate School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Manabu Kubota
- Department of Pathology, School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Shigeko Oonuma
- Department of Pathology, School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Ichiro Maeda
- Department of Pathology, Kitasato University Kitasato Institute Hospital, Minato, 1080072, Japan.,Department of Pathology, Kitasato University School of Medicine, Sagamihara, 2520374, Japan
| | - Miki Yoshiike
- Department of Urology, School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Wataru Usuba
- Department of Urology, School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Kimino Minagawa
- Department of Pharmacogenomics, Graduate School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Eleina Hames
- K International School Tokyo, Koto, 1350021, Japan
| | - Rei Meguro
- K International School Tokyo, Koto, 1350021, Japan
| | - Sunny Cho
- K International School Tokyo, Koto, 1350021, Japan
| | | | - Shiro Urabe
- K International School Tokyo, Koto, 1350021, Japan
| | - Sookhee Pae
- K International School Tokyo, Koto, 1350021, Japan
| | | | - Toshio Kumai
- Department of Pharmacogenomics, Graduate School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Kazuo Yudo
- Department of Frontier Medicine, Institute of Medical Science, Graduate School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Eiji Kikuchi
- Department of Urology, School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan
| | - Ko Sato
- Department of Frontier Medicine, Institute of Medical Science, Graduate School of Medicine, St. Marianna University, Kawasaki, 2168511, Japan.
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16
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Yin QH, Liu BZ, Xu MQ, Tao L, Wang K, Li F, Zhang WJ. A Nomogram Based on Preoperative Clinical Bio-Indicators to Predict 5-year Survivals for Patients with Gastric Cancer After Radical Gastrectomy. Cancer Manag Res 2020; 12:3995-4007. [PMID: 32547234 PMCID: PMC7264156 DOI: 10.2147/cmar.s242772] [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: 12/17/2019] [Accepted: 04/24/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose This study aimed to improve the prediction of postoperative survival outcomes for patients with gastric cancer (GC) using a nomogram based on preoperative bio-indicators. Patients and Methods This retrospective study included 303 GC patients who had undergone radical gastrectomy from 2004 to 2013 at the First Affiliated Hospital, Shihezi University. The patients were followed up for 175 months after surgery and then divided into short-term (n=201) or long-term (n=102) survival groups. We used an expectation-maximization method to fill any missing data from the reviewed patient files. We then employed the Cox proportional hazard regression to identify biochemical markers that could predict 5-year overall survival (OS) as an endpoint among GC patients. Based on the results from the biochemical analysis, we developed a nomogram and assessed its performance and reliability. Results The variables significantly associated with OS in a multivariate analysis were age, body mass index (BMI), cell differentiation, high-density lipoprotein cholesterol (HDL-C), as well as serum potassium or serum magnesium. Combining all these predictors allowed us to establish a nomogram (C-index=0.701) whose accuracy of predicting survival was higher than the TNM staging system established by the 8th American Joint Committee on Cancer (C-index=0.666; p=0.016). Furthermore, decision curve of this nomogram was shown to have an ideal net clinical benefit rate. Conclusion We have developed an algorithm using preoperative bio-indicators and clinical features to predict prognosis for GC patients. This tool may help clinicians to strategize appropriate treatment options for GC patients prior to surgery.
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Affiliation(s)
- Qi Hang Yin
- Department of Pathology, The First Affiliated University Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China.,The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Bin Zheng Liu
- Department of Pathology, The First People's Hospital, Jiande, Zhejiang, People's Republic of China
| | - Meng Qing Xu
- Department of Pathology, The First Affiliated University Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China.,Department of Gastroenterology and Hepatology, Suzhou City Hospital, Suzhou, Anhui, People's Republic of China
| | - Lin Tao
- Department of Pathology, The First Affiliated University Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China.,The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Kui Wang
- Department of Preventive Medicine, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Feng Li
- Department of Pathology, The First Affiliated University Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China.,Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Wen Jie Zhang
- Department of Pathology, The First Affiliated University Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China.,The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
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17
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Xia Y, He K, Jiao L, Geng Y, Zhang D. Molecular characterization and expression analysis of protein enhancer of sevenless 2B from Artemia sinica at early embryonic development and during immune response to bacterial stimulation. FISH & SHELLFISH IMMUNOLOGY 2019; 87:582-589. [PMID: 30711491 DOI: 10.1016/j.fsi.2019.01.053] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/22/2019] [Accepted: 01/30/2019] [Indexed: 06/09/2023]
Abstract
Protein enhancer of sevenless 2B, E(sev)2B, is a key adapter protein in the Ras/MAPK signaling pathway which has been reported to be involved in innate immunity. In this study, the gene that encodes AsE(sev)2B was isolated from A. sinica. It was found to contain a 636 bp open reading frame encoding 211 amino acids with a calculated molecular mass of 24.357 kDa and a predicted isoelectric point of 5.39. The predicted protein contains a N-terminal Src homology 3 domain (SH3), a central Src homology 2 domain (SH2), and a C-terminal Src homology 3 domain (SH3). Homology analysis revealed that AsE(sev)2B shares 49%-95% identity with E(sev)2B homologs from other species. In this study, the expression pattern and location of AsE(sev)2B during different stages of embryonic development and bacterial challenge were investigated by means of real-time qPCR, Western blotting and immunohistochemistry. Results showed that the highest expression level of AsE(sev)2B was at 0 h. After challenged by Gram-positive bacteria and Gram-negative bacteria, AsE(sev)2B was remarkably upregulated at 106 cellsL-1 bacterial concentrations. These results suggested that AsE(sev)2B plays a vital role during early embryonic development and in immune responses against bacterial challenge.
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Affiliation(s)
- Yu Xia
- The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, 071002, Baoding, PR China
| | - Kang He
- The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, 071002, Baoding, PR China
| | - Lili Jiao
- The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, 071002, Baoding, PR China
| | - Yuanyuan Geng
- The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, 071002, Baoding, PR China
| | - Daochuan Zhang
- The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, 071002, Baoding, PR China.
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18
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Chatrath A, Kiran M, Kumar P, Ratan A, Dutta A. The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients. Mol Cancer Res 2019; 17:1075-1086. [PMID: 30651372 DOI: 10.1158/1541-7786.mcr-18-0996] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/22/2018] [Accepted: 01/07/2019] [Indexed: 01/01/2023]
Abstract
Lower grade gliomas are invasive brain tumors that are difficult to completely resect neurosurgically. They often recur following resection and progress, resulting in death. Although previous studies have shown that specific germline variants increase the risk of tumor formation, no previous study has screened many germline variants to identify variants predictive of survival in patients with glioma. In this study, we present an approach to identify the small fraction of prognostic germline variants from the pool of over four million variants that we variant called in The Cancer Genome Atlas whole-exome sequencing and RNA sequencing datasets. We identified two germline variants that are predictive of poor patient outcomes by Cox regression, controlling for eleven covariates. rs61757955 is a germline variant found in the 3' UTR of GRB2 associated with increased KRAS signaling, CIC mutations, and 1p/19q codeletion. rs34988193 is a germline variant found in the tumor suppressor gene ANKDD1a that causes an amino acid change from lysine to glutamate. This variant was found to be predictive of poor prognosis in two independent lower grade glioma datasets and is predicted to be within the top 0.06% of deleterious mutations across the human genome. The wild-type residue is conserved in all 22 other species with a homologous protein. IMPLICATIONS: This is the first study presenting an approach to screening many germline variants to identify variants predictive of survival and our application of this methodology revealed the germline variants rs61757955 and rs34988193 as being predictive of survival in patients with lower grade glioma.
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Affiliation(s)
- Ajay Chatrath
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
| | - Manjari Kiran
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
| | - Pankaj Kumar
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
| | - Aakrosh Ratan
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | - Anindya Dutta
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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Arcidiacono D, Dedja A, Giacometti C, Fassan M, Nucci D, Francia S, Fabris F, Zaramella A, Gallagher EJ, Cassaro M, Rugge M, LeRoith D, Alberti A, Realdon S. Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model. Int J Mol Sci 2018; 19:1198. [PMID: 29662006 PMCID: PMC5979452 DOI: 10.3390/ijms19041198] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 04/08/2018] [Accepted: 04/11/2018] [Indexed: 01/10/2023] Open
Abstract
Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.
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Affiliation(s)
- Diletta Arcidiacono
- Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.
| | - Arben Dedja
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
| | - Cinzia Giacometti
- Anatomic Pathology Unit, ULSS 6 Euganea, via Cosma, 1, Camposampiero, 35012 Padua, Italy.
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
| | - Daniele Nucci
- Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.
| | - Simona Francia
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Biomedical Sciences, University of Padua, via Bassi, 58/B, 35131, Padua, Italy.
| | - Federico Fabris
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy.
| | - Alice Zaramella
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy.
| | - Emily J Gallagher
- Division of Endocrinology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA.
| | - Mauro Cassaro
- Anatomic Pathology Unit, ULSS 6 Euganea, via Cosma, 1, Camposampiero, 35012 Padua, Italy.
| | - Massimo Rugge
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
| | - Derek LeRoith
- Division of Endocrinology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA.
| | - Alfredo Alberti
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy.
| | - Stefano Realdon
- Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.
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Shabbir A, Qureshi MA, Khalid AB, Mirza T, Shaikh A, Hasan SM. Gastric adenocarcinoma expressing human epidermal growth factor receptor in South Asian population. Saudi J Gastroenterol 2018; 24:289-293. [PMID: 29806596 PMCID: PMC6151997 DOI: 10.4103/sjg.sjg_23_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIM Gastric cancer is the third leading cause of cancer mortality worldwide. Human epidermal growth factor (Her-2/neu) has shown strong therapeutic implication in breast cancer. Although the prevalence of Her-2/neu over-expression in gastric cancer has been reported across the world, it is still unknown from South Asia. The aim of this study is to evaluate Her-2/neu expression in gastric adenocarcinomas and to correlate with various clinicopathological variables. PATIENTS AND METHODS A total of 95 consecutive patients undergoing endoscopic biopsy or gastrectomy were recruited in this study. Clinicopathological parameters of all patients were recorded and hematoxylin and eosin (H and E) staining was performed. Over-expression of Her-2/neu was investigated by immunohistochemistry using α-Her-2 antibody. To quantify Her-2/neu over-expression, the Hofmann validation scoring system was used and further its association was seen with age, gender, histopathological type, grade, and stage of the tumor. Data were entered and analyzed using SPSS version 21. A P value of <0.05 was considered as significant. RESULTS Overall, 21 (22.1%) cases were positive for Her-2/neu overexpression from the total of 95 gastric adenocarcinomas. Her-2/neu was significantly expressed in low-grade gastric cancer (grade I = 50%, grade II = 34.5%, grade III = 14.5%; P = 0.030). Although there was insignificant difference between Her-2/neu over expression and other variables, Her-2/neu score 3+ was predominantly seen in females, age >60 years, Laurens intestinal type, and IIIC stage tumors. CONCLUSION Her-2/neu is over-expressed in a limited group of gastric cancer patients in our population and indicates a significant strong association with low grades of gastric cancer.
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Affiliation(s)
- Asma Shabbir
- Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan,Address for correspondence: Dr. Asma Shabbir, Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan. E-mail:
| | - Muhammad Asif Qureshi
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Abdullah Bin Khalid
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Talat Mirza
- Department of Pathology, Doctor. Ziauddin Hospital and University, Karachi, Pakistan
| | - Asma Shaikh
- Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Syed Mehmood Hasan
- Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan
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21
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Fang W, Qian J, Wu Q, Chen Y, Yu G. ADAM-17 expression is enhanced by FoxM1 and is a poor prognostic sign in gastric carcinoma. J Surg Res 2017; 220:223-233. [DOI: 10.1016/j.jss.2017.06.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 05/15/2017] [Accepted: 06/15/2017] [Indexed: 12/30/2022]
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Takegawa N, Yonesaka K. HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. Clin Colorectal Cancer 2017; 16:247-251. [DOI: 10.1016/j.clcc.2017.03.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/10/2017] [Accepted: 03/01/2017] [Indexed: 12/15/2022]
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23
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Jiang K, Zhang M, Li F, Li D, Sun G, Liu X, Li H, Han R, Jiang R, Li Z, Kang X, Yan F. Study on the role of gga-miRNA-200a in regulating cell differentiation and proliferation of chicken breast muscle by targeting Grb2. Anim Cells Syst (Seoul) 2017. [DOI: 10.1080/19768354.2017.1400465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Keren Jiang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Meng Zhang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Fang Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Donghua Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Guirong Sun
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Xiaojun Liu
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Hong Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Ruili Han
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Ruirui Jiang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Zhuanjian Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Xiangtao Kang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Fengbin Yan
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
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Takegawa N, Nonagase Y, Yonesaka K, Sakai K, Maenishi O, Ogitani Y, Tamura T, Nishio K, Nakagawa K, Tsurutani J. DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance. Int J Cancer 2017; 141:1682-1689. [PMID: 28677116 DOI: 10.1002/ijc.30870] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/27/2017] [Accepted: 06/26/2017] [Indexed: 12/27/2022]
Abstract
Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS-8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS-8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.
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Affiliation(s)
- Naoki Takegawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Yoshikane Nonagase
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Kimio Yonesaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Osamu Maenishi
- Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Yusuke Ogitani
- Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan
| | - Takao Tamura
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
| | - Junji Tsurutani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan
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25
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Pathologic Response of HER2-positive Gastric Cancer to Trastuzumab-based Chemotherapy. Am J Surg Pathol 2017; 40:1326-33. [PMID: 27259008 DOI: 10.1097/pas.0000000000000672] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Trastuzumab-based chemotherapy is now a standard approach for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. However, histopathologic changes after treatment have yet to be elucidated. This study aims to characterize the histologic response of gastric cancer to trastuzumab treatment and its correlation with HER2 status. Twenty-one advanced HER2-positive gastric cancers treated with trastuzumab-based chemotherapy, including 10 surgically resected specimens and 11 biopsy samples from patients with inoperable tumors, were evaluated for the histologic responses and HER2 status of residual cells. We also reviewed, as controls, 10 cases undergoing surgical resection of tumors after chemotherapy without trastuzumab. Complete and partial histologic responses were obtained in 2 and 8 of the surgical cases, respectively. HER2-positive neoplastic cells were recognized at least focally in the 8 cases. Notably, the proportion of HER2-positive cells was always higher in superficial (mucosal/submucosal) layers than in deeper layers. Three specimens contained HER2-positive neoplastic cells exclusively in the superficial area or intravascular space, whereas deeply invasive or metastatic components almost completely disappeared or were HER2 negative when still present. In contrast, HER2-negative cells or residual tumor cells in control cases tended to survive as well or better in deeply invasive areas or in metastases than in superficial areas. Biopsy samples from nonoperative patients remained HER2 positive after treatment in 8 of 11 patients. Our observations suggest that HER2-positive neoplastic cells tend to survive within superficial areas or intravascular spaces after trastuzumab therapy, even when deeply invasive or metastatic lesions responded well to therapy.
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26
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Creemers A, Ter Veer E, de Waal L, Lodder P, Hooijer GKJ, van Grieken NCT, Bijlsma MF, Meijer SL, van Oijen MGH, van Laarhoven HWM. Discordance in HER2 Status in Gastro-esophageal Adenocarcinomas: A Systematic Review and Meta-analysis. Sci Rep 2017; 7:3135. [PMID: 28600510 PMCID: PMC5466678 DOI: 10.1038/s41598-017-03304-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/26/2017] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab combined with chemotherapy is standard of care for HER2 positive advanced gastro-esophageal cancers. The reported prevalence of HER2 discordance between primary tumors and corresponding metastases varies, hampering uniform patient selection for HER2 targeted therapy. This meta-analysis explores the influence of HER2 assessment methods on this discordance and investigates the prevalence of HER2 discordance in gastro-esophageal adenocarcinomas. PubMed, Embase and Cochrane databases were searched until January 2016. Differences in discordance rate between strict and broad(er) definitions of HER2 status were assessed using random-effect pair-wise meta-analysis. Random-effect single-arm meta-analyses were performed to assess HER2 discordance and the prevalence of positive and negative conversion. A significantly lower discordance rate in HER2 status between primary tumors and corresponding metastases was observed using a strict vs. broad definition of HER2 status (RR = 0.58, 95%CI 0.41-0.82), with a pooled discordance rate of 6.2% and 12.2%, respectively. Using the strict definition of HER2 assessment pooled overall discordance was 7% (95%CI 5-10%). The lowest discordance rates between primary tumors and corresponding metastasis are observed when using a strict method of HER2 positivity. Treatment outcomes of different studies will be better comparable if selection of eligible patients for HER2 targeted therapy is based on this strict definition.
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Affiliation(s)
- A Creemers
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - E Ter Veer
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - L de Waal
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - P Lodder
- Department of Methodology and Statistics/Department of Medical and Clinical Psychology, Tilburg University, Warandelaan 2, 5037 AB, Tilburg, The Netherlands
| | - G K J Hooijer
- Department of Pathology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - N C T van Grieken
- Department of Pathology, VUMC, De Boelenlaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - M F Bijlsma
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - S L Meijer
- Department of Pathology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - M G H van Oijen
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - H W M van Laarhoven
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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27
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Press MF, Ellis CE, Gagnon RC, Grob TJ, Buyse M, Villalobos I, Liang Z, Wu S, Bang YJ, Qin SK, Chung HC, Xu J, Park JO, Jeziorski K, Afenjar K, Ma Y, Estrada MC, Robinson DM, Scherer SJ, Sauter G, Hecht JR, Slamon DJ. HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib. Mol Cancer Ther 2017; 16:228-238. [PMID: 27811012 DOI: 10.1158/1535-7163.mct-15-0887] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 09/12/2016] [Accepted: 10/06/2016] [Indexed: 11/16/2022]
Abstract
HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx FISH and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4,674 patients in a central laboratory for eligibility (1,995 cases) and for confirmation of local HER2 results (333 cases). Of 1,995 adenocarcinomas screened centrally, 322 (16.1%) had HER2-amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%), 487 patients (89%) were centrally confirmed as having HER2-amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2 In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low. Mol Cancer Ther; 16(1); 228-38. ©2016 AACR.
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Affiliation(s)
- Michael F Press
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
| | | | | | - Tobias J Grob
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marc Buyse
- International Drug Development Institute, Leuven, Belgium
| | - Ivonne Villalobos
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, P.R. China
| | - Shafei Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, P.R. China
| | - Yung-Jue Bang
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Shu-Kui Qin
- PLA Cancer Center, Nanjing Bayi Hospital, Jiangsu, China
| | - Hyun Cheol Chung
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jianming Xu
- The Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China
| | - Joon Oh Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Krzysztof Jeziorski
- Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | | | - Yanling Ma
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Monica C Estrada
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | | | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - J Randolph Hecht
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Santa Monica, California
| | - Dennis J Slamon
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Santa Monica, California
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28
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Pathmanathan N, Geng JS, Li W, Nie X, Veloso J, Wang J, Hill J, Mccloud P, Bilous M. Human epidermal growth factor receptor 2 status of gastric cancer patients in Asia: results from a large, multicountry study. Asia Pac J Clin Oncol 2016; 13:249-260. [PMID: 28008715 DOI: 10.1111/ajco.12653] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 10/23/2016] [Accepted: 10/30/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Nirmala Pathmanathan
- Department of Tissue Pathology and Diagnostic Oncology; Pathology West; Westmead Breast Cancer Institute; Westmead Hospital; Western Sydney University and University of Sydney; Sydney Australia
| | - Jing-shu Geng
- Harbin Medical University Cancer Hospital; Harbin China
| | - Wencai Li
- The First Affiliated Hospital of Zhengzhou University; Zhengzhou China
| | - Xiu Nie
- Wuhan Union Hospital; Hubei China
| | - Januario Veloso
- National Kidney and Transplant Institute; Quezon City Philippines
| | - John Wang
- China Medical University Hospital; Taichung Taiwan
| | - Julie Hill
- McCloud Consulting Group Pty Ltd; Sydney Australia
| | | | - Michael Bilous
- Australian Clinical Labs; Norwest Private Hospital; Western Sydney University and University of Sydney; Sydney Australia
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Shen GS, Zhao JD, Zhao JH, Ma XF, Du F, Kan J, Ji FX, Ma F, Zheng FC, Wang ZY, Xu BH. Association of HER2 status with prognosis in gastric cancer patients undergoing R0 resection: A large-scale multicenter study in China. World J Gastroenterol 2016; 22:5406-5414. [PMID: 27340357 PMCID: PMC4910661 DOI: 10.3748/wjg.v22.i23.5406] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 05/11/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether the positive status of human epidermal growth receptor 2 (HER2) can be regarded as an effective prognostic factor for patients with gastric cancer (GC) undergoing R0 resection.
METHODS: A total of 1562 GC patients treated by R0 resection were recruited. HER2 status was evaluated in surgically resected samples of all the patients using immunohistochemical (IHC) staining. Correlations between HER2 status and clinicopathological characteristics were retrospective analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model, stratified by age, gender, tumor location and tumor-node-metastasis (TNM) stage, with additional adjustment for potential prognostic factors.
RESULTS: Among 1562 patients, 548 (positive rate = 35.08%, 95%CI: 32.72%-37.45%) were HER2 positive. Positive status of HER2 was significantly correlated with gender (P = 0.004), minority (P < 0.001), tumor location (P = 0.001), pathological grade (P < 0.001), TNM stage (P < 0.001) and adjuvant radiotherapy (74.67% vs 23.53%, P = 0.011). No significant associations were observed between HER2 status and disease free survival (HR = 0.19, 95%CI: 0.96-1.46, P = 0.105) or overall survival (HR = 1.19, 95%CI: 0.96-1.48, P = 0.118) using multivariate analysis, although stratified analyses showed marginally statistically significant associations both in disease free survival and overall survival, especially among patients aged < 60 years or with early TNM stages (I and II). Categorical age, TNM stage, neural invasion, and adjuvant chemotherapy were, as expected, independent prognostic factors for both disease free survival and overall survival.
CONCLUSION: The positive status of HER2 based on IHC staining was not related to the survival in patients with GC among the Chinese population.
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Jiang H, Li Q, Yu S, Yu Y, Wang Y, Li W, Cui Y, Liu T. Impact of HER2 expression on outcome in gastric cancer patients with liver metastasis. Clin Transl Oncol 2016; 19:197-203. [PMID: 27324991 DOI: 10.1007/s12094-016-1523-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 06/10/2016] [Indexed: 12/13/2022]
Abstract
PURPOSE We aim to investigate the correlation of HER2 expression with liver metastasis and the impact of HER2 status and trastuzumab therapy on the prognosis of gastric cancer with liver metastasis (GCLM) patients. METHODS This prospective observational study was carried out in Shanghai Zhongshan Hospital, Fudan University, from January 2012 to June 2015. HER2 status and baseline characteristics were collected from the patient record. GCLM patients were divided into three groups according to HER2 status and trastuzumab therapy. RESULTS A total of 290 patients were included, and94 patients were diagnosed with liver metastasis. The HER2 positivity was 37.2 % (35/94) in GCLM patients and 21 % (61/290) in the overall GC patients. Among 94 GCLM patients, 28 HER2-positive patients received trastuzumab-based therapy (group A), 7 HER2-positive patients received chemotherapy alone (group B) and the other 59 patients were HER2 negative (group C). The median progression-free survival (PFS) for groups A, B and C was 7.83, 6.30 and 5.33 months, respectively (P = 0.007). The median overall survival (OS) for groups A, B and C was 12.00, 10.47 and 8.67 months, respectively (P = 0.056). Further Cox analysis showed that there was no significant difference in OS (P = 0.917) and PFS (P = 0.456) between group B and C. CONCLUSIONS HER2 positivity was higher in GCLM patients. HER2 status itself was not an independent prognostic factor in GCLM patients. Trastuzumab-based therapy could significantly improve survival in HER2-positive GCLM patients.
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Affiliation(s)
- H Jiang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Q Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - S Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Y Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Y Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - W Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Y Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - T Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
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Li H, Yu C, Jiang J, Huang C, Yao X, Xu Q, Yu F, Lou L, Fang J. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther 2016; 17:346-54. [PMID: 26853765 DOI: 10.1080/15384047.2016.1139248] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Antibody-drug conjugate (ADC) is a novel class of therapeutics for cancer target therapy. This study assessed antitumor activity of ADC with an antimitotic agent, monomethyl auristatin E (MMAE) and a humanized monoclonal anti-HER2 antibody, hertuzumab, in gastric cancer. The efficacy of hertuzumab-MC-Val-Cit-PAB-MMAE (hertuzumab-vcMMAE) on human epidermal growth factor receptor 2 (HER2) positive human gastric cancer cells, NCI-N87, was evaluated in vitro and in vivo. The cytotoxicity of hertuzumab was significantly enhanced after conjugation with MMAE. Compared to trastuzumab, hertuzumab had a higher affinity to HER2 and had more potent antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. After conjugation with MMAE, the binding specificity for HER2 was not affected. Furthermore, the internalization of hertuzumab-vcMMAE in HER2 positive gastric cancer cells was verified. Although the conjugation of hertuzumab and MMAE decreased the ADCC effect, the overall cytotoxicity was dramatically increased in HER2 positive gastric cancer cells. In vitro data on this hertuzumab-vcMMAE has exerted much stronger antitumor activity compared to trastuzumab-DM1 in HER2 positive gastric cancer cells. A single administration of hertuzumab-vcMMAE at 5 or 10 mg/kg showed high potency and a sustained tumor inhibitory effect on NCI-N87 xenografts in mice. In conclusion, hertuzumab-vcMMAE conjugate is a highly effective anti-HER2 targeted therapy for HER2-positive gastric cancer.
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Affiliation(s)
- Hongwen Li
- a School of Life Sciences and Technology, Tongji University , Shanghai , China
| | - Chao Yu
- b RemeGen, Ltd. , Yantai , Shandong , China
| | - Jing Jiang
- c School of Pharmacy, Binzhou Medical University , Yantai , Shandong , China
| | | | - Xuejing Yao
- a School of Life Sciences and Technology, Tongji University , Shanghai , China
| | - Qiaoyu Xu
- b RemeGen, Ltd. , Yantai , Shandong , China
| | - Fang Yu
- b RemeGen, Ltd. , Yantai , Shandong , China
| | - Liguang Lou
- d Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
| | - Jianmin Fang
- a School of Life Sciences and Technology, Tongji University , Shanghai , China.,e Tongji University Suzhou Institute , Suzhou , Jiangsu , China.,f Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China
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Huang D, Duan H, Huang H, Tong X, Han Y, Ru G, Qu L, Shou C, Zhao Z. Cisplatin resistance in gastric cancer cells is associated with HER2 upregulation-induced epithelial-mesenchymal transition. Sci Rep 2016; 6:20502. [PMID: 26846307 PMCID: PMC4742832 DOI: 10.1038/srep20502] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 01/05/2016] [Indexed: 12/13/2022] Open
Abstract
Cisplatin remains to be primary chemotherapeutic drug for gastric cancer patients, especially for advanced stage ones. However, primary or acquired resistance often occurs with the mechanisms being not well understood, which results in relapse of the cancer and poor survival. Herein, we found that HER2 upregulation was associated with cisplatin resistance. We observed that cisplatin-resistant gastric cancer cells underwent a morphological change similar to epithelial-mesenchymal transition (EMT) which is mediated by HER2 overexpression. When specific monoclonal antibody Herceptin, small molecular targeted drug CP724714, or small interfering RNA against HER2 was applied, the EMT-like phenotypic change was dramatically reversed. More importantly, the IC50 and Resistance Index of resistant gastric cancer cells to cisplatin were also decreased by any of these treatments.We demonstrated that expression and amplification of HER2 positively correlated with expression of EMT-related transcription factor Snail in gastric cancer tissues. Furthermore, for the first time, we found that HER2/Snail double positive gastric cancer patients had poorer survival than single positive or double negative counterparts, which provided experimental evidence for the necessity of HER2/Snail double testing in gastric cancer. In conclusion, this study provides some clues of the association of cisplatin resistance with HER2 upregulation-induced EMT in gastric cancer cells.
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Affiliation(s)
- Dongsheng Huang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Hongying Duan
- Clinical Research Institute, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China.,Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Hao Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital &Institute, Beijing 100142, China
| | - Xiangmin Tong
- Clinical Research Institute, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Yong Han
- Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Guoqing Ru
- Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital &Institute, Beijing 100142, China
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital &Institute, Beijing 100142, China
| | - Zhongsheng Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
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Baykara M, Benekli M, Ekinci O, Irkkan SC, Karaca H, Demirci U, Akinci MB, Unal OU, Dane F, Turkoz FP, Balakan O, Eser EP, Ozturk SC, Ozkan M, Oksuzoglu B, Sevinc A, Demir N, Harputluoglu H, Yalcin B, Coskun U, Uner A, Ozet A, Buyukberber S. Clinical Significance of HER2 Overexpression in Gastric and Gastroesophageal Junction Cancers. J Gastrointest Surg 2015; 19:1565-71. [PMID: 26179664 DOI: 10.1007/s11605-015-2888-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 06/29/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND In this study, we investigated the rate of human epidermal growth factor receptor 2 (HER2) overexpression in gastric (GC) and gastroesophageal junction cancers (GEJCs) and the relationship with HER2 expression and clinical, pathological parameters and prognosis. METHODS Surgery or biopsy specimen of 598 (436 males, 162 females) patients with GC or GEJC was evaluated for the presence of HER2 overexpression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. RESULTS HER2 IHC scores were as follows: 418 (69.9%) IHC 0, 58 (9.7%) IHC 1+, 50 (8.4%) IHC 2+, 72 (12%) IHC 3+. Among 50 patients with IHC 2+, 18 (38.2%) were FISH positive, and 29 (61.7%) were FISH negative for HER2 amplification. Patients were regarded as HER2 positive in case of IHC 3+ disease or IHC 2+ disease with a positive FISH test result for HER2 amplification. In the primary analysis population, 90 (15%) were considered HER2 positive. HER2 positivity was higher in intestinal GC compared to diffuse GC (16.9 vs 6.6%, p = 0.014). HER2 positivity was significantly higher in well and moderately differentiated tumors than poorly differentiated tumors (p < 0.0001). HER2 positivity had no significant effect on median OS (23.2 vs 19.1 months, p = 0.44). But in the early stages (stages I and II), median OS of HER2-positive patients was shorter than HER2-negative patients (51.4 months vs not reach, p = 0.047). However, median OS was similar in patients with advanced stages (stages III and IV) HER2-positive and HER2-negative disease (16.2 vs 13.7 months, p = 0.72). CONCLUSIONS Rate of HER2 positivity is similar in Turkish patients with GC and GEJCs. HER2 positivity is associated with poor prognosis in patients with early-stage disease.
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Affiliation(s)
- Meltem Baykara
- Department of Medical Oncology, Sakarya University Training and Research Hospital, Sakarya, Turkey,
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Uprak TK, Attaallah W, Çelikel ÇA, Ayrancı G, Yeğen C. HER-2 incidence in gastric cancer, its association with prognosis and clinicopathological parameters. ULUSAL CERRAHI DERGISI 2015; 31:207-13. [PMID: 26668528 DOI: 10.5152/ucd.2015.2964] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 05/25/2015] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Human epidermal growth factor-2 (HER-2) overexpression has prognostic value in breast cancer. However, the significance of HER-2 positivity in gastric cancer is controversial. In this study, we investigated the frequency of overexpression of HER-2 and its relationship with clinicopathological findings and impact on survival in gastric cancer. MATERIAL AND METHODS Gastric cancer patients, operated in Marmara University Faculty of Medicine, Pendik Training and Research Hospital, General Surgery Department, between January 2012-December 2013 were enrolled in this study. Medical records were retrospectively evaluated. Tissue samples were stained by immunohistochemistry (IHC) method, and were followed by fluorescence in situ hybridization (FISH) in those with positive results. HER-2 expression rates and its association with other histopathological features and survival have been analyzed. RESULTS 135 patients were enrolled in the study, with 88 (65%) male and 47 (35%) female patients. The median age was 61 (29-84) years. Only 11 patients (8%) were positive for HER-2. HER-2 positive patients were similar to negative patients in terms of age, gender, tumor size, tumor location, tumor T stage, lymph node metastasis, histological type, differentiation, lymphovascular invasion, perinodal, perineural invasion and stage. No significant difference was detected on 1 and 2-year overall and disease-free survival rates between receptor positive and negative groups. CONCLUSION Consistent with the literature data, HER-2 positivity rate in this study was approximately 8%, but this positivity has not been found to be associated with either clinical and pathological parameters or overall and disease-free survival.
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Affiliation(s)
- Tevfik Kıvılcım Uprak
- Department of General Surgery, Marmara University Faculty of Medicine, İstanbul, Turkey
| | - Wafi Attaallah
- Department of General Surgery, Marmara University Faculty of Medicine, İstanbul, Turkey
| | | | - Gülçiçek Ayrancı
- Department of Pathology, Marmara University Faculty of Medicine, İstanbul, Turkey
| | - Cumhur Yeğen
- Department of General Surgery, Marmara University Faculty of Medicine, İstanbul, Turkey
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Li HE, Wang X, Tang Z, Liu F, Chen W, Fang Y, Wang C, Shen K, Qin J, Shen Z, Sun Y, Qin X. A concordant expression pattern of fatty acid synthase and membranous human epidermal growth factor receptor 2 exists in gastric cancer and is associated with a poor prognosis in gastric adenocarcinoma patients. Oncol Lett 2015; 10:2107-2117. [PMID: 26622804 PMCID: PMC4579914 DOI: 10.3892/ol.2015.3609] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 04/14/2015] [Indexed: 01/27/2023] Open
Abstract
Fatty acid synthase (FAS) and human epidermal growth factor receptor 2 (HER2) are overexpressed in gastric cancer (GC), and certain interactions have been found between FAS and HER2. A total of 94 patients were enrolled in the present study, each of whom underwent a D2 radical surgery in Zhongshan Hospital affiliated with Fudan University (Shanghai, China) between 2000 and 2005. The expression of FAS and HER2 was assessed by immunohistochemistry analysis of tissue microarrays generated from GC and non-tumor tissues. All data were analyzed by GraphPad Prism 5.0 to investigate the association between FAS and HER2 and to detect the potential association with prognosis. FAS (P<0.0001) and membranous HER2 (mHER2; P=0.0021) were overexpressed in the GC tissues, and a bidirectional and strong correlation was demonstrated between FAS and mHER2 in the tumor tissues. The expression of cytoplasmic HER2 (cHER2) was significantly lower in the GC tissues compared with the non-tumor tissues (P=0.0005), and cHER2 was expressed at a higher level in tumors that had better differentiation compared with poorly-differentiated tissues (P=0.0503). Patients with a concordant expression pattern of FAS and mHER2 showed a significantly poorer prognosis than the non-concordant group (P=0.0096; hazards ratio, 3.2801; 95% confidence interval, 1.5781-6.8176). GC tissues significantly overexpress FAS and mHER2 and the expression of these two markers is associated. Patients with a concordant expression of FAS and mHER2 are more likely to suffer a poor prognosis.
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Affiliation(s)
- H E Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Xuefei Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Zhaoqing Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Weidong Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Yong Fang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Cong Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Kuntang Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
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Song Z, Liu W, Xiao Y, Zhang M, Luo Y, Yuan W, Xu Y, Yu G, Hu Y. PRR11 Is a Prognostic Marker and Potential Oncogene in Patients with Gastric Cancer. PLoS One 2015; 10:e0128943. [PMID: 26252227 PMCID: PMC4529228 DOI: 10.1371/journal.pone.0128943] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 05/01/2015] [Indexed: 12/20/2022] Open
Abstract
PRR11 is a potential candidate oncogene that has been implicated in the pathogenesis of lung cancer, however the role of PRR11 in gastric cancer is currently unclear. In the present study, we investigated the role of PRR11 in gastric cancer by evaluating its expression status in samples from a cohort of 216 patients with gastric cancer. PRR11 was found to be overexpressed in 107 (49.5%) patients by immunohistochemistry of tissue microarrays generated using the patient samples. Furthermore, PRR11 overexpression was found to correlate significantly with clinicopathologic features such as tumor invasion, tumor differentiation, and disease stage. Survival analysis of the cohort revealed that PRR11 is an independent prognostic factor for gastric cancer patients. PRR11 was stably silenced in a gastric carcinoma cell line using an shRNA-based approach, and treated cells showed decreased cellular proliferation and colony formation in vitro and cell growth in vivo, companied by decreased expression of CTHRC1 and increased expression of LXN, proteins involved in tumor progression. Evaluation of human gastric cancer samples demonstrated that PRR11 expression was also associated with increased CTHRC1 and decreased LXN expression. These data indicate that PRR11 may be widely activated in human gastric cancer and are consistent with the hypothesis that PRR11 functions as an oncogene in the development and progression of gastric cancer.
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Affiliation(s)
- Zongchang Song
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Wenying Liu
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Yu Xiao
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Minghui Zhang
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Yan Luo
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Weiwei Yuan
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Yu Xu
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
| | - Guanzhen Yu
- Department of Medical Oncology, Shanghai East Hospital, Shanghai, 200120, China
- Department of Medical Oncology, Changzheng Hospital, Shanghai, 200070, China
| | - Yide Hu
- The Third Department of Oncology, The Second Affiliated Hospital of The Third Military Medical University, Chongqing, 400037, China
- * E-mail:
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Koopman T, Smits MM, Louwen M, Hage M, Boot H, Imholz ALT. HER2 positivity in gastric and esophageal adenocarcinoma: clinicopathological analysis and comparison. J Cancer Res Clin Oncol 2015; 141:1343-51. [PMID: 25544671 DOI: 10.1007/s00432-014-1900-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 12/18/2014] [Indexed: 12/13/2022]
Abstract
PURPOSE Primary tumor classification of gastric or esophageal cancer has changed significantly with recent alterations of the tumor-node-metastasis (TNM) staging system. Considering these alterations, human epidermal growth factor receptor 2 (HER2) positivity rates were determined and compared in gastric and esophageal adenocarcinoma. Additionally, HER2 positivity in relation to other clinicopathological characteristics was evaluated. METHODS A total of 321 patients with histologically confirmed invasive gastric or esophageal adenocarcinoma were examined for HER2 by immunohistochemy (IHC) and chromogenic in situ hybridization (CISH). IHC 3+ or IHC 2+/CISH-positive tumors were considered HER2 positive. Clinicopathological characteristics were retrospectively retrieved from the patient records. RESULTS HER2 positivity was found in 50 of 321 patients (15.6 %). In univariate and multivariate logistic models, HER2 positivity rates were significantly higher in esophageal primary tumors (esophageal 25.0 % vs. gastric 7.4 %) and in intestinal histological tumor type (intestinal 22.6 % vs. diffuse/mixed 5.7 %). No significant differences in HER2 positivity were found between males and females, age below and above 65 years, biopsies and surgical specimens or advanced and early-stage disease. Using the 7th TNM edition, many tumors (30.5 % of all included tumors and 64.5 % of all esophageal primary tumors) previously classified as gastric cancer are now classified as esophageal cancer. CONCLUSIONS HER2 positivity occurs in 15.6 % of invasive gastroesophageal adenocarcinoma in Western patients, of which the majority is esophageal primary tumors and of the intestinal tumor type. With the introduction of the 7th TNM edition, a large number of tumors previously classified as gastric are now classified as esophageal tumors instead, with relatively high HER2 positivity rates in these esophageal primary tumors.
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Affiliation(s)
- T Koopman
- Department of Medical Oncology, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE, Deventer, The Netherlands
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Overexpression of GRB2 is correlated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 7:3132-40. [PMID: 25031732 PMCID: PMC4097250 DOI: pmid/25031732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 04/17/2014] [Indexed: 02/05/2023]
Abstract
The adapter protein growth factor receptor-bound 2 (GRB2) is essential for various basic cellular functions by mediating the regulation of receptor tyrosine kinase (RTK) signaling, however, little is known about GRB2 expression in esophageal squamous cell carcinoma (ESCC). We sought to characterize GRB2 expression and its relationship with clinicopathological parameters and prognostic significance in ESCC patients. Here, it was presented that GRB2 was overexpressed in cytoplasm in 58.1% (100/172) of ESCC cases by immunohistochemistry. Survival analysis demonstrated overexpression of GRB2 protein was significantly related to poor prognosis of ESCC patients (P = 0.021). Furthermore, overexpression of GRB2 was significantly associated with the lymph node metastases. In addition, subgroup analysis according to lymph node metastasis revealed a shorter disease-free survival (DFS) in the ESCC patients with GRB2 overexpression than the patients with GRB2 low-expression (Means for DFS months: 33.8 versus 52.1). Finally, the significant difference between overexpression of GRB2 and poor survival rates exhibited in univariate analysis (P = 0.022) and multivariate Cox analysis (close to significance, P = 0.065), demonstrated that GRB2 was an independent factor in prognosis of ESCC patients. In conclusion, GRB2 expression status could be as a positive biomarker of ESCC progression and lymph node metastasis.
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Peng Z, Zou J, Zhang X, Yang Y, Gao J, Li Y, Li Y, Shen L. HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis. Chin J Cancer Res 2015; 27:163-71. [PMID: 25937778 DOI: 10.3978/j.issn.1000-9604.2014.12.09] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 11/10/2014] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND A number of studies have examined human epidermal growth factor receptor 2 (HER2) status in primary gastric cancer (GC) and associated metastasis, some showed their great concordance in HER2 expression, but others demonstrated notable discordance. There is still little consensus on HER2 discordance, therefore, a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis. METHODS PubMed, EMBASE, ASCO and The Cochrane Library were searched for studies that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March, 2014. Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions. RESULTS Eighteen articles including 1,867 patients were included for the meta-analysis in accordance with the selection criteria. Pooled discordance proportions were 7% [95% confidence interval (CI): 5-10%] for HER2 status. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17% (95% CI: 7-29%) and 4% (95% CI: 2-6%) respectively. No publication bias was found in the meta-analysis. CONCLUSIONS The discordance of HER2 status is not rare in primary and metastatic GC through our meta-analysis. Prospective studies are needed to testify the clinical significance of the discordance of HER2 status.
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Affiliation(s)
- Zhi Peng
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Jianling Zou
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Xiaotian Zhang
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Yehong Yang
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Jing Gao
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Yilin Li
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Yanyan Li
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Lin Shen
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
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Cappellesso R, Fassan M, Hanspeter E, Bornschein J, d'Amore ESG, Cuorvo LV, Mazzoleni G, Barbareschi M, Pizzi M, Guzzardo V, Malfertheiner P, Micev M, Guido M, Giacomelli L, Tsukanov VV, Zagonel V, Nitti D, Rugge M. HER2 status in gastroesophageal cancer: a tissue microarray study of 1040 cases. Hum Pathol 2015; 46:665-672. [PMID: 25800719 DOI: 10.1016/j.humpath.2015.02.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 01/28/2015] [Accepted: 02/04/2015] [Indexed: 12/16/2022]
Abstract
Among patients with gastric cancer (GC) and gastroesophageal cancer (G-EC), HER2 amplification identifies those who may benefit from trastuzumab. HER2 status assessment, however, is influenced by preanalytic, analytic, and postanalytic variables. In a series of 5426 microarray cancer tissue cores obtained from 1040 GC/G-ECs (824 GC, 216 G-EC) and 720 synchronous nodal metastases, we evaluated both the performances of 2 different immunohistochemistry (IHC) protocols and the HER2 status intratumor variability. The prevalence of HER2 amplification and protein overexpression were assessed by chromogenic in situ hybridization and by 2 IHC protocols (CB11 and 4B5). HER2 was amplified in 114 (11%) of 1040 cases; in 6 (5.3%) of 114 cases, gene amplification only involved nodal metastasis. HER2 amplification prevailed in intestinal-type (P = .001) and low-grade (P < .001) tumors, showing no correlation with patients' age/sex, tumor location, stage, and Ming histotype. Overall, 12.5% and 13.7% of cases IHC scored 2+/3+ using the CB11-IHC and the 4B5-IHC protocol, respectively. HER2 amplification was not associated with protein overexpression (score 0/1+) in 11.4% and 6.2% of cases using the CB11-IHC and the 4B5-IHC protocol, respectively. The 4B5-IHC protocol proved more sensitive than CB11-IHC (93.9% versus 88.6%) and just as specific (96.1% versus 96.9%). Tested by chromogenic in situ hybridization, intratumor HER2 status was "substantially" consistent in different tissue cores obtained from the same case (κ = 0.78). Similar results were obtained for HER2 protein expression (CB11-IHC, κ = 0.78, and 4B5-IHC, κ = 0.83). Immunohistochemistry testing, however, fails in identifying about 10% of HER2-amplified cancers, potentially excluding these patients from anti-HER2 therapy.
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Affiliation(s)
- Rocco Cappellesso
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy
| | - Esther Hanspeter
- Pathology Service, Regional General Hospital, 39100 Bolzano, Italy
| | - Jan Bornschein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39106 Magdeburg, Germany
| | | | - Lucia V Cuorvo
- Surgical Pathology Unit, Molecular Pathology Laboratory, Trentino Biobank, S. Chiara Hospital, 38122 Trento, Italy
| | - Guido Mazzoleni
- Pathology Service, Regional General Hospital, 39100 Bolzano, Italy
| | - Mattia Barbareschi
- Surgical Pathology Unit, Molecular Pathology Laboratory, Trentino Biobank, S. Chiara Hospital, 38122 Trento, Italy
| | - Marco Pizzi
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy
| | - Vincenza Guzzardo
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39106 Magdeburg, Germany
| | - Marjan Micev
- Department of Pathology, First Surgical University Hospital, Clinical Center of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Maria Guido
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy; Pathology Department, ULSS15 Alta Padovana, 35013 Padua, Italy
| | - Luciano Giacomelli
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy
| | - Vladislav V Tsukanov
- State Scientific Medical Research Institute for Northern Problems of Siberian Division of Russian Academy of Medical Sciences, 660000 Krasnoyarsk, Russia
| | | | - Donato Nitti
- Department of Surgery, University of 35128 Padua, Padua, Italy
| | - Massimo Rugge
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, 35121 Padua, Italy.
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Correlations of Human Epithelial Growth Factor Receptor 2 Overexpression with MUC2, MUC5AC, MUC6, p53, and Clinicopathological Characteristics in Gastric Cancer Patients with Curative Resection. Gastroenterol Res Pract 2015; 2015:946359. [PMID: 26060493 PMCID: PMC4427822 DOI: 10.1155/2015/946359] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 09/29/2014] [Accepted: 10/18/2014] [Indexed: 12/20/2022] Open
Abstract
Background. The purpose of this study was to evaluate the relationships between HER2 overexpression in the tumor and MUC2, MUC5AC, MUC6, and p53 status and clinicopathological characteristics of gastric cancer patients. Methods. This retrospective study included 282 consecutive patients with gastric cancer who underwent surgery at the Kosin University Gospel Hospital between April 2011 and December 2012. All tumor samples were examined for HER2 expression by immunohistochemistry (IHC) and MUC2, MUC5AC, MUC6, and p53 expression by staining. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. Results. The HER2-positive rate was 18.1%. Although no association was found between HER2 expression and MUC5AC, the expression of MUC2, MUC6, and p53 was significantly correlated with HER2 positivity, respectively (P = 0.004, 0.037, 0.002). Multivariate analysis revealed that HER2 overexpression and nodal status were independent prognostic factors. Conclusions. HER2 overexpression in gastric carcinoma is an independent poor prognostic factor.
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Li LY, Zhang K, Jiang H, Xie YM, Liao LD, Chen B, Du ZP, Zhang PX, Chen H, Huang W, Jia W, Cao HH, Zheng W, Li EM, Xu LY. Quantitative proteomics reveals the downregulation of GRB2 as a prominent node of F806-targeted cell proliferation network. J Proteomics 2015; 117:145-55. [PMID: 25659534 DOI: 10.1016/j.jprot.2015.01.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Revised: 12/15/2014] [Accepted: 01/18/2015] [Indexed: 02/05/2023]
Abstract
UNLABELLED High-throughput proteomics has successfully identified thousands of proteins as potential therapeutic targets during investigations into mechanisms of drug action. A novel macrolide analog, denoted F806, is a potential antitumor drug. Here, using the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS), we characterize the F806-regulating protein profiles and identify the potential target molecules or pathways of F806 in esophageal squamous cell carcinoma (ESCC) cells. From a total of 1931 quantified proteins, 181 proteins were found to be down-regulated (FDR p-value<0.1, H/L ratio<0.738), and 119 proteins were up-regulated (FDR p-value<0.1, H/L ratio>1.156). Among the down-regulated proteins, we uncovered the over- and under-represented protein clusters in biological process and molecular function respectively by Gene Ontology analysis. Furthermore, down-regulated and up-regulated proteins were significantly enriched in 37 pathways and 60 sub-pathways by bioinformatic analysis (FDR p-value<0.1), while a down-regulated molecule growth factor receptor-bound protein 2 (GRB2) was a prominent node in fourteen cell proliferation-related sub-pathways. We concluded that GRB2 downregulation would be a potential target of F806 in ESCC cells. BIOLOGICAL SIGNIFICANCE This study used SILAC-based quantitative proteomics screen to systematically characterize molecular changes induced by a novel macrolide analog F806 in esophageal squamous cell carcinoma (ESCC) cells. Followed by bioinformatic analyses, signal pathway networks generated from the quantified proteins, would facilitate future investigation into the further mechanisms of F806 in ESCC cells. Notably, it provided information that growth factor receptor-bound protein 2 (GRB2) would be a prominent node in the F806-targeted cell proliferation network.
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Affiliation(s)
- Li-Yan Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Kai Zhang
- Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, PR China
| | - Hong Jiang
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Yang-Min Xie
- Experimental Animal Center, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Lian-Di Liao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Bo Chen
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Ze-Peng Du
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Pi-Xian Zhang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Hong Chen
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Wei Huang
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Wei Jia
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Hui-Hui Cao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Wei Zheng
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China.
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, PR China.
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China.
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Lapatinib sensitivities of two novel trastuzumab-resistant HER2 gene-amplified gastric cancer cell lines. Gastric Cancer 2015; 17:450-62. [PMID: 23948998 DOI: 10.1007/s10120-013-0290-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 07/28/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trastuzumab (Tmab) resistance is a major clinical problem to be resolved in patients with HER2-positive gastric cancers. However, in contrast to the situation for HER2-positive breast cancer lines, the Tmab-resistant gastric cancer preclinical models that are needed to develop a new therapy to overcome this problem are not yet available. METHODS We developed three new cell lines from HER2 gene-amplified gastric cancer cell lines (GLM-1, GLM-4, NCI N-87) by a new in vivo selection method consisting of the repeated culture of small residual peritoneal metastasis but not subcutaneous tumor after Tmab treatment. We then evaluated the anti-tumor efficacy of lapatinib for these Tmab-resistant cells. RESULTS We successfully isolated two Tmab-resistant cell lines (GLM1-HerR2(3), GLM4-HerR2) among the three tested cell lines. These resistant cells differed from the parental cells in their flat morphology and rapid growth in vitro, but HER2, P95HER2 expression, and Tmab binding were essentially the same for the parental and resistant cells. MUC4 expression was up- or downregulated depending on the cell line. These resistant cells were still sensitive to lapatinib, similar to the parental cells, in vitro. This growth inhibition of the Tmab-resistant cells by lapatinib was due to both G1 cell-cycle arrest and apoptosis induction via effective blockade of the PI3K/Akt and MAPK pathways. A preclinical study confirmed that the Tmab-resistant tumors are significantly susceptible to lapatinib. CONCLUSION These results suggest that lapatinib has antitumor activity against the Tmab-resistant gastric cancer cell lines, and that these cell lines are useful for understanding the mechanism of Tmab resistance and for developing a new molecular therapy for Tmab-resistant HER2-positive gastric cancers.
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Increased expression of phospho-acetyl-CoA carboxylase protein is an independent prognostic factor for human gastric cancer without lymph node metastasis. Med Oncol 2014; 31:15. [PMID: 24924473 DOI: 10.1007/s12032-014-0015-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 04/28/2014] [Indexed: 02/07/2023]
Abstract
Upregulation of acetyl-CoA carboxylase (ACC), as a rate-limiting enzyme of fatty acid synthesis,has been recognized in multiple human cancers, implicating a critical role in cancer development and progression; yet, its role in gastric cancer still remains unclear. In the present study, we detected ACC and phosphorylated form of ACC (pACC) expression in gastric cancers and explored its clinical significance. Tissue microarray blocks containing primary gastric cancer and adjacent normal mucosa specimens obtained from 1,072 Chinese patients were used for the detection of ACC and pACC expression by immunohistochemistry. Gastric cancer cell lines were treated by metformin, and pACC was measured by Western blotting. ACC overexpression was observed in all the tumor specimens. High expression of pACC was found in 630 (58.8 %) of the 1,072 primary tumors and in 237 (66.6 %) of the 356 primary tumors without lymph node metastasis. Absent/low expression of pACC significantly correlated with advanced T stage (P < 0.001), tumor size (P = 0.010), lymph node metastasis (P < 0.001), advanced disease stage (P < 0.001), and poor histological differentiation (P = 0.014) in 1,072 primary tumors, and with advanced T stage (P = 0.015), tumor size (P = 0.017), and poor histological differentiation (P = 0.001) in 356 tumors without lymph node metastasis. Kaplan-Meier analysis showed that high expression of pACC is strongly related to better survival rates in all gastric cancer patients (P = 0.006). Cox regression analysis revealed that pACC is an independent prognostic factor only in patients without lymph node metastasis (P = 0.016). Metformin treatment leaded to increased expression of pACC, which, in turn, resulted in the reduction of cell proliferation and colony formation of gastric cancer cells (P < 0.05). Increased activation of ACC is frequent in human gastric cancer, and downregulation of pACC is an important prognostic factor, suggesting that ACC/pACC might be a potential target for cancer intervention.
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Woisetschläger M, Antes B, Borrowdale R, Wiederkum S, Kainer M, Steinkellner H, Wozniak-Knopp G, Moulder K, Rüker F, Mudde GC. In vivo and in vitro activity of an immunoglobulin Fc fragment (Fcab) with engineered Her-2/neu binding sites. Biotechnol J 2014; 9:844-51. [DOI: 10.1002/biot.201300387] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 01/12/2014] [Accepted: 03/13/2014] [Indexed: 11/06/2022]
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Yin J, Yuan L, Liu Z, Zhang F, He X, Xu Z, Wang Q, Du X, Wu X, Lu J. Recombinant fusion proteins FPTD-Grb2-SH2 and FPTD-Grb2-SH2M inhibit the proliferation of breast cancer cells in vitro. Oncol Rep 2014; 31:2669-75. [PMID: 24715105 DOI: 10.3892/or.2014.3130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 03/21/2014] [Indexed: 11/06/2022] Open
Abstract
Growth factor receptor bound protein 2 (Grb2) is a key adaptor performing a principal role in the oncogenic Ras signaling pathway. In the present study, we generated two fusion proteins. One contained an Src homology 2 (SH2) domain of Grb2, a signal peptide sequence, FLAG-tag sequence, PTD region and we named it FPTD-Grb2-SH2, while the other contained one mutant SH2 domain, added to a signal peptide sequence, FLAG-tag sequence, PTD region and we named it FPTD-Grb2-SH2M. Western blot analysis and immunofluorescence assay were used to investigate the expression and location of the fusion proteins in breast cancer cells. The proliferation and migration of the cells were estimated by MTT and Transwell cell migration assays, respectively. Flow cytometric analysis was performed to evaluate the apoptosis of the breast cancer cells. The recombinant proteins FPTD-Grb2-SH2 and FPTD-Grb2-SH2M were successfully expressed in the breast cancer cell lines regardless of HER2-phenotype, and they suppressed breast cancer cell growth and migration as expected from the lack of SH3 domain. Both FPTD-Grb2-SH2 and FPTD-Grb2-SH2M exhibited significant toxicity to breast cancer cells. The present study demonstrated that the recombinant proteins FPTD-Grb2-SH2 and FPTD-Grb2-SH2M may be used for anticancer drug development.
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Affiliation(s)
- Jikai Yin
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Ba'qiao, Xi'an, Shaanxi 710038, P.R. China
| | - Lijuan Yuan
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Ba'qiao, Xi'an, Shaanxi 710038, P.R. China
| | - Ziyu Liu
- Department of Microbiology, The Fourth Military Medical University, Chang'le, Xi'an, Shaanxi 710032, P.R. China
| | - Fanglin Zhang
- Department of Microbiology, The Fourth Military Medical University, Chang'le, Xi'an, Shaanxi 710032, P.R. China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Ba'qiao, Xi'an, Shaanxi 710038, P.R. China
| | - Zhikai Xu
- Department of Microbiology, The Fourth Military Medical University, Chang'le, Xi'an, Shaanxi 710032, P.R. China
| | - Qing Wang
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Ba'qiao, Xi'an, Shaanxi 710038, P.R. China
| | - Xilin Du
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Ba'qiao, Xi'an, Shaanxi 710038, P.R. China
| | - Xing'an Wu
- Department of Microbiology, The Fourth Military Medical University, Chang'le, Xi'an, Shaanxi 710032, P.R. China
| | - Jianguo Lu
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Ba'qiao, Xi'an, Shaanxi 710038, P.R. China
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Xie J, Li P, Gao HF, Qian JX, Yuan LY, Wang JJ. Overexpression of SLC38A1 is associated with poorer prognosis in Chinese patients with gastric cancer. BMC Gastroenterol 2014; 14:70. [PMID: 24712400 PMCID: PMC3984425 DOI: 10.1186/1471-230x-14-70] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 03/31/2014] [Indexed: 11/19/2022] Open
Abstract
Background Current literature has demonstrated that host glutamine depletion facilitates tumorigenesis. Likewise, the glutamine transporter SLC38A1 is putatively associated with malignant transformation and tumor progression. Taken together, this forms the premise for undertaking the current study. The twofold aim of this study was to provide insight into whether or not a variance in the expression of SLC38A1 exists between human gastric cancer and healthy human tissues, and to determine how silencing the SLC38A1 gene could affect the proliferation, viability, migration, and invasion of gastric cancer cells. Methods Immunohistochemical staining was used to analyze the expression of SLC38A1 in gastric cancer tissues and adjacent healthy mucosa in 896 patients with pathologically confirmed gastric cancer who had underwent R0 resection. SH-10-TC cells (a gastric cancer cell line) were used to examine whether silencing SLC38A1 with siRNA could affect cell viability, migration and invasion. Results The SLC38A1 protein was very low or undetectable in healthy gastric mucosa. In contrast, strong staining of SLC38A1 protein was found in the cytoplasm in 495 out of the 896 gastric cancer samples. More pronounced SLC38A1 expression in gastric cancer tissues was significantly associated with age, differentiation status, lymph node metastasis, TNM stage and PCNA (proliferating cell nuclear antigen) expression. Upon univariate survival analysis, SLC38A1 expression was correlated with poor survival. Multivariate survival analysis revealed that SLC38A1 was an independent prognostic factor. Conclusion SLC38A1 is overexpressed in gastric cancer, which suggests that it is contributory to tumor progression. These results encourage the exploration of SLC38A1 as a target for intervention in gastric cancer.
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Affiliation(s)
- Jing Xie
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, 270 DongAn Road, Shanghai 200032, China.
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Gowryshankar A, Nagaraja V, Eslick GD. HER2 status in Barrett's esophagus & esophageal cancer: a meta analysis. J Gastrointest Oncol 2014; 5:25-35. [PMID: 24490040 PMCID: PMC3904023 DOI: 10.3978/j.issn.2078-6891.2013.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/07/2013] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The oncogenic potential of the Human Epidermal Growth Factor Receptor 2 (HER2) is well known in the context of breast cancer however; its relationship with the development of Barrett's Esophagus (BE) and Esophageal Cancer (EC) is unclear. The aim of this meta-analysis was to determine the overall prevalence and survival of HER2+ in BE & EC. PATIENTS AND METHODS Several databases were searched including article reference lists. Inclusion criteria required that studies measured HER2 positivity in subjects with BE or EC. RESULTS 33 studies were included in the meta-analysis (10 BE & 23 EC studies). The prevalence of HER2+ was found to be 24% (95% CI: 15-36%) in BE and 26% (95% CI: 19-34%) in EC. Squamous cell carcinoma (SCC) had a higher ER of 32% (95% CI: 20-48%) in comparison with adenocarcinoma (ADC) with an ER of 21% (95% CI: 14-32%). Sub group analyses showed a high geographical variance, Asia was found to be the highest prevalent area with an ER 42% (95% CI: 22-64%). The difference in survival rate between groups HER2- & HER2+ was found to be 7 months. CONCLUSIONS Our results highlight a high prevalence of HER2+ in subjects with adenocarcinoma. HER2+ appears to decrease the survival time of EC patients.
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Affiliation(s)
- Ashwini Gowryshankar
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
| | - Vinayak Nagaraja
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
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Liang JW, Zhang JJ, Zhang T, Zheng ZC. Clinicopathological and prognostic significance of HER2 overexpression in gastric cancer: a meta-analysis of the literature. Tumour Biol 2014; 35:4849-58. [PMID: 24449506 DOI: 10.1007/s13277-014-1636-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 01/07/2014] [Indexed: 12/19/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) plays an important role in the aggressiveness and progression of gastric cancer. With the publication of trial results, we conducted a meta-analysis to investigate its prognostic significance for patients with gastric cancer. PubMed, Ovid, Web of Science, and Cochrane databases were searched. Statistical analysis was carried out by STATA version 12.0 software. The Newcastle-Ottawa scale was used to assess the quality of evidence. Fifteen studies involving 5,290 patients met the inclusion criteria. The results showed that HER2 overexpression was significantly associated with patients' overall survival (HR = 1.56, 95% confidence interval (CI) 1.05-2.07; Z = 6.03; P = 0.000). The results also suggested that HER2 overexpression was associated with Bormann type (odds ratio (OR) = 1.76, 95% CI 1.19-2.59; Z = 2.85; P = 0.004), tumor differentiation (OR = 3.14, 95% CI 1.91-5.17; Z = 4.49; P = 0.000), Lauren's classification (OR = 6.25, 95% CI 4.29-9.10; Z = 9.54; P = 0.000), lymph node metastasis (OR = 1.43, 95% CI 1.15-1.77; Z = 3.23; P = 0.001), venous invasion (OR = 1.69, 95% CI 1.15-2.48; Z = 2.67; P = 0.008), and lymphovascular invasion (OR = 1.57, 95% CI 1.21-2.04; Z = 3.4; P = 0.001). However, it had no correlation with tumor size, depth of invasion, and tumor stage. This study showed that HER2 overexpression had an unfavorable prognostic role for patients with gastric cancer. HER2-positive expression was associated with Bormann type, Lauren's classification, tumor differentiation, lymph node status, venous invasion, and lymphovascular invasion.
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Affiliation(s)
- Ji-wang Liang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, People's Republic of China,
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Bai X, Lee JY, Kim TI, Dai F, Lee TJ, Hong SJ. Molecular cloning and characterization of growth factor receptor bound-protein in Clonorchis sinensis. PLoS One 2014; 9:e85577. [PMID: 24454892 PMCID: PMC3894193 DOI: 10.1371/journal.pone.0085577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Accepted: 11/27/2013] [Indexed: 11/19/2022] Open
Abstract
Background Clonorchis sinensis causes clonorchiasis, a potentially serious disease. Growth factor receptor-bound protein 2 (Grb2) is a cytosolic protein conserved among animals and plays roles in cellular functions such as meiosis, organogenesis and energy metabolism. In the present study, we report first molecular characters of growth factor receptor bound-protein (CsGrb2) from C. sinensis as counter part of Grb2 from animals and its possible functions in development and organogenesis of C. sinensis. Methodology/Principal Findings A CsGrb2 cDNA clone retrieved from the C. sinensis transcriptome encoded a polypeptide with a SH3-SH2-SH3 structure. Recombinant CsGrb2 was bacterially produced and purified to homogeneity. Native CsGrb2 with estimated molecular weight was identified from C. sinensis adult extract by western blotting using a mouse immune serum to recombinant CsGrb2. CsGrb2 transcripts was more abundant in the metacercariae than in the adults. Immunohistochemical staining showed that CsGrb2 was localized to the suckers, mesenchymal tissues, sperms in seminal receptacle and ovary in the adults, and abundantly expressed in most organs of the metacercariae. Recombinant CsGrb2 was evaluated to be little useful as a serodiagnostic reagent for C. sinesis human infections. Conclusion Grb2 protein found in C. sinensis was conserved among animals and suggested to play a role in the organogenesis, energy metabolism and mitotic spermatogenesis of C. sinensis. These findings from C. sinensis provide wider understanding on diverse function of Grb2 in lower animals such as platyhelminths.
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Affiliation(s)
- Xuelian Bai
- Department of Medical Environmental Biology, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
| | - Ji-Yun Lee
- Department of Medical Environmental Biology, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
| | - Tae Im Kim
- Department of Medical Environmental Biology, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
| | - Fuhong Dai
- Department of Medical Environmental Biology, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
| | - Tae-Jin Lee
- Department of Pathology, Chung-Ang Univesity College of Medicine, Dongjak-gu, Seoul, Republic of Korea
| | - Sung-Jong Hong
- Department of Medical Environmental Biology, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
- * E-mail:
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