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1
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Kumar A, Das SK, Emdad L, Fisher PB. Applications of tissue-specific and cancer-selective gene promoters for cancer diagnosis and therapy. Adv Cancer Res 2023; 160:253-315. [PMID: 37704290 DOI: 10.1016/bs.acr.2023.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Current treatment of solid tumors with standard of care chemotherapies, radiation therapy and/or immunotherapies are often limited by severe adverse toxic effects, resulting in a narrow therapeutic index. Cancer gene therapy represents a targeted approach that in principle could significantly reduce undesirable side effects in normal tissues while significantly inhibiting tumor growth and progression. To be effective, this strategy requires a clear understanding of the molecular biology of cancer development and evolution and developing biological vectors that can serve as vehicles to target cancer cells. The advent and fine tuning of omics technologies that permit the collective and spatial recognition of genes (genomics), mRNAs (transcriptomics), proteins (proteomics), metabolites (metabolomics), epiomics (epigenomics, epitranscriptomics, and epiproteomics), and their interactomics in defined complex biological samples provide a roadmap for identifying crucial targets of relevance to the cancer paradigm. Combining these strategies with identified genetic elements that control target gene expression uncovers significant opportunities for developing guided gene-based therapeutics for cancer. The purpose of this review is to overview the current state and potential limitations in developing gene promoter-directed targeted expression of key genes and highlights their potential applications in cancer gene therapy.
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Affiliation(s)
- Amit Kumar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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Alekseenko IV, Pleshkan VV, Kuzmich AI, Kondratieva SA, Sverdlov ED. Gene-Immune Therapy of Cancer: Approaches and Problems. RUSS J GENET+ 2022; 58:491-506. [DOI: 10.1134/s1022795422040020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/10/2021] [Accepted: 10/14/2021] [Indexed: 01/05/2025]
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3
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Hamidi-Sofiani V, Rakhshi R, Moradi N, Zeynali P, Nakhaie M, Behboudi E. Oncolytic viruses and pancreatic cancer. Cancer Treat Res Commun 2022; 31:100563. [PMID: 35460973 DOI: 10.1016/j.ctarc.2022.100563] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Today, the pancreatic cancer prognosis is poor and genetic technology is developing to treat various types of cancers. Scientists are actively looking for a new technique to design a therapeutic strategy to treat pancreatic cancer. Several oncolytic viruses are known to be valuable tools for pancreatic cancer treatment. Recent Studies demonstrate their effectiveness and safety in various administration routes such as direct intratumoral, intracutaneous, intravascular, and other routes. METHOD In this study, all studies conducted in the past 20 years have been reviewed. Reputable scientific databases including Irandoc, Scopus, Google Scholar and PubMed, are searched for the keywords of Pancreatic cancer, oncolytic, viruses and treatment and the latest information about them is obtained. RESULTS Engineering the oncolytic viruses' genome and insertion of intended transgenes including cytokines or shRNAs, has caused promising promotions in pancreatic cancer treatment. Some oncolytic viruses inhibit tumors directly and some through activation of immune responses. CONCLUSION This approach showed some signs of success in efficiency like immune system activation in the tumor environment, effective virus targeting in the tumor cells by systemic administration, and enhanced patient survival in comparison with the control group. But of course, until now, using these oncolytic viruses alone has not been effective in elimination of tumors.
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Affiliation(s)
| | - Reza Rakhshi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Niloufar Moradi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Parisa Zeynali
- Department of Biochemistry and Biophysics, Metabolic Disorders Research Center, School of Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Mohsen Nakhaie
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
| | - Emad Behboudi
- Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran.
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4
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Luo EWC, Liao ML, Chien CL. Neural differentiation of glioblastoma cell lines via a herpes simplex virus thymidine kinase/ganciclovir system driven by a glial fibrillary acidic protein promoter. PLoS One 2021; 16:e0253008. [PMID: 34370752 PMCID: PMC8351974 DOI: 10.1371/journal.pone.0253008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/27/2021] [Indexed: 11/18/2022] Open
Abstract
Glioblastoma is a malignant brain tumor with poor prognosis that rapidly acquires resistance to available clinical treatments. The herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) system produces the selective elimination of HSVtk-positive cells and is a candidate for preclinical testing against glioblastoma via its ability to regulate proliferation and differentiation. Therefore, in this study, we aimed to establish a plasmid encoding the HSVtk/GCV system driven by a glial fibrillary acidic protein (GFAP) promoter and verify its possibility of neural differentiation of glioblastoma cell line under the GCV challenge. Four stable clones-N2A-pCMV-HSVtk, N2A-pGFAP-HSVtk, U251-pCMV-HSVtk, and U251-pGFAP-HSVtk-were established from neuronal N2A and glioblastoma U251 cell lines. In vitro GCV sensitivity was assessed by MTT assay for monitoring time- and dosage-dependent cytotoxicity. The capability for neural differentiation in stable glioblastoma clones during GCV treatment was assessed by performing immunocytochemistry for nestin, GFAP, and βIII-tubulin. Under GFAP promoter control, the U251 stable clone exhibited GCV sensitivity, while the neuronal N2A clones were nonreactive. During GCV treatment, cells underwent apoptosis on day 3 and dying cells were identified after day 5. Nestin was increasingly expressed in surviving cells, indicating that the population of neural stem-like cells was enriched. Lower levels of GFAP expression were detected in surviving cells. Furthermore, βIII-tubulin-positive neuron-like cells were identified after GCV treatment. This study established pGFAP-HSVtk-P2A-EGFP plasmids that successfully ablated GFAP-positive glioblastoma cells, but left neuronal N2A cells intact. These data suggest that the neural differentiation of glioblastoma cells can be promoted by treatment with the HSVtk/GCV system.
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Affiliation(s)
- Elizabeth Wei-Chia Luo
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Bioengineering, University of California, Los Angeles, California, United States of America
| | - Meng-Lin Liao
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- School of Medicine, College of Medicine, I‐Shou University, Kaohsiung, Taiwan
- * E-mail: (CLC); (MLL)
| | - Chung-Liang Chien
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- * E-mail: (CLC); (MLL)
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5
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Montaño-Samaniego M, Bravo-Estupiñan DM, Méndez-Guerrero O, Alarcón-Hernández E, Ibáñez-Hernández M. Strategies for Targeting Gene Therapy in Cancer Cells With Tumor-Specific Promoters. Front Oncol 2020; 10:605380. [PMID: 33381459 PMCID: PMC7768042 DOI: 10.3389/fonc.2020.605380] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer is the second cause of death worldwide, surpassed only by cardiovascular diseases, due to the lack of early diagnosis, and high relapse rate after conventional therapies. Chemotherapy inhibits the rapid growth of cancer cells, but it also affects normal cells with fast proliferation rate. Therefore, it is imperative to develop other safe and more effective treatment strategies, such as gene therapy, in order to significantly improve the survival rate and life expectancy of patients with cancer. The aim of gene therapy is to transfect a therapeutic gene into the host cells to express itself and cause a beneficial biological effect. However, the efficacy of the proposed strategies has been insufficient for delivering the full potential of gene therapy in the clinic. The type of delivery vehicle (viral or non viral) chosen depends on the desired specificity of the gene therapy. The first gene therapy trials were performed with therapeutic genes driven by viral promoters such as the CMV promoter, which induces non-specific toxicity in normal cells and tissues, in addition to cancer cells. The use of tumor-specific promoters over-expressed in the tumor, induces specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several cancer- and/or tumor-specific promoters systems have been developed to target cancer cells. This review aims to provide up-to-date information concerning targeting gene therapy with cancer- and/or tumor-specific promoters including cancer suppressor genes, suicide genes, anti-tumor angiogenesis, gene silencing, and gene-editing technology, as well as the type of delivery vehicle employed. Gene therapy can be used to complement traditional therapies to provide more effective treatments.
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Affiliation(s)
- Mariela Montaño-Samaniego
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Ciudad de México, México
| | - Diana M. Bravo-Estupiñan
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Ciudad de México, México
| | - Oscar Méndez-Guerrero
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Ciudad de México, México
| | - Ernesto Alarcón-Hernández
- Laboratorio de Genética Molecular, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Ciudad de México, México
| | - Miguel Ibáñez-Hernández
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Ciudad de México, México
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Li JY, Huang WX, Chen J, Zhao SP, Tang YY. Targeted Inhibitory Effect of Nasopharyngeal Carcinoma Cells by Hre 2.Grp78 Chimeric Promoter Regulating Fusion Gene TK/VP3. Technol Cancer Res Treat 2019; 18:1533033819875166. [PMID: 31769345 PMCID: PMC6880038 DOI: 10.1177/1533033819875166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Objective: To construct plasmids with Hre2.Grp78 chimeric promoter regulating fusion
gene TK/VP3 and elaborate the effects of overexpressed
TK/VP3 on nasopharyngeal carcinoma cells. Methods: Four plasmids were constructed, including pcDNA3.1-CMV-TK/VP3,
pcDNA3.1-Hre2.TK/VP3, pcDNA3.1-Grp78.TK/VP3, and
pcDNA3.1-Hre2.Grp78.TK/VP3. The human nasopharyngeal carcinoma cell line HNE1
cells were transfected with the 4 plasmids, respectively. Cell viabilities were
evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay, and apoptosis was conducted using flow cytometry analysis. The expression of TK,
VP3, Grp78, and hypoxia-inducible factor 1α and apoptosis-related proteins was
determined by real-time quantitative polymerase chain reaction and Western blotting. Results: The recombinant plasmids that could steadily overexpress TK and VP3 were successfully
constructed. Expression of TK and VP3 in cells transfected with
pcDNA3.1-Hre2.TK/VP3 and pcDNA3.1-Grp78.TK/VP3 was significantly higher than
pcDNA3.1-CMV-TK/VP3, and expression in cells transfected with
pcDNA3.1-Hre2.Grp78.TK/VP3 was the highest. Under glucose deprivation or
hypoxia condition, Grp78 or hypoxia-inducible factor 1α was overexpressed so that
expression of TK and VP3 was significantly upregulated, which could further inhibit cell
proliferation and enhance cell apoptosis. Conclusion: We successfully constructed 4 plasmids with Hre2.Grp78 chimeric promoter
regulating fusion gene TK/VP3, which could significantly inhibit the
proliferation as well as enhance the apoptosis of nasopharyngeal carcinoma cells under
glucose deprivation or hypoxia condition.
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Affiliation(s)
- Jin-Yun Li
- Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Xiao Huang
- Xiangya Hospital, Central South University, Changsha, China
| | - Jie Chen
- Xiangya Hospital, Central South University, Changsha, China
| | - Su-Ping Zhao
- Xiangya Hospital, Central South University, Changsha, China
| | - Yao-Yun Tang
- Xiangya Hospital, Central South University, Changsha, China
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Alekseenko IV, Pleshkan VV, Sass AV, Filyukova OB, Snezhkov EV, Sverdlov ED. A Universal Tumor-Specific Promoter for Cancer Gene Therapy. DOKL BIOCHEM BIOPHYS 2018; 480:158-161. [DOI: 10.1134/s1607672918030092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Indexed: 01/05/2023]
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Wang Y, Wang JH, Zhang XL, Wang XL, Yang L. Endoplasmic reticulum chaperone glucose-regulated protein 78 in gastric cancer: An emerging biomarker. Oncol Lett 2018; 15:6087-6093. [PMID: 29616092 DOI: 10.3892/ol.2018.8114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/15/2017] [Indexed: 12/17/2022] Open
Abstract
The endoplasmic reticulum (ER) is the principal organelle responsible for the synthesis, initial post-translational modification, folding, export and secretion of proteins. It is also responsible for the maintenance of cellular homeostasis. In response to cellular stress conditions including glucose deprivation, hypoxia and changes in calcium homeostasis, ER stress machinery is activated and triggers the unfolded protein response, resulting in the restoration of homeostasis or activation of cell death. Glucose-regulated protein 78 (GRP78), a molecular chaperone, may be induced by ER stress at the transcriptional and translational level. A number of studies have demonstrated that GRP78 serves an important role in tumor cell proliferation, metastasis, angiogenesis and drug-resistance. The present review systematically describes the association between GRP78 expression and gastric cancer pathogenesis, and emphasizes that GRP78 is a novel diagnostic and therapeutic biomarker of gastric cancer.
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Affiliation(s)
- Yan Wang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Jian-Hong Wang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Xun-Lei Zhang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Xiao-Li Wang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Lei Yang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
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9
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Liang L, Bi W, Chen W, Lin Y, Tian Y. Combination of MPPa-PDT and HSV1-TK/GCV gene therapy on prostate cancer. Lasers Med Sci 2018; 33:227-232. [DOI: 10.1007/s10103-017-2331-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 09/18/2017] [Indexed: 12/13/2022]
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10
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Mancini N, Marrone L, Clementi N, Sautto GA, Clementi M, Burioni R. Adoptive T-cell therapy in the treatment of viral and opportunistic fungal infections. Future Microbiol 2016; 10:665-82. [PMID: 25865200 DOI: 10.2217/fmb.14.122] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Viral infections and opportunistic fungal pathogens represent a major menace for immunocompromised patients. Despite the availability of antifungal and antiviral drugs, mortality in these patients remains high, underlining the need of novel therapeutic options based on completely different strategies. This review describes the potential of several T-cell-based therapeutic approaches in the prophylaxis and treatment of infectious diseases with a particular focus on persistent viral infections and opportunistic fungal infections, as these mostly affect immunocompromised patients.
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Affiliation(s)
- Nicasio Mancini
- Laboratorio di Microbiologia e Virologia, Università 'Vita-Salute' San Raffaele, DIBIT2, via Olgettina 58, 20132, Milan, Italy
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11
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Pranjol MZI, Hajitou A. Bacteriophage-derived vectors for targeted cancer gene therapy. Viruses 2015; 7:268-84. [PMID: 25606974 PMCID: PMC4306838 DOI: 10.3390/v7010268] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 01/13/2015] [Indexed: 01/04/2023] Open
Abstract
Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration.
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Affiliation(s)
- Md Zahidul Islam Pranjol
- Institute of Clinical and Biomedical Science, University of Exeter Medical School, Exeter, Devon EX1 2LU, UK.
| | - Amin Hajitou
- Phage Therapy Group, Department of Medicine, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
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12
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Shao D, Li J, Xiao X, Zhang M, Pan Y, Li S, Wang Z, Zhang X, Zheng H, Zhang X, Chen L. Real-time visualizing and tracing of HSV-TK/GCV suicide gene therapy by near-infrared fluorescent quantum dots. ACS APPLIED MATERIALS & INTERFACES 2014; 6:11082-11090. [PMID: 24972118 DOI: 10.1021/am503998x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Exploring intracellular behavior of suicide gene is significant for improving the efficacy and safety of herpes simplex virus thymidine kinase gene/ganciclovir (HSV-TK/GCV) system in cancer therapy. Molecular imaging represents a powerful tool to understand gene transportation and function dynamics. In this work, we reported a quantum-dot-based technique for revealing the procedure of HSV-TK/GCV suicide gene therapy by constructing covalent linkage between near-infrared fluorescent quantum dots (QDs) and TK gene. This stable QD labeling did not influence either the QDs fluorescence or the biological activity of TK gene. Furthermore, we visualized and dynamically traced the intracellular behavior antitumor effect of TK gene in vitro and in vivo. It is demonstrated that TK gene was shuttled to the nucleus after a-24 h treatment; at that time the single dose of GCV administration exerts the gradually increasing lethal effect until to 72 h. Real-time tracing the formation of hepatocellular carcinoma treated with HSV-TK/GCV suicide gene system in vivo by QD-based NIR fluorescence imaging provides useful insight toward QD-based theranostics in future cancer therapy.
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Affiliation(s)
- Dan Shao
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University , Changchun 130021, China
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Huang L, Xu AM, Li TJ, Han WX, Xu J. Should peri-gastrectomy gastric acidity be our focus among gastric cancer patients? World J Gastroenterol 2014; 20:6981-6988. [PMID: 24944492 PMCID: PMC4051941 DOI: 10.3748/wjg.v20.i22.6981] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the necessity and correctness of acid suppression pre- and post-gastrectomy among gastric carcinoma (GC) patients.
METHODS: From June 2011 to April 2013, 99 patients who were diagnosed with GC or adenocarcinoma of the gastroesophageal junction (type II or III) and needed surgical management were enrolled. They all underwent gastrectomy by the same operators [35 undergoing total gastrectomy (TG) plus Roux-en-Y reconstruction, 34 distal gastrectomy (DG) plus Billroth I reconstruction, and 30 proximal gastrectomy (PG) plus gastroesophagostomy]. We collected and analyzed their gastrointestinal juice and tissues from the pre-operational day to the 5th day post-operation, and 6 mo post-surgery. Gastric pH was detected with a precise acidity meter. Gastric juice contents including potassium, sodium and bicarbonate ions, urea nitrogen, direct and indirect bilirubin, and bile acid were detected using Automatic Biochemical Analyzer. Data regarding tumor size, histological type, tumor penetration and tumor-node-metastasis (TNM) stage were obtained from the pathological records. Reflux symptoms pre- and 6 mo post-gastrectomy were evaluated by reflux disease questionnaire (RDQ) and gastroesophageal reflux disease questionnaire (GERD-Q). SPSS 16.0 was applied to analyze the data.
RESULTS: Before surgery, gastric pH was higher than the threshold of hypoacidity (4.25 ± 1.45 vs 3.5, P = 0.000), and significantly affected by age, tumor size and differentiation grade, and potassium and bicarbonate ions; advanced malignancies were accompanied with higher pH compared with early ones (4.49 ± 1.31 vs 3.66 ± 1.61, P = 0.008). After operation, gastric pH in all groups was of weak-acidity and significantly higher than that pre-gastrectomy; on days 3-5, comparisons of gastric pH were similar between the 3 groups. Six months later, gastric pH was comparable to that on days 3-5; older patients were accompanied with higher total bilirubin level, indicating more serious reflux (r = 0.238, P = 0.018); the TG and PG groups had higher RDQ (TG vs DG: 15.80 ± 5.06 vs 12.26 ± 2.14, P = 0.000; PG vs DG: 15.37 ± 3.49 vs 12.26 ± 2.14, P = 0.000) and GERD-Q scores (TG vs DG: 10.54 ± 3.16 vs 9.15 ± 2.27, P = 0.039; PG vs DG: 11.00 ± 2.07 vs 9.15 ± 2.27, P = 0.001) compared with the DG group; all gastric juice contents except potassium ion significantly rose; reflux symptom was significantly associated with patient’s body mass index, direct and indirect bilirubin, and total bile acid, while pH played no role.
CONCLUSION: Acidity is not an important factor causing unfitness among GC patients. There is no need to further alkalify gastrointestinal juice both pre- and post-gastrectomy.
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Abstract
The glucose-regulated proteins (GRPs) are stress-inducible chaperones that mostly reside in the endoplasmic reticulum or the mitochondria. Recent advances show that the GRPs have functions that are distinct from those of the related heat shock proteins, and they can be actively translocated to other cellular locations and assume novel functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery and regulation, as well as their biological functions in cancer. Promising agents that use or target the GRPs are being developed, and their efficacy as anticancer therapeutics is also discussed.
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Affiliation(s)
- Amy S Lee
- Department of Biochemistry and Molecular Biology, University of Southern California Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 5308, Los Angeles, California 900899176, USA
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15
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A designed equine herpes thymidine kinase (EHV4 TK) variant improves ganciclovir-induced cell-killing. Biochem Pharmacol 2014; 87:435-44. [PMID: 24316433 DOI: 10.1016/j.bcp.2013.11.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 10/31/2013] [Accepted: 11/19/2013] [Indexed: 11/22/2022]
Abstract
The limitations of the ganciclovir (GCV)/herpes simplex virus thymidine kinase (HSV1 TK: EC 2.7.1.21) system as a suicide gene therapy approach have been extensively studied over the years. In our study, we focused on improving the cytotoxic profile of the GCV/equine herpes virus-4 thymidine kinase (EHV4 TK: EC 2.7.1.21) system. Our approach involved the structure-guided mutagenesis of EHV4 TK in order to switch its ability to preferentially phosphorylate the natural substrate deoxythymidine (dT) to that of GCV. We performed steady-state kinetic analysis, genetic complementation in a thymidine kinase-deficient Escherichia coli strain, isothermal titration calorimetry, and analysis of GCV-induced cell killing through generation of HEK 293 stable cell-lines expressing EHV4 TK mutants and wild-type EHV4 TK. We found that the EHV4 TK S144H-GFP mutant preferentially phosphorylates GCV and confers increased GCV-induced cytotoxicity compared to wild-type EHV4 TK.
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16
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Enhancement of expression of survivin promoter-driven CD/TK double suicide genes by the nuclear matrix attachment region in transgenic gastric cancer cells. Gene 2013; 534:177-82. [PMID: 24220851 DOI: 10.1016/j.gene.2013.10.064] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 10/27/2013] [Accepted: 10/29/2013] [Indexed: 01/10/2023]
Abstract
This work aimed to study a novel transgenic expression system of the CD/TK double suicide genes enhanced by the nuclear matrix attachment region (MAR) for gene therapy. The recombinant vector pMS-CD/TK containing the MAR-survivin promoter-CD/TK cassette was developed and transfected into human gastric cancer SGC-7901 cells. Expression of the CD/TK genes was detected by quantitative real-time PCR (qPCR) and Western blot. Cell viability and apoptosis were measured using the methyl thiazolyl tetrazolium (MTT) assay and flow cytometry. When the MAR fragment was inserted into the upstream of the survivin promoter, the qPCR result showed that the expression of the CD/TK genes significantly increased 7.7-fold in the transgenic SGC-7901 cells with plasmid pMS-CD/TK compared with that without MAR. MTT and flow cytometry analyses indicated that treatment with the prodrugs (5-FC+GCV) significantly decreased the cellular survival rate and enhanced the cellular apoptosis in the SGC-7901 cells. The expression of the CD/TK double suicide genes driven by the survivin promoter can be enhanced by the MAR fragment in human gastric cancer cells.
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Kia A, Przystal JM, Nianiaris N, Mazarakis ND, Mintz PJ, Hajitou A. Dual systemic tumor targeting with ligand-directed phage and Grp78 promoter induces tumor regression. Mol Cancer Ther 2012; 11:2566-77. [PMID: 23053496 DOI: 10.1158/1535-7163.mct-12-0587] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The tumor-specific Grp78 promoter is overexpressed in aggressive tumors. Cancer patients would benefit greatly from application of this promoter in gene therapy and molecular imaging; however, clinical benefit is limited by lack of strategies to target the systemic delivery of Grp78-driven transgenes to tumors. This study aims to assess the systemic efficacy of Grp78-guided expression of therapeutic and imaging transgenes relative to the standard cytomegalovirus (CMV) promoter. Combination of ligand and Grp78 transcriptional targeting into a single vector would facilitate systemic applications of the Grp78 promoter. We generated a dual tumor-targeted phage containing the arginine-glycine-aspartic acid tumor homing ligand and Grp78 promoter. Next, we combined flow cytometry, Western blot analysis, bioluminescence imaging of luciferase, and HSVtk/ganciclovir gene therapy and compared efficacy to conventional phage carrying the CMV promoter in vitro and in vivo in subcutaneous models of rat and human glioblastoma. We show that double-targeted phage provides persistent transgene expression in vitro and in tumors in vivo after systemic administration compared with conventional phage. Next, we showed significant tumor killing in vivo using the HSVtk/ganciclovir gene therapy and found a systemic antitumor effect of Grp78-driven HSVtk against therapy-resistant tumors. Finally, we uncovered a novel mechanism of Grp78 promoter activation whereby HSVtk/ganciclovir therapy upregulates Grp78 and transgene expression via the conserved unfolded protein response signaling cascade. These data validate the potential of Grp78 promoter in systemic cancer gene therapy and report the efficacy of a dual tumor targeting phage that may prove useful for translation into gene therapy and molecular imaging applications.
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Affiliation(s)
- Azadeh Kia
- Centre for Neuroinflammation and Degeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, United Kingdom
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Li Z, Li Z. Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Biophys Acta Rev Cancer 2012; 1826:13-22. [PMID: 22426159 DOI: 10.1016/j.bbcan.2012.02.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 02/26/2012] [Accepted: 02/27/2012] [Indexed: 12/27/2022]
Abstract
Glucose regulated protein 78 (GRP78) has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found to be present in cell plasma membrane, cytoplasm, mitochondria, nucleus as well as cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor microenvironmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which feels and adapts to the alteration in the tumor microenvironment. This article reviews the potential contributions of GRP78 to the acquisition of cancer hallmarks based on intervening in stress responses caused by tumor niche alterations. The paper also introduces several potential GRP78 relevant targeted therapies.
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Affiliation(s)
- Zongwei Li
- Institute of Biotechnology, The Key Laboratory of Clinical Biology and Molecular Engineering of Education Ministry, Shanxi University, 030006 Taiyuan, PR China
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Alekseenko IV, Kopantzev EP, Vinogradova TV, Sverdlov ED. Bicistronic vector for combined expression of the HSVtk killer gene and cytokine GM-CSF gene in cancer cells. DOKL BIOCHEM BIOPHYS 2011; 439:174-7. [PMID: 21928138 DOI: 10.1134/s1607672911040065] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- I V Alekseenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997 Russia
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ParAB-mediated intermolecular association of plasmid P1 parS sites. Virology 2011; 421:192-201. [PMID: 22018490 DOI: 10.1016/j.virol.2011.09.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Revised: 08/05/2011] [Accepted: 09/28/2011] [Indexed: 11/20/2022]
Abstract
The P1 plasmid partition system depends on ParA-ParB proteins acting on centromere-like parS sites for a faithful plasmid segregation during the Escherichia coli cell cycle. In vivo we placed parS into host E. coli chromosome and on a Sop(+) F plasmid and found that the stability of a P1 plasmid deleted for parA-parB could be partially restored when parB was expressed in trans. In vitro, parS, conjugated to magnetic beads could capture free parS DNA fragment in presence of ParB. In vitro, ParA stimulated ParB-mediated association of intermolecular parS sites in an ATP-dependent manner. However, in the presence of ADP, ParA reduced ParB-mediated pairing to levels below that seen by ParB alone. ParB of P1 pairs the parS sites of plasmids in vivo and fragments in vitro. Our findings support a model whereby ParB complexes P1 plasmids, ParA-ATP stimulates this interaction and ParA-ADP inhibits ParB pairing activity in a parS-independent manner.
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Samaras K, Botelho NK, Chisholm DJ, Lord RV. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity (Silver Spring) 2010; 18:884-9. [PMID: 20019678 DOI: 10.1038/oby.2009.443] [Citation(s) in RCA: 202] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age- and gender- matched controls). Metabolic parameters were measured in the fasted state: body composition by dual-energy X-ray absorptiometry and insulin action by hyperinsulinemic-euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase-PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein (MIP), interleukin-8 (IL-8)). Fasting glucose related to VAT expression of TNFalpha, MIP, serum amyloid A (SAA), IL-1alpha, IL-1beta, IL-8, and IL-8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element-binding protein (CREBP), IL-1beta, and IL-8. Insulin action related inversely to VAT complement C3 expression only. There were depot-specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol-binding protein-4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.
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Affiliation(s)
- Katherine Samaras
- [1] Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia [2] Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
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