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Gene editing technology CRISPR/Cas9 and its derivative editing technologies including base editor and prime editor can precisely edit the target genome sequences, having been widely used in tumor therapy and achieved remarkable clinical results in tumor immunotherapy, human papilloma virus infection treatment and oncolytic virotherapy, providing a new means for tumor therapy.
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Abstract Background: Viruses are being used as alternative and complementary tools for treating cancers. Oncolytic viruses exhibit tumor tropism, ability to enhance anti-tumor immunity and ability to be used in combination with conventional chemotherapy and radiotherapy. We have recently selected some rotavirus isolates which are adapted to efficiently infect and kill tumor cell lines. Aim: We tested five tumor cell-adapted rotavirus isolates for their ability to infect the human adenocarcinoma cell line MCF-7. Methods: Cell surface membrane-associated proteins mediating virus particle attachment were characterized using ELISA, immunoprecipitation, FACS analysis, and antibody blocking. Results: It was found that heat shock proteins (HSPs) such as Hsp90, Hsp70, Hsp60, and Hsp40 are expressed on the cell surface forming complexes with protein disulfide isomerase (PDI), integrin β3, and heat shock cognate protein 70 (Hsc70) in lipid raft microdomains. Interaction of rotavirus isolates with these cellular proteins was further confirmed by a competition assay and an inhibition assay involving the HSPs tested. Conclusion: Our findings suggest that the tumor cell-adapted rotavirus isolates studied here offer a promising tool for killing tumor cells, thus encouraging further research into this topic, including animal models.
Resumen Antecedentes: Los virus se utilizan como herramientas alternativas y complementarias para el tratamiento del cáncer. Los virus oncolíticos exhiben tropismo por tumores, capacidad para intensificar la inmunidad antitumoral y la capacidad para utilizarse en combinación con quimioterapia y radioterapia convencionales. Recientemente, hemos seleccionado algunos aislamientos de rotavirus que están adaptados para infectar y eliminar de manera eficiente líneas de células tumorales. Objetivo: Se ensayaron cinco aislamientos de rotavirus adaptados a células tumorales para determinar su capacidad para infectar la línea celular de adenocarcinoma humano MCF-7. Métodos: Las proteínas asociadas a la membrana de la superficie celular que median la unión de partículas de virus se caracterizaron mediante ELISA, inmunoprecipitación, análisis FACS y bloqueo de anticuerpos. Resultados: Se encontró que las proteínas de choque térmico (HSPs) como Hsp90, Hsp70, Hsp60 y Hsp40 se expresan en la superficie celular formando complejos con la proteína disulfuro isomerasa (PDI), la integrina β3 y la proteína análoga de choque térmico 70 (Hsc70) en microdominios lipídicos (rafts). La interacción de los aislamientos de rotavirus con estas proteínas celulares se confirmó adicionalmente mediante un ensayo de competición y un ensayo de inhibición que incluía las HSP ensayadas. Conclusión: Nuestros hallazgos sugieren que los aislamientos de rotavirus adaptados a las células tumorales estudiados aquí ofrecen una herramienta prometedora para eliminar las células tumorales, lo que estimula más investigaciones sobre este tema, incluidos los modelos animales.
Subject(s)
Humans , Adenocarcinoma , Rotavirus , Oncolytic Viruses , Heat-Shock Proteins , Adenocarcinoma/therapy , HSC70 Heat-Shock Proteins , MCF-7 CellsABSTRACT
China is a country with a high incidence of gastric cancer, ranking the top three in terms of morbidity and mortality. More than 70% of new patients with gastric cancer have been diagnosed at advanced stage. Traditional chemotherapy drugs have hit the plateau. In recent years, oncolytic virus, which specifically kills tumor cells, has developed rapidly. It is considered to have the characteristics of targeting tumor. A large number of viruses replicate in tumor cells, leading to cell lysis or inducing immune response by releasing virus molecules and cytokines further to fight against tumor. The genetically engineered strains of oncolytic virus have shown effective anti-tumor ability both in vivo and in vitro. Its safety and effectiveness have been proved in clinical practice. So the oncolytic virotherapy is expected to be a new direction and breakthrough point in the treatment of gastric cancer. This paper reviews the anti-tumor mechanism, the research progress of genetically engineered strains in the treatment of gastric cancer and the existing challenges of oncolytic virus.
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Resumen Introducción. Los virus oncolíticos son virus atenuados, mutados o que por naturaleza se dirigen y matan específicamente células tumorales, sin afectar a las células normales. La administración intratumoral del virus ofrece la oportunidad de tratar el tumor primario pero no focos metastásicos, los cuales pueden ser alcanzados mediante la administración intravenosa. Sin embargo, su eficiencia puede disminuir por la presencia de una respuesta inmunológica preexistente en los sujetos tratados. Objetivo. Exponer las técnicas utilizadas para envolver y transportar los virus con el fin de eludir el sistema inmunológico antes de que el virus llegue al tumor. Materiales y métodos. Se realizó una búsqueda narrativa de la literatura original y de revisión en las bases de datos PubMed, JSTOR y EBSCO sobre métodos o técnicas utilizadas para el tratamiento del cáncer mediante el uso de virus oncolíticos. Resultados. La formación de nanocomplejos entre los virus oncolíticos y biopolímeros -ya sea mediante la unión química o mediante la unión a través de interacciones electrostáticas o el uso de micropartículas, células transportadoras, liposomas, ultrasonido o terapias combinadas- es eficaz para evitar la respuesta inmunológica del huésped contra el virus. Conclusión. Para evitar la respuesta inmunológica del huésped contra los virus oncolíticos se han desarrollo diversos métodos que permiten la liberación controlada y especifica de los mismos. Sin embargo, debido a la diversidad de los virus, se debe tener en cuenta que la eficacia de los métodos de protección y transporte depende de las características bioquímicas tanto del biomaterial como del virus.
Abstract Introduction: Oncolytic viruses are attenuated, mutated, or naturally ocurring viruses that specifically kill tumor cells without affecting normal cells. Intratumoral administration of the virus offers the opportunity to treat the primary tumor but not metastatic foci, which can be done through intravenous administration. However, its efficacy may be reduced by the presence of a pre-existing immune response in treated subjects. Objective: To present the techniques used to wrap and transport viruses in order to bypass the immune system before the virus reaches the tumor. Materials and methods: A narrative search of original and review literature was conducted in the PubMed, JSTOR and EBSCO databases on methods or techniques used for the treatment of cancer using oncolytic viruses. Results: The formation of nanocomplexes between oncolytic viruses and biopolymers -either by chemical binding or electrostatic interactions, or cell-derived microparticles, carrier cells, liposomes, ultrasound or combination therapies- is effective in preventing the host's immune response against the virus. Conclusion: Different methods that depend on the type of oncolytic virus have been developed to increase the efficacy of the therapeutic response. Controlled and specific-release virus delivery systems have been developed to avoid the immune response against them. However, due to the diversity of viruses, it should be borne in mind that the effectiveness of protection and transport methods depends on the biochemical characteristics of both the biomaterial and the virus.
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Oncolytic virus therapy is a new strategy of tumor treatment by special targeting and lysing tumor cells where the virus continuously replicates. The virus molecules and their related cytokines released from these lysed cells induce the anti-tumor immune response to kill tumor cells. The key roles of oncolytic virus rely on the tumor-targeting mechanism and tumor-killing mechanism. Recently, the wild virus strains are optimized by molecular biological technology, and are designed to generate more oncolytic effect and lower side effect as an antitumor drug for clinical treatment. This paper reviews the research development, function mechanism and clinical application of oncolytic virus.
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Objective: To construct cytokine-induced killer (CIK) cell vehicles carrying recombinant adenovirus carrying tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene, and preliminarily observe its anti-hepatoma ability. Methods: Lymphocytes were isolated from peripheral blood to culture CIK cells. The phenotypic identification of CIK cells was performed by flow cytometry (FCM). Then, the lentiviral pLenti-hCD40L-E1AB containing CD40L promoter and the recombined adenovirus vector pAd5/35-TRAIL were constructed, respectively. The two viruses were infected into CIK cells by two-step method. After that, the secretory function and proliferative capacity of CIK cells as well as the effect on angiogenesis and the ablility of colony-formation of hepatoma cells were assessed by ELISA, MTT method, Tubule formation assay and soft agarose assay, respectively. Results: The CIK lymphocytes grew vigorously, in which the expressions of CD3, CD56, CD11a and CD226 were positive, while the expressions of CD8 and CD305 were negative. The lentiviral pLenti-hCD40L-E1AB containing active hCD40L promoter and adenovirus E1 gene was successfully constructed, and the recombined adenovirus vector pAd5/35-TRAIL containing human TRAIL gene was also constructed. In CIK cells infected with Ad5/F35-TRAIL and pLenti-hCD40L-E1AB, the expression level of interferon-? was significanly increased (P < 0.05), and the angiogenesis and the colony-formation rate of hepatoma cells were inhibited, but the proliferative capacity of CIK cells was less affected. Conclusion: CIK cell vehicles carrying adenovirus and expressing TRAIL gene are successfully constructed. The growth inhibition of hepatoma cells may be induced by CIK cells. Copyright © 2013 by TUMOR.
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After near a century of research,the diverse and complicated relationship between viruses and tumors has been elucidated gradually.Last century it was demonstrated that some retroviruses and some herpes viruses could induce lymphoma and leukemia in some animals.However,it is more complicated in human.During the last two decades it has been confirmed that several types of hepatitis viruses could cause hepatocellular carcinoma and the relationship between human papillomaviruses and cervix carcinoma has been established.These viral vaccines became useful tools to prevent prevalence of these carcinomas.Because of the successful inoculation of live attenuated viral vaccines all around the world in recent 15 years,oncolytic virotherapy is revived,and provides a novel strategy for treatment of refractory tumors.
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Cancer is a major cause of deaths in humans. Though there has been significant progress in cancer therapy, the limited efficacy and toxicities of current chemo- and radiotherapies have provided an impetus for the search of new therapeutics. A therapeutic approach, which uses viruses for the treatment of cancer termed, oncolytic virotherapy has recently emerged. Newcastle disease virus (NDV) is one such virus with an inherent oncolytic property. NDV causes a highly infectious disease in poultry worldwide. In humans it is reported to have oncolytic and immuno-stimulatory effects. It specifically replicates in tumour cells while sparing normal cells and cause oncolysis. For many years different strains of the NDV have been investigated for treatment of various human cancers. Recent advances in reverse genetics provided investigators the tools to produce recombinant NDV with improved oncolytic property.