Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny

Tanoue, Kazuo; Wang, Yuqing; Ikeda, Minako; Mitsui, Kiyofumi; Irie, Rie; Setoguchi, Takao; Komiya, Setsuro; Natsugoe, Shoji; Kosai, Ken Ichiro

doi:10.1186/1479-5876-12-27

Cited by 16 publications

(21 citation statements)

References 31 publications

(67 reference statements)

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“…The CA and survivin promoters, which were used to explore the feasibility of this system, were introduced into pPS, yielding pPS‐CA and pPS‐survivin as follows. CA and survivin promoters, which we reported previously , were subcloned from other plasmids, yielding pPS‐CA or pPS‐survivin.…”

Section: Methodsmentioning

confidence: 99%

“…After an 8‐day culture in suspension, EBs were transferred on to gelatin‐coated plates and cultured for an additional 20 days. Subsequently, the differentiated cells were seeded at 1 × 10 4 cells/well on gelatin‐coated 96‐well culture plates and cultured with 0, 0.01, 0.1, 1, 10, or 100 µg/ml GCV for an additional 7 days, and cell viability was determined by WST‐8 assay using the Cell Count Reagent SF (Nacalai Tesque) . On the other hand, to assess cytotoxicity against undifferentiated hPSCs, cells were seeded at 2 × 10 4 cells/well on Matrigel‐coated 96‐well culture plate under nondifferentiating conditions and subsequently cultured with 0, 0.01, 0.1, 1, 10, or 100 µg/ml GCV for 7 days, followed by WST‐8 assay to determine cell viability.…”

Section: Methodsmentioning

confidence: 99%

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A Novel Construction of Lentiviral Vectors for Eliminating Tumorigenic Cells from Pluripotent Stem Cells

et al. 2017

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The risk of tumor formation poses a challenge for human pluripotent stem cell (hPSC)-based transplantation therapy. Specific and total elimination of tumorigenic hPSCs by suicide genes (SGs) has not been achieved because no methodology currently exists for testing multiple candidate transgene constructs. Here, we present a novel method for efficient generation of tumorigenic cell-targeting lentiviral vectors (TC-LVs) with diverse promoters upstream of a fluorescent protein and SGs. Our two-plasmid system achieved rapid and simultaneous construction of different TC-LVs with different promoters. Ganciclovir (GCV) exerted remarkable cytotoxicity in herpes simplex virus thymidine kinase-transduced hPSCs, and high specificity for undifferentiated cells was achieved using the survivin promoter (TC-LV.Surv). Moreover, GCV treatment completely abolished teratoma formation by TC-LV.Surv-infected hPSCs transplanted into mice, without harmful effects. Thus, TC-LV can efficiently identify the best promoter and SG for specific and complete elimination of tumorigenic hPSCs, facilitating the development of safe regenerative medicine. STEM CELLS 2018;36:230-239 SIGNIFICANCE STATEMENTThe risk of tumor formation has raised safety concerns in human pluripotent stem cells (hPSCs)-based regenerative medicine. Here, a novel method for efficiently generating diverse tumorigenic cell-targeting lentiviral vectors, which can specifically and efficiently kill tumorigenic cells in transduced hPSCs, was developed. This study demonstrates the utility of this methodology and reveals that the products, including hPSCs with the herpes simplex virus thymidine kinase gene downstream of the survivin promoter, should pave the way toward safe clinical applications of hPSC-based regenerative medicine.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A Novel Construction of Lentiviral Vectors for Eliminating Tumorigenic Cells from Pluripotent Stem Cells

et al. 2017

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“…Another group employed a similar Tert-responsive CRA in a human cancer trial and reported a positive local effect and safety 28 . Surv.m-CRA demonstrated elevated effectiveness against cancer stem cells, which are often resistant to conventional anticancer medications and radiotherapy 29 . We are currently implementing a first-in-human investigator-initiated trial of Surv.m-CRA for the treatment of refractory malignant bone and soft tissue tumors.…”

Section: Main Textmentioning

confidence: 99%

Viral Vector-Based Innovative Approaches to Directly Abolishing Tumorigenic Pluripotent Stem Cells for Safer Regenerative Medicine

Mitsui

Ide

Takahashi

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Human pluripotent stem cells (hPSCs) are a promising source of regenerative material for clinical applications. However, hPSC transplant therapies pose the risk of teratoma formation and malignant transformation of undifferentiated remnants. These problems underscore the importance of developing technologies that completely prevent tumorigenesis to ensure safe clinical application. Research to date has contributed to establishing safe hPSC lines, improving the efficiency of differentiation induction, and indirectly ensuring the safety of products. Despite such efforts, guaranteeing the clinical safety of regenerative medicine products remains a key challenge. Given the intrinsic genome instability of hPSCs, selective growth advantage of cancer cells, and lessons learned through failures in previous attempts at hematopoietic stem cell gene therapy, conventional strategies are unlikely to completely overcome issues related to hPSC tumorigenesis. Researchers have recently embarked on studies aimed at locating and directly treating hPSC-derived tumorigenic cells. In particular, novel approaches to directly killing tumorigenic cells by transduction of suicide genes and oncolytic viruses are expected to improve the safety of hPSC-based therapy. This article discusses the current status and future perspectives of methods aimed at directly eradicating undifferentiated tumorigenic hPSCs, with a focus on viral vector transduction.

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“…11,12 Conventional staging processes are consistent of tumor, lymph node, and metastases or better known as TNM. 11,12 A modified version of this conventional method is used in the staging of RMS to indicate the advancement of the disease on a scale of 1 to 4. These stages are associated with group assignments that subsumes their initial surgical approaches, for example a group I is a patient with a localized tumor and no metastatic diseases, where the tumor can be located and completely resected.…”

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Biologic and Clinical Aspects of Rhabdomyosarcoma

Emami¹,

Sepehri²,

Gordon³

et al. 2017

Int J Basic Sci Med

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Rhabdomyosarcoma (RMS) is a muscle-derived tumor and is the most common pediatric soft tissue sarcoma representing 5% of all childhood cancers. Statistically, soft tissue sarcomas account for approximately 10% of all cancers in children, of which more than half of these tumors are RMS. Thus, RMS is a major clinical problem in pediatric oncology. RMS is caused by a disruption in the pathway of primitive mesenchymal stem cells directed towards myogenesis. In most cases of patients diagnosed with RMS there is a genetic or chromosomal alteration involved. In past few years there have been discoveries of more therapeutic approaches that has improved the quality of life in RMS patients and has resulted in a better survival rate in this population from 25% to 60%. However, Additional researches and clinical trials are needed in order to minimize the devastating consequences of the pediatric cancer including RMS. In the current mini review we will briefly discuss current knowledge in RMS focusing on most common biological and clinical aspects of the disease.

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Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny

Cited by 16 publications

References 31 publications

A Novel Construction of Lentiviral Vectors for Eliminating Tumorigenic Cells from Pluripotent Stem Cells

A Novel Construction of Lentiviral Vectors for Eliminating Tumorigenic Cells from Pluripotent Stem Cells

Viral Vector-Based Innovative Approaches to Directly Abolishing Tumorigenic Pluripotent Stem Cells for Safer Regenerative Medicine

Biologic and Clinical Aspects of Rhabdomyosarcoma

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