Apoptosis in human glioblastoma cells produced using embryonic stem cell–derived astrocytes expressing tumor necrosis factor–related apoptosis-inducing ligand

Germano, Isabelle M.; Uzzaman, Mahmud; Benveniste, Ronald J.; Zaurova, Milana; Keller, Gordon

doi:10.3171/jns.2006.105.1.88

Cited by 35 publications

(23 citation statements)

References 35 publications

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“…MSCs have been used for delivery of therapeutic cytokines like IFN-␤ (9), IL-12 (11,35), cytosine deaminase (36), and oncolytic adenovirus (37). The ability of TRAIL to selectively target tumor cells while remaining harmless to most normal cells (38)(39)(40) makes it an attractive candidate for an apoptotic therapy in highly malignant brain tumor treatment. TRAIL signals via two pro-apoptotic death receptors (DR4 and DR5), inducing a caspase-8-dependent apoptotic cascade in tumor cells (38) However, because of its short biological half-life and limited delivery across the blood-brain barrier, most promising studies using TRAIL lack applicability (41,42).…”

Section: Discussionmentioning

confidence: 99%

Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy

Sasportas

Kasmieh

Wakimoto

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

416

369

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The poor prognosis of patients with aggressive and invasive cancers combined with toxic effects and short half-life of currently available treatments necessitate development of more effective tumor selective therapies. Mesenchymal stem cells (MSCs) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential and fate in different cancer models is lacking. In this study, we explored the engineering potential, fate, and therapeutic efficacy of human MSCs in a highly malignant and invasive model of glioblastoma. We show that engineered MSC retain their ''stem-like'' properties, survive longer in mice with gliomas than in the normal brain, and migrate extensively toward gliomas. We also show that MSCs are resistant to the cytokine tumor necrosis factor apoptosis ligand (TRAIL) and, when engineered to express secreted recombinant TRAIL, induce caspase-mediated apoptosis in established glioma cell lines as well as CD133-positive primary glioma cells in vitro. Using highly malignant and invasive human glioma models and employing real-time imaging with correlative neuropathology, we demonstrate that MSC-delivered recombinant TRAIL has profound anti-tumor effects in vivo. This study demonstrates the efficacy of diagnostic and therapeutic MSC in preclinical glioma models and forms the basis for developing stem cell-based therapies for different cancers.gliomas ͉ in vivo imaging ͉ TRAIL

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Section: Discussionmentioning

confidence: 99%

Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy

Sasportas

Kasmieh

Wakimoto

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

416

369

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“…Since TRAIL is a membranebound protein, cell contact was necessary. 43 In this experiment, we showed that 24 hours after induction with Dox, the apoptotic rate of the human glioma cells was 58% (Fig. 4).…”

Section: Esc-derived Astrocytes Conditionally Expressing a Pro-apoptomentioning

confidence: 98%

Gene delivery by embryonic stem cells for malignant glioma therapy: hype or hope?

Germano

Uzzaman²,

Keller³

2008

Cancer Biology & Therapy

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Patients with glioblastomas have a poor prognosis and new treatments paradigms are needed. The futility of current treatments lies in part on the difficulty of delivering therapeutic agents to the tumor. In this article, we review and discuss current knowledge of adjuvant treatment for glioblastomas including gene therapy and viral vectors. Additionally, this review provides an update on recent progress, which has focused on improving delivery methods including the development of new approaches such as stem cells. Particular emphasis is given to laboratory data showing the use of embryonic stem cells used as vectors to deliver pro-apoptotic genes to glioblastoma cells.

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“…In particular, diseases that shelter themselves from conventional treatments, such as chemotherapy, are in need for such therapy. Human high-grade gliomas (hHGG) are the most common primary brain tumors and remain a clinical challenge with an average life expectancy of 14 months after state of the art surgical, radiation, and chemotherapy treatments [19][20][21][22][23]. The infiltrative pattern of hHGG combined with the difficulty of chemotherapy to cross the blood-brain barrier is the main reason for treatment failure [24][25][26] and sparked interest in exploring cell-based therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Stem cell-derived astrocytes are highly desirable vectors as they have the potential for maintaining migrating capacity and, therefore, could offer advantages over other delivery vectors in the treatment of brain tumors. We have published that mouse ESC (mESC)-derived astrocytes can be successfully used as cell-based gene therapy for treatment of experimental HGG [23,28]. To translate these results to the clinical setting, patient-specific iPSC derived without viral vectors, that is, ''footprint-free'', are needed.…”

Section: Introductionmentioning

confidence: 99%

“Footprint-Free” Human Induced Pluripotent Stem Cell-Derived Astrocytes for In Vivo Cell-Based Therapy

Mormone

D'Sousa

Alexeeva

et al. 2014

Stem Cells and Development

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The generation of human induced pluripotent stem cells (hiPSC) from somatic cells has enabled the possibility to provide patient-specific hiPSC for cell-based therapy, drug discovery, and other translational applications. Two major obstacles in using hiPSC for clinical application reside in the risk of genomic modification when they are derived with viral transgenes and risk of teratoma formation if undifferentiated cells are engrafted. In this study, we report the generation of ''footprint-free'' hiPSC-derived astrocytes. These are efficiently generated, have anatomical and physiological characteristics of fully differentiated astrocytes, maintain homing characteristics typical of stem cells, and do not give rise to teratomas when engrafted in the brain. Astrocytes can be obtained in sufficient numbers, aliquoted, frozen, thawed, and used when needed. Our results show the feasibility of differentiating astrocytes from ''footprint-free'' iPSC. These are suitable for clinical cell-based therapies as they can be induced from patients' specific cells, do not require viral vectors, and are fully differentiated. ''Footprint-free'' hiPSC-derived astrocytes represent a new potential source for therapeutic use for cell-based therapy, including treatment of high-grade human gliomas, and drug discovery.

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Apoptosis in human glioblastoma cells produced using embryonic stem cell–derived astrocytes expressing tumor necrosis factor–related apoptosis-inducing ligand

Cited by 35 publications

References 35 publications

Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy

Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy

Gene delivery by embryonic stem cells for malignant glioma therapy: hype or hope?

“Footprint-Free” Human Induced Pluripotent Stem Cell-Derived Astrocytes for In Vivo Cell-Based Therapy

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