Bystander Killing of Malignant Glioma by Bone Marrow–derived Tumor-Infiltrating Progenitor Cells Expressing a Suicide Gene

Miletić, Hrvoje; Fischer, Yvonne; Litwak, Sara; Giroglou, Tsanan; Waerzeggers, Yannic; Winkeler, Alexandra; Li, Huongfeng; Himmelreich, Uwe; Lange, Claudia; Stenzel, Werner; Deckert, Martina; Neumann, Harald; Jacobs, Andréas H.; Laer, Dorotheé von

doi:10.1038/sj.mt.6300155

Cited by 142 publications

(75 citation statements)

References 39 publications

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“…Meanwhile, they showed that the presence of this bystander effect is correlated with the expression of Cx43 in untransduced glioma target cells. Furthermore, Miletic et al 24 confirmed the gap junction communication between bone marrow (BM) and tumorinfiltrating cells (TICs) (a highly proliferative subpopulation of bone marrow-derived mesenchymal stem cells) and 9L cells. Their cell culture experiments showed that BM-TIC-TK cells exert a strong bystander effect on 9L glioma cells on GCV treatment.…”

Section: Discussionmentioning

confidence: 97%

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

Huang

Xz²,

et al. 2009

Cancer Gene Ther

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The disseminated neoplastic foci of malignant gliomas are essentially responsible for the limited efficacy of current available therapeutic modalities. Bone marrow-derived stem cells (BMSCs) have the ability to migrate into these tumors and even track infiltrating tumor cells, making them to be promising cellular vehicles for delivering therapeutic agents to glioma cells. The herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) suicide gene therapy with a potent bystander effect has been considered as one of the most promising therapeutic strategies for malignant gliomas. In this study, we evaluate the anti-glioma effect of suicide gene therapy using BMSCs expressing HSV-TK combined with overexpression of connexin 43 (Cx43), which can restore the gap junction of intercellular communication and may enhance the bystander effect of suicide gene therapy. To assess the potential of BMSCs to track glioma cells, a spheroid co-culture system in matrigel was used to show that some BMSCs migrated to C6 glioma cell microspheres. Transwell assay showed the tumor tropic property of BMSCs. In addition, BrdU-labeled BMSCs injected directly into the cerebral hemisphere opposite to the established C6 rat gliomas were capable of migrating into the xenograft gliomas. C6 cell growth was more intensively inhibited by HSV-TK/GCV treatment mediated by BMSCs, and could be further enhanced by combination with Cx43 transfection into glioma cells. The same result was observed in vivo by the growth of C6 gliomas and the survival analysis of rats bearing C6 glioma. In conclusion, Cx43 combined with HSV-TK/GCV gene therapy using BMSCs as vehicles was highly effective in a rat glioma model and therefore hold great potential as a novel approach for the gene therapy of human malignant gliomas.

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Section: Discussionmentioning

confidence: 97%

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

Huang

Xz²,

et al. 2009

Cancer Gene Ther

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“…MSCs have been shown to migrate toward gliomas (9) and track microscopic tumor deposits and infiltrating tumor cells in the brain (10,11). Furthermore, engineered MSCs have been shown to exert potent inhibition of tumor growth in an in vivo glioma model and also exhibit a protective effect for the normal brain (12).…”

mentioning

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.

415

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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“…Bystander effects were observed after intratumoral administration of MSCs and intraperitoneal injection of gancyclovir, with a significant fraction of mouse model animals surviving long-term period [99]. A novel and worth mentioning aspect of this study was the use of imaging techniques PET and MRI to track the injected cells and the possibility of determinate the therapeutic efficacy.…”

Section: Recently Published Patents (2012-present) Concerning Mscs Asmentioning

confidence: 99%

“…Prepare a conditioned extracellular medium as an apoptosis-modulating cell-free composition [92] MSCs particles Particles (vesicle or exosome) possess biological properties of a MSC [95] Expressing a suicide gene High selective anticancer effects (conversion of a prodrug to an anticancer agent at the cancer site) [98][99][100][101][102] Micro carriers for protein delivery Deliver large quantities of the therapeutic agent for extended periods of time [104,105] Secreting TRAIL Inducing apoptosis and inhibition of tumor growth [108,[114][115][116] Delivering of oncolytic viruses Induction of apoptosis [117] Engineered MSCs for secretion of antibody-like molecules Can lead to elimination of early cancer cell metastasis [118] With a number of target therapeutics currently under development as anticancer therapy, not only cancer cells, but also cells from the microenvironment (endothelial cells or MSCs) are targeted. This therapeutic approach may have many adverse effects associated with the elimination of cells not involved in cancer progression or in chemoresistance.…”

Section: New Facts Raised Concerns About Use Of Mscs As An Anticancermentioning

confidence: 99%

Perspectives in Engineered Mesenchymal Stem/Stromal Cells Based Anti- Cancer Drug Delivery Systems

Ackova¹,

Kanjevac²,

Rimondini³

et al. 2016

PRA

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Understanding and apprehension of the characteristics and circumstances in which mesenchymal stem cells (MSCs) affect and make alterations (enhance or reduce) to the growth of tumors and metastasis spread is pivotal, not only for reaching the possibility to employ MSCs as drug delivery systems, but also for making forward movement in the existing knowledge of involvement of major factors (tumor microenvironment, soluble signaling molecules, etc.) in the process of carcinogenesis. This capability is reliable because MSCs present a great basis for engineering and constructions of new systems to target cancers, intended to secrete therapeutic proteins in the tumor region, or for delivering of oncolytic viruses' directly at the tumor site (targeted chemotherapy with enzyme prodrug conversion or induction of tumor cell apoptosis). MSCs as a crucial segment of the tumor surroundings and their confirmed tumor tropism, are assumed to be an open gateway for the design of promising drug delivery systems. The presented paper reviews current publications in this fieldwork, searches out the most recent patents that were published after 2012 (WO2014066122, US20140017787, WO2015100268, US20150086515), and tries to present the current progress and future prospective on the design and development in anti-cancer drug delivery systems based on MSCs.

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Bystander Killing of Malignant Glioma by Bone Marrow–derived Tumor-Infiltrating Progenitor Cells Expressing a Suicide Gene

Cited by 142 publications

References 39 publications

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

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

Perspectives in Engineered Mesenchymal Stem/Stromal Cells Based Anti- Cancer Drug Delivery Systems

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