Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors

Amara, Ikrame; Touati, Walid; Beaune, Philippe; Waziers, Isabelle de

doi:10.1016/j.biochi.2014.06.016

Cited by 53 publications

(49 citation statements)

References 87 publications

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“…Although there are several stem cell culture medias and supplements commonly used for enriching TICs/spheroids we used a serum-free media formula with EGF and FGF, but without the addition of B27 or N-2 supplements. These supplements, commonly used for neuronal cell culture and enriching for stem cells, have been shown to promote a mesenchymal phenotype 25,26 and there remains some uncertainty in the field as to whether TICs having a mesenchymal or epithelial phenotype are more tumorigenic [27][28][29] .…”

Section: Introductionmentioning

confidence: 99%

<em>In vitro</em> Enrichment of Ovarian Cancer Tumor-initiating Cells

House¹,

Hernandez²,

Annunziata³

2015

JoVE

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Evidence suggests that small subpopulations of tumor cells maintain a unique self-renewing and differentiation capacity and may be responsible for tumor initiation and/or relapse. Clarifying the mechanisms by which these tumor-initiating cells (TICs) support tumor formation and progression could lead to the development of clinically favorable therapies. Ovarian cancer is a heterogeneous and highly recurrent disease. Recent studies suggest TICs may play an important role in disease biology. We have identified culture conditions that enrich for TICs from ovarian cancer cell lines. Growing either adherent cells or non-adherent 'floater' cells in a low attachment plate with serum free media in the presence of growth factors supports the propagation of ovarian cancer TICs with stem cell markers (CD133 and ALDH activity) and increased tumorigenicity without the need to physically separate the TICs from other cell types within the culture. Although the presence of floater cells is not common for all cell lines, this population of cells with innate low adherence may have high tumorigenic potential.Compared to adherent cells grown in the presence of serum, TICs readily form spheres, are significantly more tumorigenic in mice, and express putative stem cell markers. The conditions are easy to establish in a timely manner and can be used to study signaling pathways important for maintaining stem characteristics, and to identify drugs or combinations of drugs targeting TICs. The culture conditions described herein are applicable for a variety of ovarian cancer cells of epithelial origin and will be critical in providing new information about the role of TICs in tumor initiation, progression, and relapse.

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Section: Introductionmentioning

confidence: 99%

<em>In vitro</em> Enrichment of Ovarian Cancer Tumor-initiating Cells

House¹,

Hernandez²,

Annunziata³

2015

JoVE

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“…MSC have been engineered to produce a wide variety of cancer therapeutic proteins, such as interleukins (IL-2 [12], IL-12 [53], IL-18 [54]), interferon-β [55], and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [56]. MSC have also been engineered to produce prodrug-activating enzymes [57]. In this case, the genetically modified cells are followed by administration of the inactive prodrug locally, which is activated by the enzyme.…”

Section: Techniques For Engineering Mscmentioning

confidence: 99%

“…This, in principle, would provoke the cell-killing action only at the site populated by MSC, minimizing the systemic toxicity. Some of the combination therapies that have shown success are: herpes simplex virus thymidine kinase with Ganciclovir, E. coli cytosine deaminase with 5-fluorocytosine, carboxylesterase with irinotecan, and cytochrome P450 with cyclophosphamide or ifosfamide [57]. Incorporating a tetracyclin-induced promoter to turn off the gene expression confers safety to the transplanted MSC.…”

Section: Techniques For Engineering Mscmentioning

confidence: 99%

Engineering mesenchymal stem cells for regenerative medicine and drug delivery

Park

Suryaprakash

Lao

et al. 2015

Methods

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Researchers have applied mesenchymal stem cells (MSC) to a variety of therapeutic scenarios by harnessing their multipotent, regenerative, and immunosuppressive properties with tropisms toward inflamed, hypoxic, and cancerous sites. Although MSC-based therapies have been shown to be safe and effective to a certain degree, the efficacy remains low in most cases when MSC are applied alone. To enhance their therapeutic efficacy, researchers have equipped MSC with targeted delivery functions using genetic engineering, therapeutic agent incorporation, and cell surface modification. MSC can be genetically modified virally or non-virally to overexpress therapeutic proteins that complement their innate properties. MSC can also be primed with non-peptidic drugs or magnetic nanoparticles for enhanced efficacy and externally regulated targeting, respectively. Furthermore, MSC can be functionalized with targeting moieties to augment their homing toward therapeutic sites using enzymatic modification, chemical conjugation, or non-covalent interactions. These engineering techniques are still works in progress, requiring optimization to improve the therapeutic efficacy and targeting effectiveness while minimizing any loss of MSC function. In this review, we will highlight the advanced techniques of engineering MSC, describe their promise and the challenges of translation into clinical settings, and suggest future perspectives on realizing their full potential for MSC-based therapy.

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“…Beispiele für derartige Ansätze sind die Verwendung des Herpes-simplex-Virus-Thymidinkinasegens in Kombination mit dem Therapeutikum Ganciclovir, des Cytochrom-P450-Gens mit Cyclophosphamid bzw. Ifosfamid oder des E.-coli-Cytosindeaminasegens mit 5-Fluorocytosin [29]. Anstelle von autologen MSCs könnten auch allogene MSCs eingesetzt werden, da durch die immunsupprimierenden Eigenschaften der MSCs sowie des Tumors eine geringe Abstoßungsreaktion dieser körper-fremden Zellen erwartet wird [29,30].…”

Section: Genetisch Modifizierte Mesenchymale Stromazellen (Mscs)unclassified

Genetisch modifizierte Zellen zur Therapie verschiedener Erkrankungen

Anliker

Renner

Schweizer

2015

Bundesgesundheitsbl.

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Medicinal products containing genetically modified cells are, in most cases, classified as gene therapy and cell therapy medicinal products. Although no medicinal product containing genetically modified cells has been licensed in Europe yet, a variety of therapeutic strategies using genetically modified cells are in different stages of clinical development for the treatment of acquired and inherited diseases. In this chapter, several examples of promising approaches are presented, with an emphasis on gene therapy for inherited immunodeficiencies and on tumour immunotherapy with genetically modified T-cells expressing a chimeric antigen receptor or a recombinant T-cell receptor.

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Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors

Cited by 53 publications

References 87 publications

<em>In vitro</em> Enrichment of Ovarian Cancer Tumor-initiating Cells

<em>In vitro</em> Enrichment of Ovarian Cancer Tumor-initiating Cells

Engineering mesenchymal stem cells for regenerative medicine and drug delivery

Genetisch modifizierte Zellen zur Therapie verschiedener Erkrankungen

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