Review
Advances in stem cell therapy against gliomas

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Malignant gliomas are one of the most lethal cancers, and despite extensive research very little progress has been made in improving prognosis. Multimodality treatment combining surgery, radiation, and chemotherapy is the current gold standard, but effective treatment remains difficult due to the invasive nature and high recurrence of gliomas. Stem cell-based therapy using neural, mesenchymal, or hematopoietic stem cells may be an alternative approach because it is tumor selective and allows targeted therapy that spares healthy brain tissue. Stem cells can be used to establish a long-term antitumor response by stimulating the immune system and delivering prodrug, metabolizing genes, or oncolytic viruses. In this review, we discuss current trends and the latest developments in stem cell therapy against malignant gliomas from both the experimental laboratory and the clinic.

Section snippets

Stem cell-based therapy against gliomas

Gliomas account for approximately 60% of all primary central nervous system (CNS) tumors with a very poor prognosis. Glioblastoma (GBM), the most malignant type of glioma, has a median survival of approximately 18–21 months 1, 2. The characteristics of this malignancy include uncontrolled cellular proliferation, invasiveness with both long root-like processes and single invasive cells, areas of necrosis, resistance to apoptosis, extensive angiogenesis, and multiple genetic alterations (Figure 1

Stem cells for cargo delivery

Genetic manipulation is one of the research strategies most often investigated for glioma, because it has an almost unlimited range of potential targets. Therapeutic genes stimulating the immune system, inducing tumor cell death, inhibiting angiogenesis, and limiting metastatic potential have been extensively studied, and many different approaches and gene combinations have been used (Box 2). However, gene therapy (and/or viral therapy) alone has not been able to live up to its full potential,

Routes of administration and enhancement of the stem cell model

Several studies have focused on developing alternative strategies to increase the therapeutic effect of stem cell-based therapy to brain tumors by enhancing delivery mode, tumor tropism, and cellular delivery vehicles (Table 1 and Box 2).

Glioma stem cell therapy in the clinic

Although a vast amount of interesting and exciting research is being explored using stem cells as a therapeutic strategy for malignant gliomas, most of these studies are being performed in the laboratory setting. This indicates that although the bench results are promising, translating this therapy to the clinic remains difficult with only a single clinical trial in progress (Box 3). At the City of Hope (California) by Aboody et al., NSCs (HB1.F3-CD) genetically modified to express Escherichia

Concluding remarks

Stem cells provide a highly promising and innovative approach for the treatment of malignant gliomas. Provided that some of the discussed issues/limitations can be addressed, this therapeutic strategy could become of tremendous value in the search for a cure for tumors as heterogeneous and as difficult to reach as glioblastoma. Other exciting strategies such as gene therapy and oncolytic viral therapy, which by themselves have failed to establish clinically relevant antitumor effects, are now

Acknowledgments

B.A.T. is supported by grants from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke (1R01NS064983) and the National Cancer Institute (1R01CA166077). M.H.D. is supported by a Fulbright scholarship, the Saal van Zwanenberg Foundation, VSB fonds, Dr Hendrik Muller Vaderlandschfonds, the Dutch Cancer Foundation (KWF Kankerbestrijding), the Hersenstichting brain fund, as well as the Jo Keur (Leiden hospital). M.S.B. is supported by a Fulbright

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    These authors contributed equally.

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