Each strategy has specific advantages and disadvantages. as vehicles for delivery of agents targeting glioma stem cells, which have been implicated in the resistance of high-grade glioma to treatment. Overall, stem cells are providing an unprecedented opportunity for cell-based approaches in the treatment of high-grade gliomas, which have a persistently dismal prognosis and mandate a continued search for therapeutic options. strong class=”kwd-title” Keywords: cancer stem cells, cell-based therapy, high-grade glioma, stem cells The use of stem cells (SC) as therapeutic vehicles for brain tumors has garnered much attention over the past decade. This is attributable to the fundamental ability of SC to migrate, or home, to brain tumors1 irrespective of the blood brain barrier (BBB) and to be manipulated into expressing various therapeutic molecules.2 These characteristics, together with their inherent immunosuppressive properties3C5 and the difficulties encountered in the use of viruses in gene therapy clinical trials 6 spurred the exploration of SC as vehicles for cell-based therapy of human high-grade gliomas (hHGG), the most common and devastating Cl-C6-PEG4-O-CH2COOH FHF4 type of primary malignant brain tumor. Thus far, hHGG continue to carry an extremely poor prognosis. Patients with glioblastoma, the most common type of hHGG 7,8 have an overall survival of less than 10% at 5 years after standard-of-care treatment with surgery, ionizing radiation, and temozolomide.9 Recent evidence has revealed the presence of cancer SC in gliomas, also known as glioma stem cells (GSC), and suggested that they may be the culprits behind the resistance of hHGG to therapy.10 Initial strategies to improve delivery of genes or other therapeutic agents for hHGG used neural stem cells (NSC) as vehicles 2 but as knowledge of SC expanded, mesenchymal stem cells (MSC)11 and embryonic stem cells (ESC)12 were also tested. Important to the development of SC as vehicles were observations in preclinical models that SC have immunomodulatory functions enabling immune evasion and suppression of the immune system, particularly of T cells 3C5 the main effectors of cellular rejection. In Cl-C6-PEG4-O-CH2COOH NSC, this effect has been postulated to be indirect via peripheral mechanisms 3 whereas MSC and ESC appear to have more direct effects.4,5 In addition, MSC have been reported to induce T cell apoptosis4 and ESC to have diminished T cell activation from low major histocompatibility molecule expression, although susceptible to epigenetic modification.5 Preclinical testing of SC-based therapies is typically performed in immunodeficient mouse models in which tumors are created by the injection of hHGG cells either intracranially or into the flank.13 Intracranial injection of hHGG cells (i.e., orthotopic xenograft model) has the advantage of providing a native environment. However, it has significant limitations 13 including low histopathologic similarity of the resultant tumors to clinical ones and the inability to recapitulate tumor-specific immune responses with implications for SC migration. These limitations heighten concern over the translation of results to the clinic, particularly with respect to SC migration as highlighted in the discussion. Nevertheless, this type of Cl-C6-PEG4-O-CH2COOH model is a mainstay of Cl-C6-PEG4-O-CH2COOH preclinical testing based on a number of practical factors, such as cost, availability, and ease of handling.13,14 To date, SC have been manipulated to deliver the following: cytokines, enzyme/prodrug suicide combinations, viral particles, matrix metalloproteinases, and antibodies. Table?1 provides a summary of the agents delivered by SC, as discussed below. Of note, the therapeutic agents are classified according to the final target being delivered, because viruses are often used to transfect SC. Viral particles refer to oncolytic viruses, where by definition, the virus is the effector mechanism. Table?1. Summary of stem cells (SC) as vehicles for the treatment of human high-grade glioma (hHGG). thead valign=”top” th align=”left” rowspan=”1″ colspan=”1″ SC /th th align=”center” rowspan=”1″ colspan=”1″ Therapeutic strategy /th th align=”left” rowspan=”1″ colspan=”1″ Agent /th th align=”left” rowspan=”1″ colspan=”1″ (Refs) /th /thead EmbryoniccytokineTRAIL(18,21,23)mda-7/IL-24(24)NeuralcytokineIL-4(26)IL-12(27)IL-23(28)TRAIL BMZ(29,30)S-TRAIL MIR/TMZ(31,32,34,35)enzyme/prodrugtk/GCV(37C40)CD/5FC IFN(41C44)viral particlesmutant HSV-1(45)CRAd-survivin(46,47,49)matrix metalloproteinasePEX(51)MesenchymalcytokineIL-2(53)IFN(55)IFN(56)IL-18(57)TRAIL PI3KI(58C61,64)IL-12(62,63)enzyme/prodrugtk/GCV(66,67)viral particlesCRAd-CXCR4(68)CRAd-Rb(69)CRAd-survivin(71)antibodyEGFRvIII(72,73) Open in a separate window ESC ESC are found in the inner cell mass of a blastocyst formed after the union of sperm and egg.15 A major advantage of ESC over other types of SC is their capacity to be permanently and genetically modified using homologous recombination.12 The enthusiasm of using ESC is tempered by the regulatory, political, and ethical issues behind their procurement.16 Recent work on inducible pluripotent stem cells (iPSC), for which patient-specific cells may be easily obtained from peripheral Cl-C6-PEG4-O-CH2COOH blood and reprogrammed into pluripotent SC similar to ESC, may overcome these limitations.17 However, no studies to date have tested iPSC as vehicles for cell-based therapy against hHGG. Experimental.