Neural stem cell therapy for cancer
Introduction
Over the past two decades, the dogma in the central nervous system has shifted from one of a static organ incapable of change to the current understanding of adult neurogenesis [1]. The key to much of this change was the discovery of neural stem cells (NSCs). NSCs are generated by the differentiation of embryonic tissue and can serve as a source for replenishing neurons and glial cells in the adult brain throughout life. NSCs are defined by the expression of classic markers, including Nestin and Sox2, as well as their expansion in growth factor rich media that contains fibroblast growth factor and epidermal growth factor. NSCs display the hallmarks of stem cells, both self-renewing as well as differentiating into neurons, astrocytes, and oligodendrocytes. This differentiation capacity has led to significant investigation into the use of NSCs for regenerative medicine applications to correct damage to the brain and central nervous system caused by physical trauma or disease states. These studies have shown that NSC transplants survive in the diseased or damaged brain, and have therapeutic benefits in certain disease models.
In contrast to these traditional NSC therapies, the use of NSCs as tumor-homing drug carriers is an emerging area of interest that holds promise for treating malignant brain cancer [2], [3], [4], [5]. Pioneering studies by Aboody et al. and Benedetti et al. first revealed the unique ability of NSCs to home to brain cancer [6], [7]. These studies showed that NSCs transplanted at different sites throughout the brain migrated through the non-diseased parenchyma to localize selectively with cancer foci. When the NSCs were engineered with anti-cancer gene products, cytotoxic NSC therapy significantly inhibited the progression of cancer xenografts. These studies opened the door to the possibility of harnessing drug-loaded NSCs as a tumor-homing therapy. Ensuing studies over the past 15 years have further developed this concept, exploring novel cytotoxic agents, different routes of administration, and numerous molecular assays to define the mechanisms of migration. This exciting work has rapidly moved cytotoxic NSC therapy from preclinical mouse studies to a recent first-in-human clinical trial.
Section snippets
Glioblastoma
Glioblastoma (GBM) is the most common primary brain tumor, yet effectively treating this aggressive form of cancer remains a daunting challenge. GBM is classified as a grade IV glioma by the World Health Organization [8], [9]. The current clinical standard of care for GBM is surgical resection followed by chemo- and radiation therapy. Yet, median survival for GBM remains only 12–15 months and only 5% of patients survive 5 years [10], [11], [12]. GBM survival has not significantly improved in
Endogenous NSCs
NSCs possess the capacity to both self-replicate as well as differentiate into the primary cell types found in the CNS: neurons, astrocytes, and oligodendrocytes. While NSCs are ubiquitous in the developing brain, small populations of dormant NSCs that respond to injury can also be harvested from the subventricular zone (SVZ) or the subgranular zone (SGZ) of the dentate gyrus (DG) in adults [1], [19]. Isolation procedures vary yet typically involve microdissection and enzymatic digestion of
Homing
The main function of NSCs in the brain is to replace lost or injured neurons and glia by differentiation after migration to the injured zone. This migration to injured tissue is triggered by hypoxia through the associated up-regulation of the transcription factor hypoxia-inducible factor-1α (HIF-1α), which in turn activates the expression of NSC chemoattractants. These include chemokines and pro-angiogenic growth factors such as stromal cell-derived factor 1 (SDF-1), monocyte chemotactic
Enzyme/prodrug
Enzyme/prodrug therapy was the first approach used for engineered NSC therapy and the first strategy to enter human patient testing [6], [32]. In this approach, the NSCs are engineered to express an enzyme that converts a non-toxic prodrug into a cytotoxic product. This allows more precise control of the timing, levels, and location of drug release. This approach also adds an additional layer of safety as the prodrug typically kills the NSC drug carrier [75]. Cytosine deaminase (CD) was used in
Routes of administration
Determining the most effective route to administer cytotoxic NSC therapies represents an important step for eventual human use. Direct injection into the established GBM has been the mainstay of cytotoxic NSC delivery, and as numerous studies have found, this method leads to efficient NSC transplant and robust tumor killing [2], [93], [100]. However, directly injecting NSCs into the immunosuppressive tumor niche improves the survival of human NSC transplants and neglects their defining ability
Conclusions
Tumoricidal NSC therapy is opening new doors for cancer therapy. The tumor-homing capacity of these cells creates a powerful drug delivery platform that provides access to invasive cancer foci which traditional surgery, chemotherapy, and radio-therapy cannot typically access. NSCs have been engineered with a wide range of therapeutic agents, and typically achieve tumor reductions of 70–90% in preclinical models. Despite the success of these studies, many challenges still remain. The treatment
Acknowledgements
This work was supported by the UNC Lineberger Comprehensive Cancer Center’s University Cancer Research Fund and the UNC Translational and Clinical Sciences Institute (KL2TR001109, UL1TR001111).
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