Stem Cell Transplantation in Brain Tumors: A New Field for Molecular Imaging?
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Neural stem cells have been proposed as a new and promising treatment modality in various pathologies of the central nervous system, including malignant brain tumors. However, the underlying mechanism by which neural stem cells target tumor areas remains elusive. Monitoring of these cells is currently done by use of various modes of molecular imaging, such as optical imaging, magnetic resonance imaging and positron emission tomography, which is a novel technology for visualizing metabolism and signal transduction to gene expression. In this new context, the microenvironment of (malignant) brain tumors and the blood-brain barrier gains increased interest. The authors of this review give a unique overview of the current molecular-imaging techniques used in different therapeutic experimental brain tumor models in relation to neural stem cells. Such methods for molecular imaging of gene-engineered neural stem/progenitor cells are currently used to trace the location and temporal level of expression of therapeutic and endogenous genes in malignant brain tumors, closing the gap between in vitro and in vivo integrative biology of disease in neural stem cell transplantation.
Neural stem cells (NSCs) have the tremendous potential to migrate to areas of pathology in the central nervous system (CNS) (1,2). When implanted into diseased or injured CNS, NSCs can travel great distances and engraft within discrete areas as well as diffuse neuronal abnormalities (1,2). Engraftment is often followed by integration into the local neural milieu, accompanied by stable gene expression from the NSCs (1,2). In addition, the pluripotency of NSCs endows them with the capability to replace diseased CNS tissues in an appropriate manner (1,2). Recent evidence has also suggested that engrafted exogenous NSCs may have effects on the surrounding microenvironment, such as promoting neuroprotection and/or regeneration of host neural pathways (1, 2, 3, 4). These characteristics of NSCs make them ideal agents for the treatment of various CNS pathologies, especially brain tumors (1,2).
Biological use of Neural Stem Cells for Brain Tumor Therapy
Brain tumors are generally difficult to treat because of the unique neuroanatomical location of the lesions next to critical neurovascular structures (1,5,6). In addition, the extensive infiltrative nature of the tumor cells makes their effective and total eradication challenging. These difficulties are reflected in the high rate of treatment failure and disease recurrence (1). In addition, normal brain structures are distorted and often destroyed by the growing neoplasm (1). Even with effective therapy to surgically resect and destroy the neoplastic tissues, the brain is still injured, which often leaves the patient in a debilitated state (1,3,4).
The inherent tumor tropism of NSCs to primary and invasive tumor foci can be exploited to deliver therapeutic agents to invasive brain tumor cells in humans (1,2). NSCs have tremendous potential to migrate to the pathological brain areas. When implanted into a diseased or injured nervous system, NSCs can travel great distances to, and engraft within, target areas (1). Engraftment is often followed by integration into the local neural milieu, accompanied by stable gene expression from the NSCs (1,7). The use of such a strategy to convert prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines has shown efficacy in animal models (1,2). In addition, the pluripotency of NSCs endows them with the capability to replace diseased (neural) tissues in an appropriate manner. Recent evidence has also suggested that engrafted exogenous NSCs may have effects on the surrounding microenvironment, such as promoting protection and/or regeneration of host neural pathways (1,7). These characteristics of NSCs may make them ideal agents for the treatment of brain tumors (1,2).
The Microenvironment of Brain Tumors
The pathological characteristics of malignant brain tumors are exemplified by active invasiveness, necrosis and a specialized form of angiogenesis, known as microvascular hyperplasia. Such pathological features are thought to be due to tissue hypoxia. Therefore hypoxia is a critical aspect of the surrounding microenvironment of brain tumors and is generally associated with unfavorable clinical outcomes (3,4,8, 9, 10, 11, 12). Cells that are under hypoxic stress can develop an adaptive response that includes increased rates of glycolysis and angiogenesis or undergo cell death by promoting apoptosis and/or necrosis (3,8,13). The ability of tumor cells to maintain a balance between adaptation to hypoxia and cell death is regulated by hypoxia-inducing factors, a family of transcription factors that are essential for the regulation of the expression of a large number of hypoxia-responsive genes (13,14). Tumor hypoxia is hypothesized to facilitate metastases, tumor recurrence, invasive potential and resistance to chemotherapy and radiotherapy, which culminate in decreased patient survival. For this reason, effective targeting of hypoxic areas in brain tumors remains a significant therapeutic challenge (3,4,8, 9, 10). New NSC therapeutic options for tumor-targeted drug delivery show promise in treatment of brain tumors that are refractory to traditional therapies (1,3,4,9). However, the molecular mechanisms of NSC-targeting to hypoxic tumor areas are not well understood (3,4,9). The unique ability of NSCs to “home in” on tumor cells and then deliver a desired gene product makes NSCs a promising agent in brain tumor therapy (1). Cytolytic viruses and genes coding for antitumor cytokines, prodrug-converting enzymes and various neurotrophic factors have all been engineered into engraftable NSCs for delivery to tumors (1). Novel brain tumor treatment strategies that involve transplantation or infusion of cells that seek out invading tumor cells demand thorough in vivo monitoring (3, 4, 5, 6, 7, 8,15,16). In particular, NSCs have attracted great interest because they have demonstrated tropism to tumor cells and even long-distance migration to single tumor cells (17,18). It is thought that the migration of NSCs to neoplastic cells is mediated by the secretion of chemical factors, such as vascular endothelial growth factor (19), that are involved in the proliferation, growth and maintenance of tumors. Transplantation of unaltered NSCs has resulted in prolonged survival of animals with experimentally induced tumors (20), and the insertion of antitumor cytokine genes (for example, IL-12) or proapoptotic genes (for example, TRAIL) has further improved the efficiency of this approach (21). Little is known about how these cells exert their beneficial effects in vivo. Despite contrary evidence from preclinical studies, there is some concern that transplantation of stem cells could further exacerbate tumor formation. This is caused by mounting evidence that brain tumors may be caused by a single NSC that did not differentiate (22). The ability to monitor cell therapy in vivo is therefore desirable because it may provide more control over the activity of NSCs (23). One possibility is that stem cells will be engineered with a suicide gene (24) that could be activated if transplanted cells did not behave in a therapeutic manner.
The Problem of the Blood-Brain Barrier
One hallmark of malignant brain tumors is the disruption of the normal homeostasis between angiogenic and antiangiogenic factors. The resulting vasculature is characterized by tortuous vessels that feature disruptions in their structural integrity, increased leakiness, uneven focal thickness and arteriovenous shunts not seen in the normal brain vasculature as well as changes in the physiology of the blood-brain barrier (BBB). However, brain delivery of therapeutic cells is physiologically limited by the BBB, which remains one of the recognized rate-limiting steps (25,26). As the BBB limitation has been more and more acknowledged, many innovative surgical and pharmacological strategies have been developed to circumvent it. Since opening of the BBB was first reported by Rapoport et al. in 1972 (27), preclinical studies have provided important information on the extent of BBB permeation. Although the BBB is frequently leaky in the center of malignant brain tumors, the well-vascularized actively proliferating edge of the tumor has been shown to have variable and complex barrier integrity (27). Current experimental data show that brain penetration of peripherally circulating cells, such as stem cells and immune cells targeting the CNS, requires BBB disruption and is limited to the immediate perivascular space. In addition, oncolytic virus treatment of rat gliomas has been shown to be associated with a significant increase in the permeability of the tumor vasculature and consequently with significant increases in tumor inflammation and leukocyte infiltration (28).
Representative examples of different molecular-imaging modalities in experimental brain tumor models related to neural stem cells.
Hata etal. (57), 2010
Shah et al. (54), 2008
Brekke etal. (55), 2007
Migration, therapeutic efficacy
Anderson et al. (56), 2005
Miletec etal. (58), 2007
From Bench to Bedside
Current investigations of the use of monitoring by molecular imaging are increasing our understanding of stem cells and stem-cell regulation, which in turn will facilitate the development of novel therapies to eliminate (malignant) brain tumors. Given the current status of therapeutic developments in neurooncology, we can expect a number of drug targets to emerge that can be exploited by means of interstitial or intracavitary delivery, are not neurotoxic, and may even be imaged in action with new molecular imaging modalities (59). For effective therapy for (malignant) brain tumors, convection-enhanced delivery, conditional replication of oncolytic viruses and motile, genetically engineered neural stem cells all seem to fulfill the distribution requirements needed to overcome the very limited efficacy offered by surgery, conventional chemotherapy and radiation treatments. Although these genomics-based discovery approaches are not specific for neurooncological targets, the development of delivery strategies is highly specific for the CNS, thus creating a unique set of organ- and disease-specific therapies.
The authors declare that they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.
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