Interestingly, neither modification on its own conferred immune protection to hESC derivatives experiments in general, can be translated to animal models
Interestingly, neither modification on its own conferred immune protection to hESC derivatives experiments in general, can be translated to animal models. anticancer biological brokers (TABLE 1). The strategy is usually twofold: SCs can disseminate solid tumours and migrate towards micrometastatic lesions, enabling site-specific delivery. Furthermore, SCs can be modified to stably express or release various anticancer agents, thereby circumventing the short half-lives that many chemotherapeutic brokers exhibit. Table 1 Stem cell sources studies have found that transplantation of various adult and induced allogeneic donor SCs elicits an immune response, thereby resulting in their rejection5C9. For example, although allogeneic mesenchymal SCs (MSCs) seem to be less immunogenic than allogeneic non-SC donor cells, such as fibroblasts (as determined by their relatively long persistence in immunocompetent hosts8), they should not be considered to be immune privileged but rather to have the ability to transiently escape host rejection10. The migratory capacity of neural SCs (NSCs) and neural progenitors was initially BMS-790052 2HCl shown in xenograft mouse models by their ability to home to intracranial brain tumours and non-neural tumours in other regions of the body11C13. Moreover, NSCs not only integrate into the primary tumour bed but also track towards small intracranial microsatellite deposits that typify malignant brain tumours such as glioblastoma11. These tumour-tropic characteristics have BMS-790052 2HCl been reported in numerous types of human SCs14C16. The cellular and molecular mechanisms that underlie the tumour tropism of SCs are far from being completely comprehended. Various chemokineCchemokine receptor pairs have been associated with tumour tropism, and perhaps the best studied is usually stromal cell-derived factor 1 (SDF1; also known as CXCL12) and its receptor CXC-chemokine receptor 4 (CXCR4). To date, the SDF1CCXCR4 signalling axis has been shown BMS-790052 2HCl to have a major role in the migration of multiple SC types, including adult SCs17C20, embryonic SCs (ESCs)21 and induced pluripotent SCs (iPSCs)22. Other influential signalling pathways have been elucidated and include PI3K signalling23, urokinase-type plasminogen activator (uPA)CuPA receptor (uPAR)24,25, vascular endothelial growth factor receptor 2 (VEGFR2)26 and matrix metalloproteinase 1 (MMP1)Cproteinase-activated receptor 1 (PAR1)27. The degree of SC migration towards a tumour is usually influenced by diverse factors, including the nature of the SC (the heterogeneity of the population, culture conditions and the expression of migratory factors) and the tumour microenvironment (the degree of hypoxia, the extent of vascularization, and inflammation). A better understanding of the factors influencing the migratory potential of SCs will allow a greater ability to tailor SC migration and ultimately increase the therapeutic potential of these SCs. Creating anticancer stem cells Unmodified SCs can have intrinsic antitumour effects attributed to factors that are secreted by SCs and physical interactions that are established between the SC and tumour cells28C30. In addition, SCs have been modified in various ways BMS-790052 2HCl to treat cancer, and some of the most promising are discussed below. Genetic modification of stem cells to secrete anticancer proteins SC secretion of therapeutic proteins can be divided into two broad categories depending on whether they act directly on malignant cells or on supporting cells of the tumour, BMS-790052 2HCl such as blood vessels and stroma (FIG. 1a). SCs are typically modified by viral transduction to express transgenes encoding secretable effector proteins, although nonviral methods have been reported that offer certain advantages, such as lower host immunogenicity31,32. Direct effectors include the pro-apoptotic protein tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) that binds to death receptor 4 (DR4; also known as TRAILR1) and DR5 (also known as TRAILR2) (which are preferentially expressed on cancerous cells) and induces apoptosis33,34. Using proteins that can outcompete or sterically block the binding of endogenous ligands to their cognate receptor is usually another strategy that results in inhibition of proliferation pathways in the cancer and associated cells. For example, SC-expression of biological brokers that bind to epidermal growth factor receptor (EGFR) or its tumour-specific variant EGFRvIII (REFS 35,36), and cytokines such as interferon- (IFN)37C40 and IFN41, have all been shown to negatively regulate tumour growth in various preclinical cancer models. Open in a separate window Physique 1 Using stem cells (SCs) to promote tumour cell deathSCs can be modified Dicer1 in various ways to generate antitumour capabilities. a | SCs can be engineered to secrete therapeutic proteins that function directly on tumour cells or indirectly on cells of.