ABSTRACT
Cancer cells and the immune system are closely related and thus influence each other. Although immune cells can suppress cancer cell growth, cancer cells can evade immune cell attack via immune escape mechanisms. Natural killer (NK) cells kill cancer cells by secreting perforins and granzymes. Upon contact with cancer cells, NK cells form immune synapses to deliver the lethal hit. Mature NK cells are differentiated from hematopoietic stem cells in the bone marrow. They move to lymph nodes, where they are activated through interactions with dendritic cells. Interleukin-15 (IL-15) is a key molecule that activates mature NK cells. The adoptive transfer of NK cells to treat incurable cancer is an attractive approach. A certain number of activated NK cells are required for adoptive NK cell therapy. To prepare these NK cells, mature NK cells can be amplified to obtain sufficient numbers of NK cells. Alternatively, NK cells can be differentiated and amplified from hematopoietic stem cells. In addition, the selection of donors is important to achieve maximal efficacy. In this review, we discuss the overall procedures and strategies of NK cell therapy against cancer.
Subject(s)
Humans , Cell Differentiation , Cell- and Tissue-Based Therapy , Gene Expression Regulation , Hematopoietic Stem Cells/cytology , Immunotherapy, Adoptive , Killer Cells, Natural/cytology , Lymphocyte Activation/immunology , Signal TransductionABSTRACT
Reactive Oxygen Species (ROS) are a class of signaling molecules that regulate intracellular signaling cascades in response to external stimuli. Once accumulated in cells, they can damage DNA modifying gene transcription and affecting protein expression and function in ways that accelerate tumorigenesis. In cancer cells, the accumulation of ROS can increase cell proliferation and cell invasion into other tissues, while, antioxidant enzymes and molecules can protect cells from oxidative stress so as to maintain cellular homeostatic redox status. Cancer cells often do not have sufficient levels of antioxidant enzymes which are needed to rescue cells from oxidative stress. The redox status of cancer cells appears to be a key factor in maintaining the malignant phenotype. Cancer stem cells, on the other hand, have been shown to maintain low levels of ROS in order to retain their self renewal and differentiation potential, even though the exact mechanism is not known yet. ROS and antioxidant enzymes are novel targets for developing anti-cancer therapeutics. In this review, the current understanding for redox regulation of cancer cells and neoplastic stem cells as well as the role and function of anti-oxidant enzymes and molecules is discussed.
Subject(s)
Antioxidants , Cell Proliferation , Cell Transformation, Neoplastic , DNA , Hand , Neoplastic Stem Cells , Oxidation-Reduction , Oxidative Stress , Phenotype , Reactive Oxygen SpeciesABSTRACT
Natural killer (NK) cells play key roles in innate and adaptive immune defenses. NK cell responses are mediated by two major mechanisms: the direct cytolysis of target cells, and immune regulation by production of various cytokines. Many previous reports show that the complex NK cell activation process requires de novo gene expression regulated at both transcriptional and post-transcriptional levels. Specialized un-translated regions (UTR) of mRNAs are the main mechanisms of post-transcriptional regulation. Analysis of post-transcriptional regulation is needed to clearly understand NK cell biology and, furthermore, harness the power of NK cells for therapeutic aims. This review summarizes the current understanding of mRNA metabolism during NK cell activation, focusing primarily on post-transcriptional regulation.
Subject(s)
Biology , Cytokines , Gene Expression , Killer Cells, Natural , RNA, MessengerABSTRACT
BACKGROUND: Molecular mechanisms of natural killer (NK) cell development from hematopoietic stem cells (HSCs) have not been clearly elucidated, although the roles of some genes in NK cell development have been reported previously. Thus, searching for molecules and genes related NK cell developmental stage is important to understand the molecular events of NK cell development. METHODS: From our previous SAGE data-base, Gpnmb (Glycoprotein non-metastatic melanoma protein B) was selected for further analysis. We confirmed the level of mRNA and protein of Gpnmb through RT-PCR, quantitative PCR, and FACS analysis. Then we performed cell-based ELISA and FACS analysis, to know whether there are some molecules which can bind to Gpnmb. Using neutralizing antibody, we blocked the interaction between NK cells and OP9 cells, and checked IFN-gamma production by ELISA kit. RESULTS: Gpnmb expression was elevated during in vitro developmental stage and bound to OP9 cells, but not to NK precursor cells. In addition, we confirmed that the levels of Gpnmb were increased at NK precursor stage in vivo. We confirmed syndecan4 as a candidate of Gpnmb's binding molecule. When the interaction between NK cells and OP9 cells were inhibited in vitro, IFN-gamma production from NK cells were reduced. CONCLUSION: Based on these observations, it is concluded that Gpnmb has a potential role in NK cell development from HSCs.
Subject(s)
Antibodies, Neutralizing , Enzyme-Linked Immunosorbent Assay , Hematopoietic Stem Cells , Killer Cells, Natural , Melanoma , Polymerase Chain Reaction , RNA, Messenger , Syndecan-4ABSTRACT
In the early host defense system, effector function of natural killer (NK) cells results in natural killing against target cells such as microbe-infected, malignant, and certain allogenic cells without prior stimulation. NK cell cytotoxicity is selectively regulated by homeostatic prevalence between a repertoire of both activating and inhibitory receptors, and the discrimination of untransformed cells is achieved by recognition of major histocompatibility complex (MHC) class I alleles through inhibitory signals. Although it is well known that the bipotential T/NK progenitors are derived from the common precusor, functional mechanisms in terms of the development of NK cells remain to be further investigated. NK cells are mainly involved in innate immunity, but recent studies have been reported that they also play a critical role in adaptive immune responses through interaction with dendritic cells (DC). This interaction will provide effector functions and development of NK cells, and elucidation of its precise mechanism may lead to therapeutic strategies for effective treatment of several immune diseases.
Subject(s)
Adaptive Immunity , Alleles , Dendritic Cells , Discrimination, Psychological , Homicide , Immune System Diseases , Immunity, Innate , Killer Cells, Natural , Major Histocompatibility Complex , PrevalenceABSTRACT
BACKGROUND: The pathogenesis of transition from viral myocarditis to dilated cardiomyopathy is elusive, although the incidence of dilated cardiomyopathy in human is increasing. METHODS: To clarify the role of the tissue inhibitor of matrix metaloproteinase-2 (TIMP-2) in this event, we performed immunohistochemistry, immunoblotting and immunoassay of matrix metalloproteinase-9 (MMP-9) and TIMP-2 in the serum and heart tissue of mice, which were inoculated with 4000 plaque-forming units of coxsackie B virus. RESULTS: The MMP-9 was expressed in damaged cardiomyocytes, and the TIMP-2 was expressed in mainly interstitial connective tissue between cardiac muscle bundles by immunohistochemistry. The level of serum MMP-9 was higher in the complicated than non-complicated group (p<0.001), but the level of TIMP-2 was much lower in complicated than non-complicated group (p<0.05). These findings were similar to the results of immunohistochemistry and immunoblotting in tissues. CONCLUSIONS: These results suggest that an imbalance in the level of MMP-9 and its inhibitor might activate cardiac complication in viral myocarditis.