Lactate dehydrogenase (LDH) among many biochemical parameters represents a very valuable enzyme in patients with cancer with possibility for easy routine measurement in many clinical laboratories. Previous studies where mostly based on investigated LDH in serum of patients with cancer with aims to estimate their clinical significance. The new directions in investigation of LDH where based on the principle that tumor cells release intracellular enzymes trough damaged cell membrane, that is mostly consequence in intracellular mitochondrial machinery alteration, and apoptosis deregulation. This consideration can be used not only in-vitro assays, but also in respect to clinical characteristics of tumor patients. Based on new techniques of molecular biology it is shown that intracellular characteristics of LDH enzyme are very sensitive indicators of the cellular metabolic state, aerobic or anaerobic direction of glycolysis, activation status and malignant transformation. Using different molecular analyses it is very useful to analyzed intracellular LDH activity in different cell line and tumor tissues obtained from patients, not only to understanding complexity in cancer biochemistry but also in early clinical diagnosis. Based on understandings of the LDH altered metabolism, new therapy option is created with aims to blocking certain metabolic pathways and stop tumors growth.
Natural killer cells, as an important subpopulation of cells of the innate immune system have an essential role in defense of the rise and spread of malignancy. These cells have a CD3-CD16 + CD56+ phenotype and they are functionally defined by their ability to lyses tumor cells. We here show that decrease of NK cell activity was significantly associated with advanced clinical stage, increased lactate dehydrogenase (LDH), percentage infiltration of bone marrow with plasma cells, and beta-2 microglobulin. The patients with higher NK cell activity at presentation after receiving VAD protocol have better cumulative survival in comparison with those with low NK cell activity.
NK cells have become a subject of investigation not only in the field of tumor immunology and infectious diseases, but also within all aspects of immunology, such as transplantation, autoimmunity, and hypersensitivity. Our early studies aside from investigating NK cell activity in experimental animals and humans included studies of perforin expression and modulation in this lymphocyte subset. As NK cell activity is modified by their environment, we showed clinical stage-dependent impairment of their activity and in vitro effect of different sera, Th1 cytokines, and their combination in breast cancer, Hodgkin's disease, and non-Hodgkin's lymphoma patients, especially with respect to metabolic and cell membrane changes of peripheral blood lymphocytes evaluated by spontaneous release of the enzyme lactate dehydrogenase (LDH) that led to the correction of the LDH enzyme release assay for natural cytotoxicity. By long-term immuno-monitoring of patients with malignancies, we also showed the kinetics of NK cell modulation during chemo-immunotherapy. In our more recent studies, we give data of NK function and novel families of NK cell receptor expression in healthy individuals that may be of help in NK cell profiling, by giving referent values of basic and cytokine-induced expression of some NK cell receptors either in evaluation of disease or in immuno-monitoring during cytokine therapy of patients with malignancies. Moreover, we give novel aspects of modulation of NK cell activity by cytokines approved for immunotherapy, IFN and IL-2, in melanoma and other malignancies with respect to alterations in new activating (NKG2D and CD161) and inhibitory (CD158a and CD158b) receptor characteristics and signaling molecules in CD16- and CD56-defined NK cells and their small immunoregulatory and large cytotoxic subsets in peripheral blood and lymph nodes, as NK cell-mediated killing of tumor cells depends on the balance between stimulatory and inhibitory signaling.
TNF-α can induce cell death (apoptosis and necrosis), and these effects mostly depend on expression of TNF-receptor superfamily molecules. As determination of certain intracellular enzymes like LDH, released from cultured tumor cells, reflects early membrane alterations, we compared LDH release with changes in cell surface membrane molecule expression during culture of K-562 cells in the presence of TNF-α. TNF-α-mediated CD45 and CD30 shedding is shown to be to be time- and dose-dependent and associated with significant increase in LDH release, with maximal effects after 24 h of treatment. The percentage of decrease of all examined cell surface molecules on K-562 cells after TNF-α treatment was not uniform and appeared to depend on the respective constitutive level of expression and molecule type. The presence of these molecules was confirmed in supernatants using Western blot analyses. These results indicated the complexity of events on the cell membrane, including early LDH release that is associated with a difference in shedding of CD30 and CD45. Shedding of CD30 occurs before apoptosis induction, while shedding of CD45 is associated with apoptosis.
The aim of this study was to investigate the presence of mast cells in a series of odontogenic tumors. Forty-five cases of odontogenic tumors were investigated using immunohistochemistry for mast cell triptase, and differences between groups were statistically evaluated. Mast cells were present in 96% of odontogenic tumors. Mast cells present in solid ameloblastoma were observed in the tumor stroma surrounding more solid and follicular epithelial islands, with or without squamous metaplasia. The odontogenic mixoma showed few mast cells. In odontogenic tumors with a cystic structure, the mast cells were distributed throughout all areas of the lesions, mainly in keratocystic odontogenic tumor. In addition, the total density of mast cells between all odontogenic tumors showed no significant difference (p> 0.05). A greater mast cells distribution was found in keratocystic odontogenic tumor in relation to adenomatoid odontogenic tumor (p < 0.01), and when the unicystic ameloblastoma and keratocistic odontogenic tumor were compared to the odontogenic myxoma (p < 0.05). Syndrome keratocystic odontogenic tumor showed a higher mean of mast cells when compared with the other tumors of the sample. Mast cells values presented by syndrome keratocystic odontogenic tumor were significantly greater than those of the sporadic keratocystic odontogenic tumor that were not associated with the syndrome (p = 0.03). Mast cells are probably one of the major components of the stromal scaffold in odontogenic tumors. We found significant differences of mast cells between syndrome nonsyndrome keratocystic odontogenic tumors, although their distribution did not seem to have any influence on the biologic behavior of benign odontogenic tumors.
The cytotoxic activity of NK (natural killer) cells is very important in immunological surveillance against the appearance and especially the spread of malignant disease. The aim of this study was to investigate the function of this subpopulation of cells in breast cancer patients in different clinical stages of disease prior to therapy. NK cell activity was determined in breast cancer patients and healthy controls by three different methods: standard 51-chromium-release assay and by the original colorimetric uncorrected and corrected lactate dehydrogenase (LDH) release assay. A discrepancy was shown between the assays, as the uncorrected LDH assay showed, not only, much higher values, but no stage-dependent depression in NK cell activity compared to the chromium-release assay. Further analyses of separately cultured peripheral blood lymphocytes (PBL) revealed that this difference arose from an increasing, clinical stage-dependent, spontaneous LDH release from PBL of breast cancer patients. Furthermore, a stage-dependent increase in intracellular LDH activity of PBL was found, although without difference in LDH-H and LDH-M isotype ratio, compared to controls. Increased spontaneous LDH release and intracellular LDH activity was more evident in young patients, under 40 years. Correction of the original LDH-release assay for the spontaneous LDH release activity from PBL present in the assay, gave values of NK cell activity comparable to those determined by the chromium assay and indicated that breast cancer patients have a significant depression in NK cell activity which correlates with the stage-dependent increase in spontaneous LDH release. Moreover, as both assays measure the secretory, perforin-mediated, NK cell cytotoxic pathway against tumor cells, it can be concluded that the appearance of spontaneous LDH release is an indicator of cell membrane damage which not only allows the loss of LDH, but also of the components of the secretory killing pathway, resulting in NK cell dysfunction with the progression of disease. The novel findings obtained in this work reveal the association of PBL membrane damage with clinical stage of breast cancer that can, aside from reflecting NK cell depression, underlie the defect in other PBL subsets and subsequently facilitate progression of the malignant process.
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