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Quantitative reduction in the RNP-contents of lymphocytes as a tool for early cancer diagnostics
Quantitative reduction in TIL RNP-content in cancer as possible sign of RNAi
Cancer-induced reduction in TIL cytoplasmic RNP - a sign of thymocyte apoptosis?
Reduction in the RNP-contents of human T-lymphocytes in malignancies and viral diseases
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Elissaveta B. Zvetkova, Assoc. prof., MD, Ph.D. Institute of experimental morphology and anthropology - BAS, 1113 - Sofia, Bulgaria
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ezvetkova{at}hotmail.com Elissaveta B. Zvetkova, et al.
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Dear Editor, Several reports have described the detection of circulating, cancer related RNA molecules in serum or plasma from cancer patients and their potential as a tool for cancer diagnostics (1), but little is known about the biology of RNA/RNP of tumour-infiltrating lymphocytes (TIL). We have previously reported (2 - 4; 6,7) that some cytochemical features with regard to the quantity and distribution of nucleoproteins (RNP and DNP) in different T-lymphocyte populations from the peripheral blood of cancer patients and tumour-bearing animals could be precise criteria for early diagnosis and determining the course and prognosis of neoplastic disease. Our opinion is that the reduction (mainly by clasmatoses) and the uneven distribution of cytoplasmic RNP in the peripheral blood T-lymphocytes of cancer patients and tumour-bearin animals are first cytochemical signs or early cytological signals of tumour-induced apoptosis in these cells. The results obtained could encourage further investigations regarding TIL RNA/RNP. Although our hypothesis should be examined by further biochemical experiments, it is important to elucidate the detection of circulating, TIL-related different RNA molecules in serum or plasma from cancer patients in different stages of the disease; the characteristics of these circulating extracellular RNAs as a morphological sign of transcriptional arrest during TIL apoptotic cell death(5); and their eventual potential as a tool for early cancer diagnostics (2 - 4). We suggest that some reorganization of TIL RNP- containing structures [involving positive changes in their antitumour resistance upon lymphocyte/tumour cells adhesion (4) under the influence of drugs, plant extracts etc. (6 - 8)] could be important in cancer prevention and therapy. REFERENCES: 1. Tafal El-Hefnawy et al. Characterization of amplifiable, circulating RNA in plasma and its potential as a tool for cancer diagnostics. Clinical Chemistry 50, 2004, 564 - 574. 2. Zvetkova, E., S. Koshucharov, A. I. Hadjioloff. Cytochemistry of nucleoproteins RNP and DNP)and some cationic proteins in the peripheral blood leucocytes of patients with lung cancer. Folia Haematol., 106/2, 1979, 205 - 223. 3. Zvetkova E., G. Kostov, A. I. Hadjioloff, I. Zvetkov. Sur la cytochimie des leucocytes chez les cancereux et les precancereux. Arch. Union Med. Balk., XX/1-2, 1984, 140 - 142. 4. Zvetkova E., G. Kostov. Microdensitometrical studies on tumour-induced programmed cell death of peripheral blood tumour-infiltrating lymphocytes (TIL) in cancer patients: possible application for early tumour diagnosis. Acta morphologica et anthropologica (Sifia) 5, 2000, 3 - 10. 5. Biggiogera M., C. Pellicciary. Heterogeneous ectopic RNP-derived structures(HERDS) are markers of transcriptional arrest. The FASEB Journal., 14, 2000, 828 - 843. 6. Zvetkova E., et al. Protective effect of ranopterin neopterin on experimentally induced Graffi tumours in hamsters. Pteridines 9, 1998, 196 - 200. 7. Zvetkova E., B. Wirleitner, N.T. Tram, H. Schennach, D. Fuchs. Aqueous extracts of Crinum latifolium (L.) and Camellia sinensis show immunomodulatory properties in human peripheral blood mononuclear cells. International Immunopharmacology, 1/12, 2001, 2143 - 2150. 8. Bhattacharyya, A., M. Debaprasad, L. Lahiry, G. Sa, T. Das. Black tea protects immunocytes from tumor-induced apoptosis by changing Bcl-2/Bax ratio. Cancer letters, 209/2, 2004, 147 - 154. |
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Elissaveta B. Zvetkova, Assoc. prof., MD, Ph.D. Institute of experimental morphology and anthropology with museum - BAS, Georgi Kostov
Send letter to journal:
ezvetkova{at}hotmail.com Elissaveta B. Zvetkova, et al.
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Dear Editor, We have previously described a quantitative reduction and uneven distribution of cytoplasmic RNP in the peripheral blood lymphocytes of cancer patients as a tool for early cancer diagnostics (1). Our explanation is that the changes in the cytoplasmic RNP content of the circulating tumour-infiltrating T lymphocytes (TIL) of cancer patients and tumour-bearing animals are early cytological signals of tumour-induced apoptosis in these cells. Additionally, it was determined (2, 3) that tumours can induce impaired cytolytic activity and apoptosis in peripheral blood T cells (tumour-infiltrating T lymphocytes) from carcinoma patients and subdue any antitumour host immune response. We supposed that the reduction and cytochemical reorganization of cytoplasmic RNP-containing structures in TIL could be related to the release of RNP-complexes from human T lymphocytes as an early marker of the transcriptional arrest. Our first cytochemical data (4) demonstrated capacity of the same T lymphocyte subpopulation to secrete its cytoplasmic RNP-containing granules (often by microclasmatoses) to the tumour cell membranes and vice-versa. On the delivery and interference between both cells’ RNP granules, the cytoplasmic RNP in the tumour cells and lymphocytes remained unstained (“destroyed”) only in places of cell-to- cell contacts. In some cases RNP-containg cytoplasmic protrusions (clasmatoses) form intercellular structures - “RNP-bridges” between T lymphocytes and tumour (target) cells. The precise molecular mechanisms of lymphocyte-mediated tumour cell lysis and tumour cell-mediated lymphocyte programmed cell death, remain unclear: a possible influence of cytolytic proteins – perforin, integrins and several proteases or other biologically active substances (granulysin), involving changes in the cellular plasma membrane permeability and a secondary cytoplasmic and nuclear damage, has been elucidated in the scientific literature (5, 6). The cytochemical and ultrastructural results obtained (4) provide evidence that the process of double stranded RNA interference (dsRNAi; siRNAi) between tumour cells and TIL population upon lymphocyte/tumour cell conjugation and adhesion should be also investigated. Recently siRNAs have been used extensively to silence the expression of target genes in mammalian cells (7). The mechanism of small interfering RNA (siRNA) mediated RNA interference (RNAi) involves target mRNA cleavage and destruction in the cytoplasm, which may be of value for adoptive cellular therapy by transduction with small interfering RNAs. Recent report (8) described a possible therapeutic role for these molecules in lentiviral-mediated siRNA delivery into primary T cells. The first successful attempt to transfect siRNAs mediating gene silence in T lymphocytes has been also performed (9). Moreover, the phenomenon, known as RNA interference (RNAi), has not been yet thoroughly demonstrated at the cytological/cytochemical and ultrastructural levels in the lymphocytes as well as in cases of tumour target cell lysis by cytotoxic T lymphocytes (TIL). We hypothesized that impaired TIL cytolytic activity possibly caused by a subset of tumour siRNAs occurs in the peripheral blood T cells of cancer patients. References 1. Zvetkova E., et al.. Quantitative reduction in the RNP-contents of lymphocytes as a tool for early cancer diagnostics. Clinical Chemistry – eLetter for El-Hefnawy et al., 50/3, 564 - 573 2. Crocenzi T.S., et al. Impaired cytolytic activity in peripheral blood T cells from renal cell carcinoma patients. Clin. Immunol., 2005 (Paper in press) . 3. Dotti G., et al. Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. Blood, 105/12, 2005, 4677 – 4684 4. Zvetkova E., G. Kostov. Microdensitometrical studies on tumour- induced programmed cell death of peripheral blood tumour-infiltrating lymphocytes (TIL) in cancer patients: possible application for early tumour diagnosis. Acta morphologica et anthropologica (Sofia), 5, 2000, 3 – 10 5. Podack, E. R. Killer lymphocytes and how they kill. Current Opinion in Cell Biology, 1, 1989, 929 – 933 6. Clayberger C. and A.M.Krensky. Granulysin. Current Opinion in Immunology, 15/5, 2003, 560 – 565 7. Robb GB., KM Brown, J. Khurana, T.M.Rana. Specific and potent RNAi in the nucleus of human cells. Nat Struct Mol Biol., 12/2, 2005, 133 – 137 8. Qin, X-F., D.S. An, ISY Chen, D. Baltimore. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA 100/1, 2003, 183 - 188 9. McManus M.T., et al. Small interfering RNA-mediated gene silencing in T lymphocytes. J. Immunol 169, 2002, 5754 – 5760 |
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Elissaveta B. Zvetkova, Assoc. prof., MD, PhD IEMAM - BAS, Georgi Kostov
Send letter to journal:
ezvetkova{at}hotmail.com Elissaveta B. Zvetkova, et al.
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Dear Editor, We have previously proposed that the quantitative reduction and uneven distribution of cytoplasmic RNP in the peripheral blood T-lymphocytes of cancer patients (probably tumor-infiltrating T-lymphocytes - TILs), could be cytochemical signals of tumor-induced TIL apoptosis and a tool for early diagnosis of malignancies [1, 2]. A recent study [3] demonstrated that down-regulation of T cell-mediated immune functions in cancer patients may be related to tumor-induced thymocyte apoptosis and thymic involution. Derivatives of thymic hormones (mainly thymosins) have been employed in the early diagnosis of neoplasia [4]. We would like to update our previous opinion [1]suggesting that the reduced cytoplasmic TIL RNP-content in cancer patients could be also an early sign of tumour-induced thymocyte apoptosis and thymic involution. Interestingly, we and other authors working in this field [1,3] suppose that positive changes in TIL- and thymocyte antitumour resistance could be obtained under the influence of some plant extracts (i.e. black tea, etc.). References: [1] Zvetkova E., et al. Quantitative reduction in the RNP-content of lymphocytes as a tool for early cancer diagnostics. Clinical Chemistry - eLetter for El-Hefnawy et al., 50/3, 2004, 564-573. [2] Zvetkova E., G. Kostov. Quantitative reduction in TIL RNP-content in cancer as possible sign of RNAi. Clinical Chemistry - eLetter for El- Hefnawy et al., 50/3, 2004, 564-573. [3] Mandal D., L. Lahiry, A. Bhattacharyya, S. Bhattacharyya, G. Sa, T. Das. Tumor-induced thymic involution via inhibition of IL-7Ra and its JAK- STAT signaling pathway: Protection by black tea. Int. Immunopharmacol., 6/3, 2006, 433-444. [4] Bodey B. Jr., B. Bodey, Jr., S. E. Siegel, H. E. Kaiser. Review of thymic hormones in cancer diagnosis and treatment. Int. J. Immunopharmacol., 22/4, 2000, 261-273. |
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Elissaveta B. Zvetkova, Asooc. Prof. IEMAM - BAS, Sofia
Send letter to journal:
ezvetkova{at}hotmail.com Elissaveta B. Zvetkova
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Dear Editor, We described a quantitative decrease in the RNP-amount of spontaneously apoptotic T-lymphocytes in both - malignancies (1 - 3) and viral diseases (1). In both cases the reduction of cellular RNP-contents in T-cells could be linked to the extracellular extrusion and release of ribonucleoproteins (RNPs) by cytoplasmic blebs and microclasmatoses (1 - 3). Further investigations could elucidate whether these early apoptotic events in T-lymphocytes of cancer and leukemia patients might be due to viral/retroviral infection (4, 5). REFERENCES |
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