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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neoplastic transformation is one possible consequence of genomically disturbed intracellular feedback mechanisms normally governing life, differentiation, function and death of an individual cell. Neoplastic growth can be thought of as the abnormal activation of the mitotic program and/or the inactivation of programs for growth-inhibition and apoptosis. This article reviews the current knowledge on three types, or families, of proteins that act on different levels of subcellular organization and are involved in controlling the integrity of the genome, survival and death: i) the DNA-binding nuclear protein p53 inducing cell cycle arrest and apoptosis, ii) the bcl-2 family of proteins acting as regulators of prolonged survival and programmed cell death and iii) APO-1/Fas, a cell surface receptor transducing an apoptotic signal delivered either by the cell itself (cis death) or by another cell (trans death). Although much is still unknown, especially concerning the functional linkages of these three principles, the data available allow a fascinating insight into the society of cells, which we are, after all.
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PMID:Pathophysiological aspects of tumor development. 748 52

The bcl-2 protooncogene encodes a 26-kD protein that extends cell survival by blocking apoptosis. This protein has been found to be overexpressed in neoplastic neural cell lines, although its expression in reactive and neoplastic astrocytes in vivo has not been well characterized. The authors hypothesized that bcl-2 oncoprotein expression in gliomas might be positively correlated with the tumor's degree of malignancy. Sixty-three gliomas of various subtypes and histological grades were immunostained by bcl-2 protein and the percentage of positive cells was quantitatively assessed. All tumors contained neoplastic cells that were immunoreactive for the bcl-2 protein (range of cell positivity 1%-53%). It was found that bcl-2 expression did not vary significantly as a function of tumor subtype or grade (p < 0.1, one-way analysis of variance (ANOVA) on ranks) as compared to the cell proliferation marker Ki-67 (MIB-1) in which a very significant correlation with tumor grade was noted (p < 0.0000001, one-way ANOVA on ranks). In fact, the highest percentage of bcl-2 immunoreactive cells was noted in low-grade gliomas, that is, in juvenile pilocytic astrocytomas and oligoastrocytomas. The specificity of bcl-2 overexpression was also assessed in 10 nonneoplastic lesions associated with prominent reactive astrocytosis. In nine of these cases (90%), bcl-2-positive reactive astrocytes were observed, often in large numbers, whereas relatively few Ki-67 immunoreactive cells were noted. The authors conclude that bcl-2 oncoprotein expression as assessed immunohistochemically does not correlate with glial tumor type or grade and its overexpression is not confined only to neoplastic conditions. Instead, the finding of robust bcl-2 expression in low-grade glial tumors and in reactive astrocytes warrants the inference that resistance to apoptosis is a nonspecific finding in astrocytes associated with both reactive and neoplastic conditions.
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PMID:Expression of bcl-2 in reactive and neoplastic astrocytes: lack of correlation with presence or degree of malignancy. 749 Jun 15

Custom-made monoclonal anti-idiotype antibodies (anti-Id MoAbs) have been tested as a treatment modality in 34 non-Hodgkin's lymphoma (NHL) patients. Partial or complete tumor remissions have been induced with this treatment in 68% of these patients. One mechanism by which anti-idiotype antibodies may have induced these tumor responses is via a direct antiproliferative effect on the tumor cells, resulting in apoptosis. Primary NHL cells do not proliferate well enough in vitro to test this hypothesis directly. Therefore, we studied the effect of anti-idiotype antibodies on signal transduction through the surface Ig receptor as measured by the induction of cellular protein tyrosine phosphorylation. To assess whether bcl-2 protein could protect lymphoma cells from death induced by anti-Id MoAb, we also measured the level of bcl-2 protein in the same tumor cells. We found a strong correlation between the ability of an anti-Id MoAb to induce an increase in tyrosine phosphorylation in vitro and its ability to induce a tumor regression in the patient. By contrast, the level of bcl-2 expressed by the tumor cells was not correlated with clinical response to anti-Id MoAb treatment.
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PMID:Lymphoma regression induced by monoclonal anti-idiotypic antibodies correlates with their ability to induce Ig signal transduction and is not prevented by tumor expression of high levels of bcl-2 protein. 750 10

The expression of bcl-2 and p53 was investigated by immunocytochemistry in combination with that of conventional structural and differentiation antigens on the archival material of 22 cases of undifferentiated carcinoma (UC) and 19 of poorly differentiated carcinoma (PDC) of the thyroid gland. The restriction of bcl-2 expression to PDC in comparison to UC was 84.2% versus 13.6% of cases, respectively, in contrast to an almost equal percentage of p53 expression in the two histologic types, that is, 52.6% and 54.5% of cases of PDC and UC, respectively. However, the pattern of distribution of p53-immunoreactive cells was definitely different, being restricted to areas showing active infiltrating growth in PDC and involving almost all tumor cells in UC. Furthermore, in the subset of cases of UC showing the residual presence of a differentiated component, a distinctive mutual exclusion of bcl-2 and p53 immunoreactivity was observed in the two components. The results suggest that the evaluation of bcl-2 expression may be usefully applied to the differentiation of PDC from UC, whereas all morphologic findings related to p53 expression are in keeping with a significant role of the deregulation of this gene in the mechanism of dedifferentiation and progression of the disease.
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PMID:A novel panel of antibodies that segregates immunocytochemically poorly differentiated carcinoma from undifferentiated carcinoma of the thyroid gland. 752 12

Angiotropic lymphoma is a rare, aggressive, intravascular non-Hodgkin's lymphoma, usually of B-cell phenotype. Because lymphoma is often clinically unsuspected, the small skin or muscle biopsies typically obtained for evaluation make assessment of lymphoid clonality through cell surface markers or Southern blot hybridization analysis difficult or impossible. The recent development of polymerase chain reaction methodologies to detect chromosomal translocations and immunoglobulin heavy chain gene rearrangement on paraffin-embedded tissue offers an attractive alternative for ascertaining the clonality of lymphoproliferative processes. We report a case of B-cell angiotropic lymphoma in which a monoclonal variable diversity joining region rearrangement of the immunoglobulin heavy chain locus was detected by polymerase chain reaction in both ante- and postmortem, formalin-fixed, paraffin-embedded skeletal muscle. The use of polymerase chain reaction in assessing clonality in angiotropic lymphoma is enhanced by the general absence of a background of reactive B-lymphoid cells in angiotropic lymphoma, which can obscure the monoclonal band and/or compromise sensitivity. No amplification product was obtained for t(14;18) involving the bcl-2 major breakpoint region. It is interesting to note that this case exhibited rare circulating lymphoma cells and more extensive bone marrow involvement (more than 100 tumor cells/high magnification field) than has been previously described.
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PMID:Intravascular (angiotropic) large cell lymphoma: determination of monoclonality by polymerase chain reaction on paraffin-embedded tissues. 752 70

Murine monoclonal antibody (mAb) 7C11 binds to the same cell surface epitope as anti-APO-1 and anti-Fas and reacts specifically with cells transfected with a cDNA encoding the human Fas antigen. Furthermore, incubation with 7C11 causes death of hematopoietic cell lines that express APO-1/Fas but not APO-1/Fas-negative cell lines. 7C11 therefore recognizes the human APO-1/Fas (CD95) antigen, a 40 to 50 kDa cell surface glycoprotein that can trigger apoptosis or programmed cell death. Expression of APO-1/Fas antigen by normal and neoplastic hematopoietic cells was determined by flow cytometry using 7C11. APO-1/Fas is expressed by approximately 30 to 40% of resting peripheral blood T cells, B cells, and monocytes and by approximately 5% of resting NK cells and thymocytes. It was not detected on granulocytes, erythrocytes, or platelets. Approximately 80 to 90% of activated T cells, B cells, and thymocytes express APO-1/Fas, as do the majority of activated NK cells. Perturbation of APO-1/Fas by 7C11 does not affect the viability of resting lymphocytes or monocytes. In contrast, activated T cells and NK cells undergo apoptosis within 3 hours of exposure to 7C11. Other mAb that stimulate T cells or NK cells do not cause rapid induction of programmed cell death. APO-1/Fas antigen is expressed by many cell lines of lymphoid and myeloid lineage. However, this antigen was detected on neoplastic cells from only one of 69 patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, or multiple myeloma. Only 3 out of 25 tumor samples from patients with non-Hodgkin's lymphoma were found to express APO-1/Fas. All three of these lymphomas harbored the bcl-2-Ig fusion gene associated with the chromosomal translocation t (14;18). Conversely, only 27% of lymphomas that possessed the bcl-2-Ig gene were found to express the APO-1/Fas antigen. Like normal activated lymphocytes, leukemia and lymphoma cells that expressed APO-1/Fas antigen were found to undergo apoptosis in vitro after incubation with 7C11. The APO-1/Fas antigen appears to regulate the growth of normal hematopoietic cells, and the marked upregulation of this antigen on activated normal lymphocytes contrasts sharply with the absence of APO-1/Fas on neoplastic cells of hematopoietic lineage. Defects in the apoptotic signal delivered through this antigen might contribute to the pathogenesis of hematopoietic neoplasms. Thus, the gene encoding APO-1/Fas can be considered a novel type of tumor suppressor gene, just as bcl-2 can be considered a cellular proto-oncogene.
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PMID:Functional consequences of APO-1/Fas (CD95) antigen expression by normal and neoplastic hematopoietic cells. 753 60

Tumor necrosis factor (TNF) induces cel death in several tumor cell lines by undefined mechanisms. Using a cDNA expression cloning strategy we identified two cDNAs that completely inhibit the TNF-induced death pathway in MCF7 breast carcinoma cells. These cDNAs encoded for Bcl-2 and Bcl-x. To compare the cytotoxic signal transduction pathway induced by the TNF receptor versus that induced by Fas, we transfected MCF7 cells with a Fas expression construct. The resulting cell line, MCF-Fas, was highly sensitive to cytotoxicity induced by TNF or anti-Fas. Expression of either bcl-2 or bcl-x in these cells rendered them completely resistant to lysis induced by either TNF or Fas. Interestingly, exposure of MCF-Fas cells to anti-Fas or TNF induced activation of phospholipase A2 (PLA2), while only TNF activated NF-kappa B. Activation of PLA2 was completely blocked whereas activation of NF-kappa B was unaffected by overexpression of either bcl-x or bcl-2. Moreover, PLA2-inhibitors, quinacrine and dexamethasone, partially inhibited cytotoxicity induced by either TNF or anti-Fas. These data suggest an involvement of PLA2 in both TNF- and Fas-mediated cytotoxicity and a novel mechanism of action for bcl-2 and bcl-x, i.e. inhibition of arachidonic acid metabolism, by which they may, in addition of apoptosis, modulate inflammation.
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PMID:Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells. 754 Feb 78

Hypothetical Products from Noncoding Frames (i.e., HyPNoFs) are hypothetical, not-coded proteins, translated from alternate reading frames (i.e., coding + 1 and coding + 2) of cDNAs. HyPNoFs of CD4, PKC, oncostatin, bcl-2 proto-oncogene, tumor suppressor p53, cystic fibrosis transmembrane regulator (CFTR), and tumor necrosis factors alpha and beta were searched as query sequences vs the SWISS-PROT data bank. Homology searchers carried out revealed that hypothetical products (i.e., HyPNoFs) may share high similarity with real protein products actually coded. Sequence similarity of hypothetical products to real proteins is sometimes very high, suggesting common conformational features, according to the Sander and Schneider cutoff value. This finding supports the hypothesis that eukaryotic DNA, currently considered to be monocistronic, might occasionally have polycistronic regions, carrying different protein messages on overlapping frames. As yet, polycistronic genes have been observed in viral genomes only. The presence of polycistronic regions in eukaryotic genes is likely reminiscent of an ancient strategy, rather than a present feature of the genome in eukaryotes. These data suggest that thorough investigation of HyPNoFs is likely to improve our ability to trace genes' evolution and to investigate structure-function relationships of protein and DNA sequences.
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PMID:Investigating hypothetical products from noncoding frames (HyPNoFs). 754 50

The tumor suppressor gene p53 regulates G1 checkpoint prior to the initiation of DNA synthesis, which can either induce G1 arrest or signal apoptosis. The involvement of p53 in apoptosis may also be related to its ability to down-regulate transcription of the bcl-2 gene. The bcl-2 gene product prevents most types of apoptotic cell death, suggesting that bcl-2 interferes with an essential signaling molecule involved in the apoptotic cell death pathway. Although the bcl-2 protein is shown to be overexpressed in many types of human tumor including breast cancer, its biochemical or pathological consequences are poorly understood. To determine the effects of bcl-2 overexpression on apoptosis and transformation of breast epithelial cells and to investigate whether bcl-2 interferes with the p53 pathway, we introduced the bcl-2 expression vector into MCF10A cells, which were derived from diploid human breast epithelial cells containing the wild-type p53 gene. Overexpression of bcl-2 prevented free radical-induced apoptosis and induced a partially transformed phenotype in MCF10A cells. Although overexpression of bcl-2 did not affect the expression of the p53 gene, p53-dependent gene transcription such as p21WAF1/CIP1 was suppressed. These results suggest that bcl-2 may inhibit p53 functional activity and is involved in the regulation of an early commitment step either to proliferate or suicide.
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PMID:bcl-2 suppresses expression of p21WAF1/CIP1 in breast epithelial cells. 755 20

Recent evidence suggests that resistance to antineoplastic therapy may result from mutations in genes mediating the apoptotic response to DNA damage. To determine the effects of epigenetic changes on tumor responsiveness to cytotoxic agents inducing DNA damage, we examined the chemosensitivity of neuroblastoma (NB) after differentiation by retinoic acid (RA). Differentiation of the cell lines SH-SY5Y and SMS-KCNR by RA abolished the cytotoxic effects of adriamycin (Adr) and cisplatin. Chemoresistance was not the result of decreased proliferation induced by RA because: (a) growth arrest by nutrient deprivation did not affect sensitivity; (b) growth arrested NB cell lines, which did not differentiate, remained chemosensitive; and (c) RA concentrations which promoted differentiation without affecting growth, induced resistance. Apoptosis characterized NB cells responding to Adr, although differentiated SH-SY5Y did not apoptose and were resistant to Adr and cisplatin. Marked induction of bcl-2 in NB cells followed RA-induced differentiation, whereas in cell lines failing to differentiate, bcl-2 was not detected. Our data indicate that NB differentiation induces drug resistance after a loss of the apoptotic response to antineoplastic drugs and suggest that bcl-2 overexpression is an important mechanism of resistance in differentiated tumor cells.
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PMID:Differentiation of neuroblastoma enhances Bcl-2 expression and induces alterations of apoptosis and drug resistance. 755 53


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