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

Transgenic mice bearing an oncogene targetted for expression in a specific tissue can reveal how that oncogene influences differentiation and help to delineate the pathways to malignancy. To explore lymphoid neoplasia, we have made strains of transgenic mice bearing different oncogenes driven by the immunoglobulin heavy chain enhancer (E mu), which promotes expression within lymphocytes and certain myeloid cells. The prototype E mu-myc mice succumb to pre-B and B cell lymphomas, following a preneoplastic phase in which cycling pre-B cells are overproduced. The similar fate of E mu-N-myc mice suggests that N-myc and myc have overlapping functions. Surprisingly, E mu-N-ras mice develop T lymphomas and macrophage tumours but no B lineage tumours; thus the ability of ras to initiate tumorigenesis may be lineage specific. Similarly, the high predisposition of E mu-v-abl mice to develop plasmacytomas may indicate that v-abl is oncogenic only at certain stages of B cell maturation. The bcl-2 gene promotes cell survival rather than proliferation, and E mu-bcl-2 mice produce copious resting B lymphocytes. The random onset and monoclonality of tumours in the transgenic strains argues for spontaneous genetic alterations that cooperate with the trans-oncogene. Indeed, most plasmacytomas of E mu-v-abl mice bear spontaneous myc rearrangements. Moreover, a minority of E mu-myc B lymphomas exhibit ras mutation, and the tumorigenesis can be reconstructed by crossing E mu-myc and E mu-ras mice, or by retroviral delivery of v-ras or v-raf, either in vitro or in vivo. To access novel cooperating oncogenes, we are using a retrovirus lacking an oncogene as an insertional mutagen. This approach should be applicable to any trans-oncogenic strain and help to delineate the genetic events that trigger malignant clones.
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PMID:The transgenic window on lymphoid malignancy. 251 88

We investigated 16 lymphoid proliferations occurring in the ocular adnexa, salivary glands, breast, and thyroid gland and satisfying the histopathologic and immunophenotypic criteria of benign lymphoid hyperplasia for the presence of clonal rearrangements of the antigen receptor, c-myc, bcl-1, and bcl-2 genes and Epstein-Barr virus (EBV) DNA sequences. Each of these 16 extranodal, noncutaneous lymphoid neoplasms exhibited clonal immunoglobulin heavy and/or light chain and lacked T-cell receptor (TCR) beta-chain gene rearrangements. The patterns of immunoglobulin gene rearrangements included solitary and multiple barely perceptible to faint bands, solitary clear and definite bands, and solitary high-intensity bands superimposed on a background of multiple less-intense bands. Three ocular adnexal lymphoid neoplasms exhibited bcl-1 or bcl-2 gene rearrangements. None of the 16 lymphoid neoplasms contained EBV DNA sequences. Two patients developed a histopathologically confirmed malignant lymphoma in an extranodal site. None of the remaining 14 patients developed additional lymphoid neoplasms during a mean follow-up period of 30 months, despite conservative therapy. These results demonstrate that extranodal, noncutaneous lymphoid neoplasms meeting the histopathologic and immunophenotypic criteria for benign lymphoid hyperplasia frequently contain occult monoclonal and oligoclonal B-cell populations representing a continuous and progressive spectrum of B-cell neoplasia up to and including malignant lymphoma.
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PMID:Extranodal noncutaneous lymphoid hyperplasias represent a continuous spectrum of B-cell neoplasia: demonstration by molecular genetic analysis. 254 Aug 55

Great progress has been made in clinical research on non-Hodgkin's lymphoma during the last 15 years. Surface marker and DNA analyses of immunoglobulin and T-cell receptor genes are essential for new classification of the disease according to the cellular origin of tumor cells. This approach resulted in the establishment of new disease entities such as adult T-cell leukemia/lymphoma(ATL), immunoblastic lymphoadenopathy (IBL)-like T-cell lymphoma, and the pleural B-lymphoma occurring in long-standing pyothorax. New retrovirus, HTLV-I, was found during studies on ATL. Prevention of HTLV-I infection is an important project. HTLV-I negative ATL was also found and is of particular interest in understanding leukemogenesis of ATL. An oncogen such as bcl-2 is important for characterization of follicular lymphoma. Prognostic factors of patients with T-lymphoma are completely different from those of B-lymphoma. Risk grouping by combination of major prognostic factors is useful for the selection of the best treatment modality and the accurate estimation of prognosis of patients at initial presentation. The effect of combination chemotherapy should be evaluated separately between T- and B-lymphomas because of the difference in response rate and prognostic factors.
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PMID:[Recent progress in non-Hodgkin's lymphoma study in Japan]. 290 43

To detect occult lymphoma, the polymerase chain reaction (PCR) technique was used to amplify joined bcl-2/JH DNA sequences at the juncture of the t(14:18) translocation in follicular lymphoma. Using the heat-stable DNA polymerase Taq and automated cycling of the reaction, we were able to detect as few as one to two copies of bcl-2/JH. Under these conditions, PCR proved to be at least 10,000-fold more sensitive than either conventional flow cytometry or Southern blot restriction analysis. In addition, genomic DNA sequences of four lymphomas confirmed that the size of the amplified segment serves as a tumor marker. Direct application of PCR to patient staging revealed occult malignant lymphoma in tissue otherwise considered uninvolved by standard criteria. We conclude that the striking enhancement in diagnostic sensitivity attained by DNA amplification can serve as a valuable adjunct to the staging and clinical monitoring of follicular lymphoma.
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PMID:Detection of occult follicular lymphoma by specific DNA amplification. 314 Sep 14

A common feature of follicular lymphoma, the most prevalent haematological malignancy in humans, is a chromosome translocation (t(14;18] that has coupled the immunoglobulin heavy chain locus to a chromosome 18 gene denoted bcl-2. By analogy with the translocated c-myc oncogene in other B-lymphoid tumours bcl-2 is a candidate oncogene, but no biological effects of bcl-2 have yet been reported. To test whether bcl-2 influences the growth of haematopoietic cells, either alone or together with a deregulated c-myc gene, we have introduced a human bcl-2 complementary DNA using a retroviral vector into bone marrow cells from either normal or E mu-myc transgenic mice, in which B-lineage cells constitutively express the c-myc gene. Bcl-2 cooperated with c-myc to promote proliferation of B-cell precursors, some of which became tumorigenic. To determine how bcl-2 expression impinges on growth factor requirements, the gene was introduced into a lymphoid and a myeloid cell line that require interleukin 3 (IL-3). In the absence of IL-3, bcl-2 promoted the survival of the infected cells but they persisted in a G0 state, rather than proliferating. These results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.
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PMID:Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. 326 2

For many non-Hodgkin's lymphomas, the bcl-2 gene has been implicated as a likely proto-oncogene, since it is consistently located at or near the breakpoint sites of t(14;18) chromosomal translocations. To define the role of the protein product of the bcl-2 gene in lymphoid cancers, we used anti-bcl-2 antibodies to perform immunohistochemical studies of frozen sections of 136 tissue specimens affected by lymphoma or non-neoplastic lymphoid disorders. Immunoreactive bcl-2 protein was observed in the neoplastic cells in almost all the follicular lymphomas, whereas no bcl-2 protein was detected in follicles affected by non-neoplastic processes or in normal lymphoid tissue. Every tumor with molecular-genetic evidence of t(14;18) translocation expressed detectable levels of bcl-2 protein, regardless of whether the breakpoint was located in or at a distance from the bcl-2 gene. These data show consistent expression of a proto-oncogenic protein in a large proportion of non-Hodgkin's lymphomas and provide further support of a role for bcl-2 in the pathogenesis of all lymphomas with the t(14;18) karyotypic abnormality. Increased expression of bcl-2 after t(14;18) translocations may be a specific marker for B-cell cancers, and demonstration of the protein with use of anti-bcl-2 antibodies could be useful in the diagnosis of many non-Hodgkin's lymphomas.
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PMID:Expression in non-Hodgkin's lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. 328 62

The expression of bcl-2 protein was analysed immunohistochemically in 202 female breast carcinomas. The intensity of bcl-2 expression was inversely related to tumour grade (P < 0.0001), tumor necrosis (P < 0.0001), mitotic index (P < 0.0001), oestrogen receptor content (P < 0.0001), progesterone receptor content (P = 0.0007), S-phase fraction (P = 0.00047), and apoptotic index (P = 0.087). A high fraction of bcl-2-positive cells was related to ductal or lobular type (P = 0.03) and slight nuclear pleomorphism (P = 0.03). Heterogeneous expression of bcl-2 protein was associated with high grade (P = 0.02), severe nuclear pleomorphism (P = 0.02), DNA aneuploidy (P = 0.018), high S-phase fraction (P = 0.05), and early metastasis (P = 0.03). Intense expression of bcl-2 protein was significantly related to favourable outcome in the entire cohort (P = 0.0013), as well as in axillary lymph node-negative (ANN) tumours (P = 0.0124). Long recurrence-free periods in the entire cohort (P = 0.037) and in ANN tumours (P = 0.08) were confined to cases with intense expression of bcl-2 protein. In multivariate analysis, bcl-2 expression had no independent prognostic value in the entire cohort or in axillary lymph node-negative breast carcinomas, whereas it was a weak independent prognostic factor in axillary lymph node-positive breast carcinomas.
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PMID:Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis. 747 79

Coexpression of the proto-oncogenes c-myc and bcl-2 under the control of the immunoglobulin enhancer E mu provokes the rapid development of primitive lymphoid tumors in transgenic mice. In the present study we show that the myc family members N-myc and L-myc also cooperate with bcl-2 in oncogenesis and can provoke the development of more mature pre-B, B and T cell type lymphomas. The analysis of prelymphomatous B-cells from single E mu N-myc and bcl-2-Ig transgenic animals and from young, tumor free, double transgenic E mu N-myc/bcl-2-Ig mice revealed that E mu directed expression of N-myc leads to very rapid apoptosis after explantation and culturing compared to B-cells from normal mice. As expected, B-cells from bcl-2-Ig transgenics were protected to a certain degree from apoptosis. Strikingly however, B-cells from E mu N-myc/bcl-2-Ig double transgenic animals were found to be almost completely resistant towards a number of different apoptotic stimuli. Furthermore, after treatment with H2O2, which can trigger apoptosis, B-cells from E mu N-myc animals reach levels of intracellular free Ca2+ concentrations that are comparable to B-cells from normal mice, whereas B-cells from bcl-2-Ig or E mu N-myc/bcl-2-Ig double transgenic mice show no increase in intracellular Ca2+ concentrations after stimulation with H2O2. These findings suggest that the prevention of apoptosis conferred by bcl-2 correlates with the inhibition of intracellular Ca2+ fluxes whereas induction of apoptosis mediated by N-myc requires normal Ca2+ levels. We hypothesize therefore that the regulation of intracellular Ca2+ concentrations represent one important parameter in the oncogenic cooperation between bcl-2 and N-myc.
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PMID:Survival and death of prelymphomatous B-cells from N-myc/bcl-2 double transgenic mice correlates with the regulation of intracellular Ca2+ fluxes. 747 38

Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53.
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PMID:Bcl-XL protects cancer cells from p53-mediated apoptosis. 747 61

E mu-bcl-2 transgenic mice bearing the bcl-2 proto-oncogene linked to the immunoglobulin enhancer (E mu) sporadically develop B or T cell lymphomas after a long latent period. To identify genes that play important roles in development of lymphoid malignancies, proviral insertional mutagenesis with Moloney murine leukemia virus (MMuLV) was carried out in two lines of transgenic mice expressing the bcl-2 gene primarily in B or T cells. MMuLV infection of non-transgenic mice induced primarily mature T cell lymphomas. By contrast, infection of newborn E mu-blc-2 mice with the virus accelerated lymphomagenesis, and nearly all of the mice eventually succumbed to clonal pre-B, B, or mainly immature T cell lymphoma, indicating the active contribution of the bcl-2 gene in lymphomagenesis. Southern blot analysis of tumor DNA from MMuLV-infected transgenic mice revealed a proviral insertion at the c-myc gene in 26% (9/35) of tumors, at the pim-1 gene in 6% (2/35) and at the pim-2 (recently renamed tic-1) gene in 23% (8/35). Some tumors carried two activated oncogenes. No insertion was detected at the bmi-1 gene. These data suggest the usefulness of this transgenic system for analysis of lymphomagenesis involving the activated bcl-2 gene.
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PMID:Moloney murine leukemia virus infection accelerates lymphomagenesis in E mu-bcl-2 transgenic mice. 747


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