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

The neu oncogene encodes a 185,000 dalton transmembrane glycoprotein, p185. The current study examined the effects of p185-specific monoclonal antibody administration on the tumorigenic growth of neu-transformed NIH3T3 cells implanted into nude mice. Treatment with anti-p185 monoclonal antibodies of the IgG1, IgG2a, IgG2b subclasses was able to profoundly inhibit the growth of neu-transformed cells. Furthermore, while none of these antibodies individually was able to cause complete eradication of tumors, the administration of mixtures of antibodies reactive with two distinct regions on the p185 molecule resulted in synergistic anti-tumor effects and complete eradication of tumors in a substantial fraction of the treated animals. The effect was oncogene specific, since the growth of ras transformed cells was not influenced by anti p185 antibodies. These results demonstrate that antibodies reactive with multiple domains of a tumor antigen can exert synergistic anti-tumor effects, and suggest that therapy with monoclonal antibodies specific for the neu oncogene product may play a role in cancer treatment.
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PMID:Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo. 245 Dec

Six-micron paraffin sections of paraformaldehyde-fixed specimens of 24 ovarian benign and neoplastic specimens were assayed for tumor cell-specific oncogene expression by a sensitive, quantitative in situ hybridization technique with probes for 17 oncogenes, beta-actin, and E. coli beta-lactamase. In the benign, borderline, and invasive adenocarcinomas, multiple oncogenes, including neu, fes, fms, Ha-ras, trk, c-myc, fos, and PDGF-A chains, were expressed at significant levels relative to a housekeeping gene (beta-actin). In the mixed-Mullerian tumors, a rather different pattern of oncogene expression was observed, characterized primarily by expression of sis (PDGF-B chain). For the adenocarcinomas, statistical analysis demonstrated that expression of several genes (fms, neu, PDGF-A) was closely linked to others (c-fos, c-myc) known to have important roles in the control of cell proliferation, but only one gene, fms, correlated very strongly with clinicopathologic features (high FIGO histologic grade and high FIGO clinical stage) predictive of aggressive clinical behavior and poor outcome. The authors discuss the role that tumor epithelial cell expression of the fms gene product might play in the auto- and paracrine control of growth and dissemination of ovarian adenocarcinomas.
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PMID:Oncogene expression in vivo by ovarian adenocarcinomas and mixed-mullerian tumors. 255 64

To determine whether the amplification of the proto-neu oncogene (also called c-erbB-2) plays a role in tumorigenicity, we previously generated an NIH 3T3 transfectant (DHFR/G-8) that carried the amplified proto-neu gene. The DHFR/G-8 cells exhibited normal morphology. Their growth curve was similar to that of NIH 3T3 cells but was different from that of the B104-1 cell, and NIH 3T3 transfectant that carries the activated neu oncogene. When injected into nude mice, B104-1 cells produced tumors within 2 weeks, whereas the DHFR/G-8 cells did not produce tumors until 3 months after injection, and the NIH 3T3 cells did not produce any tumors even after 3 months. The tumors produced by the injection of the DHFR/G-8 cells were excised and grown in culture. The cells derived from the tumors were of transformed morphology and highly tumorigenic. The DNAs from the tumor cells were transfected into NIH 3T3 cells. The transfection resulted in foci on the NIH 3T3 monolayer. Southern analysis indicated that the foci derived from the transfection contained the neu gene. Using oligonucleotides as probes, the neu gene in the foci was found to carry a single-point mutation identical to the one previously found in the rat neuroblastoma and glioblastoma induced by the ethylnitrosourea. We conclude that the DNA region encoding the transmembrane domain of neu is a hot spot for converting the proto-neu gene into an activated oncogene and that amplification of the proto-neu gene facilitates mutation of the hot spot.
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PMID:Amplification of the proto-neu oncogene facilitates oncogenic activation by a single point mutation. 256 34

The HER2/c-erbB-2 gene encodes the epidermal growth factor receptorlike human homolog of the rat neu oncogene. Amplification of this gene in primary breast carcinomas has been show to correlate with poor clinical prognosis for certain cancer patients. We show here that a monoclonal antibody directed against the extracellular domain of p185HER2 specifically inhibits the growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2 gene product and prevents HER2/c-erbB-2-transformed NIH 3T3 cells from forming colonies in soft agar. Furthermore, resistance to the cytotoxic effect of tumor necrosis factor alpha, which has been shown to be a consequence of HER2/c-erbB-2 overexpression, is significantly reduced in the presence of this antibody.
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PMID:p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. 256 7

Various monoclonal antibodies reactive with protooncogene products or tumor-associated antigens have been utilized to investigate breast carcinoma biology or antigen expression with potential prognostic relevance. Murine monoclonal antibody TA1, generated by immunization of BALB/c mice with whole c-erbB-2 (neu) transformed NIH/3T3 cells, recognizes the extracellular domain of the c-erbB-2 protein and binds a Mr 185,000 protein by immunoprecipitation. Using avidin-biotin-peroxidase techniques and monoclonal antibody TA1, 313 archival primary adenocarcinomas of the breast were evaluated for c-erbB-2 overexpression; 290 of these were used for multiparametric statistical analysis. Historical, clinical (age, laterality), histological (nuclear grade, tumor size, lymph node status, lymphatic or blood invasion), and hormone receptor data as well as clinical outcome (minimal follow-up, 6 years; median follow-up, 8.5 years) were compared to TA1 staining. For these 290 patients Cox regression multivariate analysis showed the strongest correlation between lymph node status or estrogen receptor status and overall survival (P = 0.0001 and 0.049, respectively). TA1 staining did not significantly correlate with survival (P = 0.395). However, univariate analysis of certain patient subpopulations showed a significant correlation if the examined tumors were subdivided into negative or focally reactive and those with greater than or equal to 40% cellular reactivity. For T3, T4 patients, strong TA1 immunoreactivity correlated with a shortened disease-free survival (log rank P = 0.0018; Wilcoxon p = 0.0078) and overall survival (log rank P = 0.0002; Wilcoxon P = 0.0013). For these patients the overall survival at 6 years was markedly different between the strongly reactive tumors (0%) and the negative to weakly reactive tumors (55%). In lymph node-positive patients a trend between high TA1 reactivity and a worse overall survival was also noted (log rank P = 0.128; Wilcoxon P = 0.054), with a 6-year survival of 42% in the strongly reactive tumors (n = 16) and 65% in the negative to weakly reactive carcinomas (n = 105). No correlation between TA1 immunoreactivity and other historical, clinical, and histological features were noted. c-erbB-2 overexpression as measured by immunohistochemical techniques, therefore, may have clinical significance in certain patient subpopulations.
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PMID:Analysis of c-erbB-2 expression in breast carcinomas with clinical follow-up. 257 26

Cellular antigens encoded by tumor viruses and some antigens encoded by cellular oncogenes offer advantages as targets for immunotherapy by being inextricably associated with the neoplastic phenotype. For example, monoclonal antibodies (MAb) specific for an antigen encoded by the neu oncogene have a direct inhibitory effect on proliferation of antigen-positive tumor cells. Many of the oncogene-encoded cell surface molecules are growth factor receptors, as are some tumor-associated differentiation antigens (TADAs). Therefore, it is not surprising that their level of cancer specificity is similar. There have been some promising findings from using TADAs as targets for various forms of immunotherapy, and one would expect the results to further improve by targeting to molecules that are more directly involved in cell proliferation and/or in maintaining the malignant state.
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PMID:Oncogene-associated tumor antigens as targets for immunotherapy. 264 2

EGF was used to stimulate a chimeric receptor consisting of the epidermal growth factor receptor (EGFR) extracellular, transmembrane, and protein kinase C-substrate domains linked to the intracellular tyrosine kinase and carboxyl terminal domains of the rat neu protein in NIH/3T3 cells. EGF-induced rapid and delayed morphological changes consisted of membrane ruffling, increased pinocytosis, extension of lamellar actin-containing footpads at the cell periphery and partial reorganization of the actin stress fibers in the cells. EGF bound to the cells was rapidly internalized in a complex with the EGFR/neu protein, as shown by loss of EGF binding and EGFR antigens from the cell surface. The movement of the EGFR/neu protein was followed with indirect immunofluorescence into a vesicular intracellular compartment using antibodies against both EGFR and neu protein domains. Metabolic labeling and pulse-chase experiments indicated that the receptor was degraded soon after its internalization. EGF treatment also induced the junB transcription factor mRNA and a dose-dependent stimulation of DNA synthesis in cultures expressing the chimeric receptor. The tumor promoter TPA led to a transient loss of cell surface receptors and prevented EGF stimulation of DNA synthesis but did not completely abolish junB mRNA induction or increase degradation of the chimeric receptor. These results show that the chimeric EGFR/neu receptor undergoes typical downregulation upon ligand binding and TPA pretreatment and is capable of transducing an EGF-induced mitogenic signal.
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PMID:Receptor downregulation and DNA synthesis are modulated by EGF and TPA in cells expressing an EGFR/neu chimera. 269 32

Transforming growth factor beta (TGF beta) is a multifunctional polypeptide that regulates proliferation, differentiation, and other functions of many cell types. The pathway of TGF beta signal transduction in cells is unknown. We report here that an early effect of TGF beta is an enhancement of the expression of two genes encoding serum- and phorbol ester tumor promoter-regulated transcription factors: the junB gene and the c-jun proto-oncogene, respectively. This stimulation was observed in human lung adenocarcinoma A549 cells which were growth inhibited by TGF beta, AKR-2B mouse embryo fibroblasts which were growth stimulated by TGF beta, and K562 human erythroleukemia cells, which were not appreciably affected in their growth by TGF beta. The increase in jun mRNA occurred with picomolar TGF beta concentrations within 1 h of TGF beta stimulation, reached a peak between 1 and 5 h in different cells, and declined gradually to base-line levels. This mRNA response was followed by a large increase in the biosynthesis of the c-jun protein (AP-1), as shown by metabolic labeling and immunoprecipitation analysis. However, differential and cell type-specific regulation appeared to determine the timing and magnitude of the response of each jun gene in a given cell. In AKR-2B and NIH 3T3 cells, only junB was induced by TGF beta, evidently in a protein synthesis-independent fashion. The junB response to TGF beta was maintained in c-Ha-ras and neu oncogene-transformed cells. Thus, one of the earliest genomic responses to TGF beta may involve nuclear signal transduction and amplification by the junB and c-jun transcription factors in concert with c-fos, which is also induced. The differential activation of the jun genes may explain some of the pleiotropic effects of TGF beta.
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PMID:Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation. 272 96

Previously reported studies have suggested that variations in the pattern of proto-oncogene expression within a specific tumor type may denote an underlying difference in the biology and clinical behavior of those tumors. To more sensitively characterize malignant tumors of the central nervous system, we have used Northern blot hybridization analysis to determine the patterns of expression of seven proto-oncogenes in 20 cell lines established from biopsy specimens of patients with malignant glioma. The following proto-oncogenes are expressed at detectable levels in 30 micrograms of total RNA from most glioma cell lines examined: c-myc (20/20), c-mil/raf-1 (18/18), neu (19/20), c-erbB (19/20), and c-myb (17/20). In contrast, only half of the cell lines expressed detectable c-sis (10/20). In none of the cell lines tested was N-myc (0/20) mRNA detected. Morphologic analysis of these 20 cell lines revealed three different growth patterns: bipolar, epithelial, and pleomorphic-glial. Detectable levels of c-sis mRNA typically occurred with either an epithelial or pleomorphic-glial morphology. The pleomorphic-glial subgroup was also characterized by the expression of glial fibrillary acidic protein.
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PMID:Patterns of proto-oncogene expression in human glioma cell lines. 281 Mar 98

Neonatal rat hepatocytes (NRH) in primary cultures were transformed upon transfection with plasmid pSV 5-neo containing polyoma virus (Py) early region sequences. Clones of cells (Py-NRH) resistant to the antibiotic G418 were obtained after selection in arginine-deficient medium with serum, epidermal growth factor (EGF), transferrin and insulin. They did not undergo senescence during serial subcultivation. One clone (Py-NRH Cl A) harbored a single integrated copy of Py early region sequences and expressed transforming Py genes, hepatocyte-specific transcripts, including albumin, alpha-fetoprotein (AFP) and tyrosine aminotransferase (TAT) mRNAs. Subclones isolated after about 45 cell doublings still contained albumin and AFP, but no TAT mRNAs, indicating that long-term stabilization of liver functions is not necessarily permanent unless selected for (e.g. arginine synthesis). Cells grew unrestricted in medium containing insulin and no longer required EGF. Cells grew in agar, secreted a beta-transforming growth factor-like activity into the medium and were tumorigenic in nude mice. Hybridization studies using v-erbB DNA as a probe showed that Py-NRH, unlike neonatal hepatocytes in primary culture, express the EGF receptor gene at low or undetectable levels. Py-NRH Cl A and a subclone (5A) derived from it, however, contained elevated levels of rat c-neu oncogene-related RNA, whereas levels in another subclone (3A) were low or undetectable. These findings demonstrate that a proto-oncogene was activated after transfection of hepatocytes with DNA tumor virus transforming genes. However, the expression of c-neu oncogene is not related to the maintenance of the transformed state.
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PMID:Transformation of differentiated neonatal rat hepatocytes in primary culture by polyoma virus early region sequences. 283 82


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