Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection with multiple sexually transmitted agents has been associated with inflammation of the cervix and an increased risk of cervical cancer in women infected with human papillomaviruses (HPVs). Two proinflammatory cytokines, interleukin 1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF-alpha), inhibited proliferation of normal epithelial cells cultured from human cervix. In contrast, both cytokines significantly stimulated proliferation of cervical cell lines (5 of 7) immortalized by transfection with HPV-16 or -18 DNAs or lines derived from cervical carcinomas (7 of 11). Stimulation was dose dependent from 0.01 to 1.0 nM and was blocked by specific inhibitors, such as the IL-1 receptor antagonist or the TNF type 1 or 2 soluble receptors. Growth stimulation by IL-1 alpha or TNF-alpha was accompanied by a 6- to 10-fold increase in RNA encoding amphiregulin, an epidermal growth factor (EGF) receptor ligand. Recombinant human amphiregulin (0.1 nM) was as effective as IL-1 alpha or TNF-alpha in promoting proliferation. Monoclonal antibodies that blocked signal transduction by the EGF receptor or that neutralized amphiregulin activity prevented mitogenic stimulation by IL-1 alpha or TNF-alpha. These studies indicate that IL-1 alpha and TNF-alpha stimulate proliferation of immortal and malignant cervical epithelial cells by an EGF receptor-dependent pathway requiring autocrine stimulation by amphiregulin. Furthermore, they suggest that chronic inflammation and release of proinflammatory cytokines might provide a selective growth advantage for abnormal cervical cells in vivo.
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PMID:Interleukin 1 alpha and tumor necrosis factor alpha stimulate autocrine amphiregulin expression and proliferation of human papillomavirus-immortalized and carcinoma-derived cervical epithelial cells. 770 34

Infection with erbB-2 (E) of Ha-ras (H) oncogene-transfected cells has been previously shown to cooperatively induce anchorage-independent growth of the MCF10A human mammary epithelial cell line in vitro, but not to induce nude mouse tumorigenicity. Here we show that oncogene-transformed MCF10A are able to halt in the lungs of nude mice, a sign of organ colonization potential. We have therefore studied the transformants for in vitro migratory and invasive properties known to correlate with the metastatic potential of human mammary carcinoma cells in nude mice. MCF10A transfected with Ha-ras, infected with a recombinant retroviral vector containing the human c-erB-2 proto-oncogene (MCF10A-HE cells), show a higher invasive index than either the single transfectant (MCF10A-H) or MCF10A-erB-2(MCF10A-E) cells in the Boyden chamber chemotaxis and chemoinvasion assays. The MCF10A-HE cells also adopted an invasive stellate growth pattern when plated or embedded in Matrigel, in contrast to the spherical colonies formed by the single transformants MCF10A-H, MCF10A-E, and the parental cells. Dot-blot analysis of gelatinase A and TIMP-2 mRNA levels revealed increasing gelatinase A mRNA levels (HE > E > H > MCF10A) and reduced TIMP-2 expression in both single and double transformants. Furthermore, MCF10A-HE cells show more MMP-2 activity than parental MCF10A cells or the single transformants. CD44 analysis revealed differential isoform banding for the MCF10A-HE cells compared to parental cells, MCF10A-H and MCF10A-E, accompanied by increased binding of hyaluronan by the double transformants. Our results indicate that erB-2 and Ha-ras co-expression can induce a more aggressive phenotype in vitro, representative of the malignancy of mammary carcinomas.
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PMID:Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes. 884 40

The treatment of cancer with tumor vaccines has been a goal of physicians and scientists ever since effective immunization against infectious disease with vaccines was developed. In the past, major tumor antigens had not been molecularly characterized. Recent advances are, however, beginning to define potential molecular targets and strategies and this had evolved with the principle that T-cell mediated responses are a key target for approaches to cancer immunization. In addition, these antigens are not truly foreign and tumour antigens fit more with a self/altered self paradigm, compared to a non-self paradigm for antigens recognized in infectious diseases. Potential antigens include the glycolipids and glycoproteins (e.g. gangliosides), the developmental antigens (e.g. MAGE, tyrosinase, melan-A and gp75) and mutant oncogene products (e.g. p53, ras, and HER-2/neu). Innovations for construction of cancer vaccines are emerging from these advances in molecular immunology and cancer biology. While vaccines against infectious agents are models for vaccine development, there are clearly distinct considerations and problems associated with cancer vaccines. One of the focal issues in designing active cancer immunotherapy is that cancer cells are derived from normal host cells. Thus, the antigenic profile of cancer cells closely mimics that of normal cells. How the immune system identifies and destroys cancer cells is therefore crucial. Clearly, the ultimate goal of tumor vaccine design is the generation of antigen-specific vaccines. The recent success identifying molecularly defined tumor antigens opens up potentially novel strategies for this approach. Vaccine possibilities include purified proteins and glycolipids, peptides, cDNA expressed in various vectors, and a range of immune adjuvants. The molecular and structural definition of tumor antigens provides an opportunity for cautious optimism that we are entering an era when we will soon begin to recapitulate the success of immunization against infectious disease.
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PMID:Definition of tumor antigens suitable for vaccine construction. 893 70

Laryngeal papilloma (LP) is the most frequent benign laryngeal epithelial tumor caused by human papillomaviruses (HPV) types 6 and 11. In the present study, we were interested in whether we can find any prognostic markers which might reflect the biological behavior of the covering epithelium in LP. We focused our attention on the determination of HPV infection, the detection of p53 protein, and c-erbB-2 protein in 24 biopsy specimens of LP. We confirmed the HPV 6 and 11 etiology in 23 of 24 LP. In these lesions the overexpression of p53 protein increased with the grade of epithelial abnormalities. The distribution of positive cells changed from scattered and focal, in simple and abnormal hyperplasia, to diffuse in atypical hyperplasia. It has been shown that in the presence of HPV types 6 and 11 found in LP, p53 can still preserve its tumor suppressor activity. Infection with HPV types 6 and 11 might therefore account for the significantly lower rate of malignant transformation in LP. Two staining patterns for c-erbB-2 protein were observed in the hyperplastic epithelium covering LP: membranous and cytoplasmic. With the increasing grade of epithelial abnormalities, cytoplasmic staining became predominant, and c-erbB-2 positivity sometimes occupied the whole epithelial thickness. This may represent either an alteration in the processing stability of the c-erbB-2 mRNA, gene amplification, or even an artefact.
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PMID:Human papillomavirus infection and expression of p53 and c-erbB-2 protein in laryngeal papillomas. 919 99

Promising results from clinical trials with unconjugated antibodies stimulated renewed interest in immune effector mechanisms of monoclonal antibodies (MoAbs). We investigated the potential of IgA as antibody isotype for cell- or complement-mediated tumor cell lysis and assessed the potential of its myeloid Fc receptor, FcalphaRI (CD89), as trigger molecule for bispecific antibody (BsAb)-mediated immunotherapy. Comparing hapten-directed antibodies of human IgA2 with IgG1 or IgG3 isotypes, we found all three to mediate effective killing of sensitized tumor target cells in whole blood assays. Analysis of effector mechanisms showed IgG-mediated lysis to be predominantly complement-dependent, whereas IgA-dependent killing was primarily effector cell-mediated. A comparison of effector cell populations in antibody-dependent cell-mediated cytotoxicity (ADCC) showed neutrophils to be most important for IgA-dependent tumor cell killing, involving FcalphaRI as shown with Fc receptor blocking antibodies. Reverse ADCC experiments against target cells sensitized with Fc receptor antibodies, or assays with FcalphaRI-directed bispecific antibodies confirmed FcalphaRI as effective trigger molecule in polymorphonuclear neutrophil (PMN)-mediated lysis. During granulocyte colony-stimulating factor (G-CSF ) therapy, (FcalphaRI x HER-2/neu) bispecific antibodies induced enhanced killing of HER-2/neu positive SK-BR-3 breast cancer cells in whole blood assays. This enhanced cytotoxicity was paralleled by increased PMN counts, which lead to higher effector to target cell ratios in G-CSF-primed blood. Furthermore, bispecific antibodies, directed to FcalphaRI and Candida albicans, enhanced neutrophils' phagocytosis of fungi. In summary, these results identify IgA as an effective antibody isotype for immunotherapy, working primarily via FcalphaRI on neutrophils. They suggest FcalphaRI-directed bispecific antibodies and G-CSF to be an attractive combination for malignant or infectious diseases.
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PMID:FcalphaRI (CD89) as a novel trigger molecule for bispecific antibody therapy. 937 59

DNA vaccine represents a novel method to elicit immunity against infectious disease. Lipopolysaccharide (LPS) copurified with plasmid DNA may affect therapeutic efficacy and immunological response. We aimed to study the effect of LPS on the therapeutic efficacy of HER-2/neu DNA vaccine in a mouse tumor animal model. Plasmid DNA purified from commercial EndoFree plasmid purification kits functioned as a better therapeutic DNA vaccine than that purified from Non-EndoFree purification kit, which contains >or=0.5 microg LPS per 100 mg DNA plasmid. To further investigate the effect of LPS on the therapeutic efficacy of DNA vaccine, increasing amount of LPS was added to endotoxin-free plasmid DNA, and inoculated on mice with established tumors. One mug of LPS significantly attenuated the therapeutic effect of neu DNA vaccine and increased Th2 immune responses bias with interleukin-4 cytokine production. In contrast, high amount (100 microg) of LPS enhanced the therapeutic efficacy of neu DNA vaccine with an increase of cytotoxic T lymphocyte response and Th1 immune response. The effect of LPS on DNA vaccine was diminished when the tumor was grown in toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice. Our results indicate that variation in the LPS doses exerts opposing effects on the therapeutic efficacy of DNA vaccine, and the observed effect is TLR4 dependent.
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PMID:The opposing effects of lipopolysaccharide on the antitumor therapeutic efficacy of DNA vaccine. 1805 24

Coronaviruses are positive-strand RNA viruses with features attractive for oncolytic therapy. To investigate this potential, we redirected the coronavirus murine hepatitis virus (MHV), which is normally unable to infect human cells, to human tumor cells by using a soluble receptor (soR)-based expression construct fused to an epidermal growth factor (EGF) receptor targeting moiety. Addition of this adapter protein to MHV allowed infection of otherwise nonsusceptible, EGF receptor (EGFR)-expressing cell cultures. We introduced the sequence encoding the adaptor protein soR-EGF into the MHV genome to generate a self-targeted virus capable of multiround infection. The resulting recombinant MHV was viable and had indeed acquired the ability to infect all glioblastoma cell lines tested in vitro. Infection of malignant human glioblastoma U87DeltaEGFR cells gave rise to release of progeny virus and efficient cell killing in vitro. To investigate the oncolytic capacity of the virus in vivo, we used an orthotopic U87DeltaEGFR xenograft mouse model. Treatment of mice bearing a lethal intracranial U87DeltaEGFR tumor by injection with MHVsoR-EGF significantly prolonged survival compared to phosphate-buffered saline-treated (P = 0.001) and control virus-treated (P = 0.004) animals, and no recurrent tumor load was observed. However, some adverse effects were seen in normal mouse brain tissues that were likely caused by the natural murine tropism of MHV. This is the first demonstration of oncolytic activity of a coronavirus in vivo. It suggests that nonhuman coronaviruses may be attractive new therapeutic agents against human tumors.
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PMID:Coronavirus genetically redirected to the epidermal growth factor receptor exhibits effective antitumor activity against a malignant glioblastoma. 1943 66