Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present studies were designed to assess the ability of primary cultures of bone marrow cells to produce nitric oxide. We found that two inflammatory stimuli, IFN-gamma and LPS, were potent inducers of nitric oxide production by bone marrow cells. In addition, the CSF granulocyte-macrophage (GM)-CSF and IL-3 as well as TNF-alpha, while inactive by themselves, were synergistic with LPS and IFN-gamma in inducing nitric oxide production. Maximal effects were observed with combinations of GM-CSF and LPS. Nitric oxide production by bone marrow cells was found to be dependent on the presence of L-arginine in the culture medium and inhibitable by NG-monomethyl-L-arginine and L-canavanine, two nitric oxide synthase inhibitors. Nitric oxide produced by the cells was also suppressed by TGF-beta 1 and the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. Separation of bone marrow cells by density gradient centrifugation and flow cytometry revealed that the granulocyte-containing fraction was largely responsible for nitric oxide production. In additional experiments we found that treatment of bone marrow cells with GM-CSF significantly stimulated bone marrow cell growth. In contrast, the combination of GM-CSF and LPS or IFN-gamma markedly suppressed cellular proliferation. This suppression was completely reversed by treatment of the cells with NG-monomethyl-L-arginine. Taken together, these data demonstrate that various inflammatory stimuli and cytokines induce nitric oxide production by primary cultures of bone marrow cells and that this mediator may play a role in the regulation of bone marrow cell growth and development.
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PMID:Production of nitric oxide by murine bone marrow cells. Inverse correlation with cellular proliferation. 151 78

Six human colon tumor cell lines were analyzed for their constitutive levels of the c-myc protein. The nuclear proto-oncogene, c-myc, was detected as an expressed product in all of the human colon tumor cell lines analyzed. The poorly differentiated cell lines HCT116, RKO and C showed c-myc levels that averaged 2-fold greater than their well-differentiated counterparts, i.e., GEO, CBS and FET. When c-myc levels and responses to serum induction were analyzed in the presence of inducers of differentiation, i.e., dimethylformamide, retinoic acid, sodium butyrate and TGF-beta, distinct patterns of sensitivity and resistance emerged. Nuclear c-myc levels were reduced in all the colon cell phenotypes treated with dimethylformamide or sodium butyrate. Only the well-differentiated human colon tumor cell lines were responsive to transforming growth factor-beta. Only one of the human colon tumor cell lines (GEO) responded to retinoic acid. Increased levels of c-myc protein were found to correlate well with greater growth rates and with poor differentiation class. Similarly, a parallel sensitivity to down-regulation of c-myc levels and attenuation of c-myc induction curves for inducers of differentiation were observed in growth sensitive human colon tumor cell lines.
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PMID:Sensitivity of nuclear c-myc levels and induction to differentiation-inducing agents in human colon tumor cell lines. 154 Sep 46

A clonal mouse prostate carcinoma was established by the introduction of the ras and myc oncogenes via the recombinant retrovirus Zipras/myc 9 using a mouse prostate reconstitution model system. A single-cell suspension derived from an early passage ras+myc-induced carcinoma was inoculated into the flanks of intact or castrated adult male C57BL/6 mice, and tumors were harvested 3 wk postinoculation for northern and Southern blotting. Tumor volume analysis showed that this carcinoma was not dependent on testicular androgens for growth. Southern blot analysis of virus-cell DNA junction fragments revealed that tumor cell populations recovered from both intact and castrated mice were progeny of the same virus-infected cell. Northern blotting showed that mRNA levels for the four growth-related genes transforming growth factor-beta 1 (TGF-beta 1), transforming growth factor-beta 3 (TGF-beta 3), tissue-type plasminogen activator (tPA), and c-myc were significantly elevated in clonal mouse prostate carcinomas grown in castrated hosts. In contrast, androgen receptor mRNA levels were significantly reduced under the same conditions. The response of TGF-beta 1, tPA, and c-myc mRNA levels in the carcinomas grown in castrated hosts was similar to that shown previously in normal rat ventral prostate. However, unlike normal rat ventral prostate after castration, increased numbers of apoptotic cells were not seen in the castrated group relative to the intact group at the time of analysis, indicating that the altered gene expression was not associated with cell death. In addition, testosterone-repressed prostate mRNA number 2 levels, shown previously to be elevated after castration in normal rat ventral prostate, were not increased in the androgen-deprived clonal mouse prostate carcinomas. Therefore, this early passage clonal ras+myc-induced prostate carcinoma demonstrates unique patterns of expression for a set of growth-related genes in an androgen-deprived environment.
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PMID:Alterations in mRNA levels for growth-related genes after transplantation into castrated hosts in oncogene-induced clonal mouse prostate carcinoma. 154 41

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts as a potent liver tumor promoter in female but not in male rats. As a basis for studying mechanisms of growth control by liver tumor promoters, the effects of TCDD, of two congeners and ethinylestradiol have been examined in primary cultures of hepatocytes. The agents alone were relatively ineffective but acted as co-mitogens when DNA synthesis was stimulated by epidermal growth factor (EGF). The co-mitogenic effect of TCDD was only observed in adult animals, which are less sensitive to EGF than juvenile animals. Similar effects were seen with two TCDD congeners (1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin and octachlorodibenzo-p-dioxin) in the rank order of their affinity to the Ah receptor. The concentration maximum required for their co-mitogenic action (3 x 10(-12) M for TCDD) was lower than that required for enzyme induction. TCDD was not able to overcome the inhibitory action of TGF-beta (1 ng/ml). Ethinylestradiol additively or even synergistically increased the effect of TCDD. The results suggest: (i) co-mitogenic actions of TCDD and congeners are mediated by the Ah receptor. They are elicited at lower concentrations than those required for the induction of drug-metabolizing enzymes. (ii) Estrogens enhance the co-mitogenic actions of dioxins.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin and ethinylestradiol as co-mitogens in cultured rat hepatocytes. 154 36

A large number of reports have described the potential of transforming growth factor beta 1 (TGF-beta 1) as an antitumor agent on the basis of its antiproliferative action on a wide variety of tumor types in culture. In this report we now extend the assessment of TGF-beta 1's antitumor potential by evaluation in vivo versus the mouse monomyelocytic leukemia, Wehi 3BD+, and the human lung adenocarcinoma, A549. In culture both Wehi 3BD+ and A549 cells, sampled from in vivo, were sensitive to inhibition (greater than or equal to 50%) by TGF-beta 1 (greater than or equal to 1 ng/ml) in a 6 day proliferation assay. Despite their sensitivity to TGF-beta 1 in culture, in vivo the growth of neither tumor was reproducibly altered following treatment with various doses, routes and schedules of TGF-beta 1. For example, the median lifespan of mice inoculated with Wehi 3BD+ cells (10(3) or 10(5) cells, ip) was not increased by TGF-beta 1, given as 9 daily ip injections or 7 days of continuous ip infusion. Dose levels in these studies ranged over greater than 2 logs and were escalated to include those frankly lethal (28 micrograms/mouse by injection or 7 micrograms/mouse/day by infusion). Furthermore, the growth of A549 tumors implanted sc in athymic mice was not inhibited by iv injection (every 3 days for 5 injections or 6 consecutive daily injections), sc treatment distal to the tumor (every 3 days for 5 injections or continuously infused for 14 days), or even sc injection adjacent to the tumor (every 3 days for 5 injections), although dose levels of TGF-beta 1 covered a wide range including those which produced lethalities. On the basis of cumulative dose, continuous infusion of TGF-beta 1 by both ip and sc routes was more toxic than frequent injections given by the same routes. These studies indicate lethality is reached without a meaningful tumor inhibition being produced following ip, sc, or iv injections, and sc or ip infusions of TGF-beta 1.
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PMID:Transforming growth factor beta 1: lack of in vivo antitumor activity on A549 and Wehi 3BD+ tumors. 156 84

Stromelysin gene expression is transcriptionally activated by a number of growth factors (e.g., EGF and PDGF), tumor promoters (e.g., TPA), and oncogenes (e.g., ras, src) through an AP-1-dependent mechanism. TGF-beta repression of stromelysin induction is mediated at the level of transcription by an element located at position -709 in the rat stromelysin promoter referred to as the TGF-beta inhibitory element (TIE). A TIE-binding protein complex is induced by treatment of rat fibroblasts with TGF-beta. This protein complex contains the protooncogene c-fos, and induction of c-fos by TGF-beta is required for the repressive effects of TGF-beta on stromelysin gene expression. Interestingly, c-fos induction is also required for stimulation of stromelysin expression by EGF in rat fibroblasts. Preliminary studies suggest that differential regulation of members of the jun family of early-response genes may explain this apparent paradox and determine whether stromelysin is induced or repressed by growth factors. TGF-beta stimulation therefore initiates a cascade of events that results in a specific pattern of gene expression: the direct stimulation of early-response genes can lead to subsequent induction or repression of other genes. Growth factor regulation of matrix metalloproteinases appears to play a role in embryonic development in the morphogenesis of the murine lung. Treatment of embryonic lungs in organ culture with the growth factors EGF or TGF-alpha results in stimulation of growth and inhibition of branching morphogenesis. A similar inhibition of branching was observed when these lung rudiments were treated with the matrix metalloproteinase collagenase. Most interestingly, the effects of EGF and TGF-alpha can be completely reversed by the tissue inhibitor of metalloproteinases, TIMP. TGF-beta has the opposite effect on growth of murine lung rudiments--growth is inhibited in a dose-dependent manner. This example illustrates a potential role for growth factor regulation of matrix-degrading metalloproteinases in complex developmental processes.
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PMID:Negative regulation of gene expression by TGF-beta. 163 49

The predominant effect of TGF-beta 1 on cell proliferation is inhibition. Earlier studies demonstrated that TGF-beta 1 inhibition of skin keratinocyte proliferation involves suppression of c-myc transcription and indirect evidence suggested that the protein product of the retinoblastoma gene (pRB) may be involved in this process. Skin keratinocytes transformed by SV40 and human papilloma virus-16 (HPV-16) or HPV-18 resisted growth inhibition and suppression of c-myc mRNA by TGF-beta. Transient expression of HPV-16 E7 gene, adenovirus E1A, and SV40 large T antigen (TAg) blocked the TGF-beta 1 suppression of c-myc transcription. Studies with transformation-defective mutants of E1A and TAg suggested that a cellular protein(s) that interacts with a conserved domain of the DNA tumor virus oncoproteins mediates TGF-beta 1 suppression of c-myc transcription and keratinocyte growth. Transient expression of pRB in skin keratinocytes repressed human c-myc promoter/CAT transcription as effectively as TGF-beta 1. The same c-myc promoter region, termed the TGF-beta Control Element (TCE), was required for regulation by both TGF-beta 1 and pRB. TCE bound a cellular protein of approximately 106 kDa and this binding was decreased by TGF-beta 1 treatment. Our data indicate that pRB can inhibit c-myc transcription and suggest the involvement of cellular factor(s) in addition to pRB in the TGF-beta 1 pathway for the suppression of c-myc transcription and growth inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TGF-beta regulation of epithelial cell proliferation. 163 56

Malignant cells in culture express elevated levels of transforming growth factor beta 1 (TGF-beta 1) mRNA and secrete an abundant amount of TGF-beta protein, but little is known about the production of TGF-beta in human malignant tissues in vivo. We estimated the levels of TGF-beta 1 mRNA expression by Northern hybridization and measured TGF-beta protein using a radioreceptor assay in tumor tissues surgically obtained from six patients with hepatocellular carcinoma (HCC). TGF-beta 1 mRNA was expressed at much higher levels in HCC tissues from all the cases compared with normal human liver, suggesting an association of the activated TGF-beta 1 gene transcription with hepatocarcinogenesis. The content of TGF-beta was 207 +/- 121 ng/g wet tissue in the HCC tissue, and it showed correlation with the level of TGF-beta 1 mRNA in the tissue (r = 0.69; P less than 0.05). An immunohistochemical study demonstrated that TGF-beta 1 staining could be observed in HCC cells. These observations suggest that human HCC strongly expresses TGF-beta 1 mRNA in vivo, leading to a high content of TGF-beta protein.
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PMID:Elevated levels of transforming growth factor beta messenger RNA and its polypeptide in human hepatocellular carcinoma. 164 98

From this data we can draw several conclusions. Although many new hormonal agents have been developed, there has not been significant improvement in tumor response to single agents over the past several decades. By applying knowledge of tumor ER and PR patient populations can be selected which will have a higher response rate to a given hormonal agent. The approach of combining chemotherapy and hormonal therapy does not appear to significantly alter the course of the disease. Sequential use of Tamoxifen, Premarin, and chemotherapy has been shown in cell lines and animal models to synchronize cells thus increasing the efficacy of chemotherapy. Clinical trials of this synchronization generally show higher response rates including significantly higher CR rates than chemotherapy alone. This approach appears promising and is undergoing further trials. LHRH agonists and tamoxifen are effective in premenopausal women with receptor positive tumors and may replace surgical ablative therapy. Aminoglutethimide is gaining wider acceptance as second-line therapy in postmenopausal ER-positive patients. The new agent 4-OHA may be as effective as AG but with fewer side effects. Toremifine a new antiestrogen and RU486 a new antiprogesterone are undergoing trials. While these new agents appear promising with fewer side effects or greater specificity of action, with the exception of sequential hormone priming/chemotherapy they represent 'the same old approach'. By this we mean manipulation of the hormonal environment of the cell in a continuous fashion acting via the estrogen receptor mechanism to achieve tumor regression. While certain new agents may be more tolerable, it is unlikely that a 'break through' will occur with this approach. The problem is the emergence of cells resistant to hormonal therapy. This occurs either through proliferation of a preexisting resistant clone or development under selective pressure of resistant tumors. Some but not all of these resistant clones have escaped by virtue of not having estrogen receptor present. Others have defects further along the action cascade of estrogen stimulation, such as a defective receptor which cannot bind effectively to the nuclear acceptor sites, or lacking certain other growth factors such as TGF-beta. Whatever the deficit, most patients eventually develop resistant tumors. It is in this direction, toward manipulating later points in the estrogen cascade which our attention should turn to achieve more effective hormonal therapy.
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PMID:New hormonal approaches to the treatment of breast cancer. 165 76

We have shown in previous studies that metastatically-competent variant subpopulations (B5, C1) derived from a non-metastatic murine mammary adenocarcinoma (SP1) have a pronounced growth advantage over their non-metastatic tumor cell counterparts in primary tumors. As a result, primary tumors can be progressively overgrown by cells having the competence to spread elsewhere in the body. This occurs despite any evidence to indicate an intrinsic in vivo growth rate advantage of the metastatic cells when grown as isolated populations. This suggested that cell-cell interactions between metastatic and non-metastatic tumor populations may be involved in the metastatic cell growth dominance process. Evidence was therefore sought for growth factors released by SP1 cells which could preferentially stimulate the B5 or C1 variants and thereby mediate this cell-cell interaction process. We found that cocultures of SP1 and C1 or B5 cells with irradiated C1, B5, or SP1 "feeder" cells showed significant stimulation of C1 and B5 by SP1 "feeder" cells. Cell growth stimulation in response to EGF, TGF-alpha, TGF-beta 1, bFGF, PDGF, NGF, IGF-1, or IGF-2 demonstrated that only TGF-beta 1 could duplicate this effect. A repeat of the coculture experiment in the presence of specific neutralizing anti-TGF-beta antibodies was therefore undertaken and this was found to markedly reduce the stimulation of C1 or B5 cells by irradiated SP1 cells. Conditioned media from the SP1 and C1 cell lines was quantitated for TGF-beta activity and contained 4.5 ng/ml and 2.0 ng/ml, respectively. However, the majority of the TGF-beta released by SP1 cells was found to be spontaneously active, whereas 70% of the TGF-beta released by C1 cells was in its latent form. Scatchard analysis revealed approximately four times the number of TGF-beta receptors, of similar type and affinity, present on C1 as compared with SP1 cells. The in vitro results support the hypothesis that active TGF-beta released by SP1 cells may stimulate the proliferation of metastatic variant cells in a paracrine like fashion. In vivo evidence for this was obtained by showing that coinjection of irradiated SP1 cells could selectively stimulate tumor growth of viable C1 cells and this effect was markedly diminished by neutralizing polyclonal anti-TGF-beta antibodies. Taken together, the results suggest a novel role for TGF-beta in clonal evolution of malignant tumor growth and as a molecular mediator of tumor cell-tumor cell interactions involved in facilitating tumor progression.
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PMID:Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo. 165 15


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