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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute phase proteins (APP) are plasma proteins whose concentration and glycosylation alters in response to tissue injury, inflammation, or tumor growth. Significant interspecies and sex differences in APP response exist. APP are produced mainly by hepatocytes, and their synthesis and glycosylation are controlled by a network consisting of cytokines, their soluble receptors, and glucocorticoids. The major cytokines involved in these processes belong to a group of interleukin-6-type cytokines that act through the hematopoietin receptor complex on hepatocytes and JAK-STAT signal transduction pathway. Transformed cells (hepatoma) display significant differences in synthesis of APP, cytokine responsiveness, expression of cytokine-receptor subunits and signal-transduction machinery. The most striking variability relates to the glycosylation alterations induced by cytokines. However, transformed cells (hepatoma) form a basic model for studying and understanding mechanisms controlling the synthesis and glycosylation of APP. Furthermore, APP may be secreted by transformed (tumor) cells of various origins and may display a growth factor-like function in certain cancer types.
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PMID:Acute phase proteins and transformed cells. 900 38

Intrapleural injections of recombinant human IFN-gamma have shown some efficacy in reducing tumor growth in early stages of diffuse malignant mesothelioma (DMM). Here, we have addressed the potential therapeutic effect of IFN-gamma in DMM by investigating the activation of the JAK/STAT signaling pathway in seven human mesothelioma cell lines (HMCLs) that were differentially responsive to the antiproliferative activity of IFN-gamma. We showed that janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) were phosphorylated on tyrosine residues within 15 min in all the HMCLs in which IFN-gamma (500 units/ml) inhibited proliferation. In addition, STAT1 binding activity to the gamma-activated sites DNA sequence was detected within 15 min in electrophoretic mobility-shift assay analysis, and IFN regulatory factor-1 RNA expression was observed within 6 h in the more responsive cells (72.7-95.2% inhibition of DNA synthesis after 72 h of treatment). Conversely, in several HMCLs, absent or limited growth suppressive effect (less than 22% inhibition of DNA synthesis) was associated with alterations in expression or activation of JAK2 or STAT1 or, downstream, with low induction of IFN regulatory factor-1 RNA expression and/or STAT1 protein expression following IFN-gamma treatment. These data suggest that at least part of the IFN-gamma effect on proliferation of HMCLs is mediated directly through activation of the JAK/STAT1 signaling pathway, and it could account for the antitumoral activity reported in DMM patients treated with IFN-gamma.
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PMID:Human malignant mesothelioma cell growth: activation of janus kinase 2 and signal transducer and activator of transcription 1alpha for inhibition by interferon-gamma. 948 44

Endothelial receptor tyrosine kinases (RTKs) and their signaling mechanisms are of interest because they may control tumor angiogenesis and thereby tumor growth. In this report we have examined activation of the signal transducers and activators of transcription (STATs) by the three known vascular endothelial growth factor receptors (VEGFR1-3), as well as by the endothelial Tie-1 and -2 receptors. We also studied signaling by the R849W mutant of Tie-2 (MTie-2), which has been shown to cause venous malformations. When overexpressed in 293T cells, MTie-2 activated STAT1 while the other endothelial RTKs failed to do so. In contrast, the three VEGFRs were strong activators of STAT3 and STAT5, suggesting that they activate only a specific subset of these signal transducers. STAT3 and STAT5 were also activated by Tie-2 and, more so, by MTie-2. Tyrosine phosphorylation and DNA binding of STATs correlated with their ability to activate transcription as judged by luciferase assays. When co-expressed with STAT5, VEGFR-1 as well as both the Tie-2 receptor forms increased expression of the cell cycle inhibitor p21. Interestingly, co-expression of the Tie-2 receptors with STAT1 resulted in appearance of a novel, p21 related transcript. Taken together, these findings identify STAT proteins as novel targets for signal transduction by the endothelial RTKs, suggesting that they may be involved in the regulation of endothelial function.
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PMID:Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. 992 14

Thrombin, a multifunctional protein, has been found to be involved in cellular mitogenesis, tumor growth, and metastasis, in addition to its well known effects on the initiation of platelet aggregation and secretion and the conversion of fibrinogen to fibrin to form blood clots. These properties of thrombin rely on its action as a serine protease, which cleaves the N-terminal region of a 7-transmembrane G protein receptor (protease-activated receptor, PAR-1), thus exposing a tethered end hexapeptide sequence capable of activating its receptor. Little is known about its effect on genes that regulate the cell cycle. This study was undertaken to investigate the possible mechanisms by which thrombin regulates tumor cell growth in several tumor cell lines: human CHRF megakaryocyte, DU145 prostate, MDAMB231 and MCF7 breast, U3A fibrosarcoma, and 2 murine fibroblast cell lines, MEFp53(-/-) and CD STAT(-/-). We have found that thrombin under the conditions of culture employed inhibits cell growth by both up-regulation of p21(waf/cip1) and induction of caspases via its PAR-1 receptor. The increased expression of p21(waf/cip1) by thrombin was p53 independent, STAT1 dependent, and protein synthesis independent. This was associated with tyrosine phosphorylation of JAK2 and STAT1, and nuclear translocation of STAT1. Induction of apoptosis is also PAR-1-specific, STAT1-dependent, and associated with up-regulation of caspases 1, 2, and 3. Our study establishes, for the first time, a link between PAR-1 receptor activation with the STAT signal pathway, which leads to cell cycle control and apoptosis. This observation broadens our understanding of the mechanism of PAR-1 activation and its effect on cell growth, and could possibly lead to therapeutic approaches for the treatment of cancer.
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PMID:Thrombin inhibits tumor cell growth in association with up-regulation of p21(waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway. 1069 50

The intracellular signals driving the proliferation of breast carcinoma (BC) cells have been widely studied. Both the mitotic and metastatic potential of BC cells have been linked to the frequent overexpression of ErbB family members. Other signaling molecules, including the estrogen receptor, the tyrosine kinases c-Src and Syk, and STAT proteins, especially STAT3, have also been implicated in BC tumor growth. Here we have examined ErbB and STAT protein expression and activation in six BC-derived cell lines. ErbB expression and tyrosine phosphorylation varied considerably among the six cell lines. However, STAT protein expression and activation were more consistent. Two levels of STAT3 activation were distinguished in DNA-binding assays: an epidermal growth factor-inducible, high level that requires both ErbB1 and Janus kinase (JAK) activity and an elevated serum-dependent level that is maintained by autocrine/paracrine signaling and requires JAK activity but is independent of ErbB1 kinase activity. BC cell growth could be inhibited by dominant-negative versions of STAT3 and the JAK inhibitor AG490 but not by PD153035 or PD168393, inhibitors of ErbB1 kinase activity. This indicates that BC cell proliferation may be a consequence of STAT3 activation by autocrine/paracrine signals.
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PMID:Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines. 1185 72

Interleukin-6 (IL-6) is a prominent tumor growth factor for malignant multiple myeloma cells. In addition to its known activation of the Janus tyrosine kinase-STAT and RAS-MEK-ERK pathways, recent work suggests that IL-6 can also activate the phosphatidylinositol 3-kinase (PI3-K)/AKT kinase pathway in myeloma cells. Because activation of the PI3-K/AKT as well as RAS-MEK-ERK pathways may result in downstream stimulation of the p70(S6K) (p70) and phosphorylation of the 4E-BP1 translational repressor, we assessed these potential molecular targets in IL-6-treated myeloma cells. IL-6 rapidly activated p70 kinase activity and p70 phosphorylation. Activation was inhibited by wortmannin, rapamycin, and the ERK inhibitors PD98059 and UO126, as well as by a dominant negative mutant of AKT. The concurrent requirements for both ERK and PI3-K/AKT appeared to be a result of their ability to phosphorylate p70 on different residues. In contrast, IL-6-induced phosphorylation of 4E-BP1 was inhibited by rapamycin, wortmannin, and dominant negative AKT but ERK inhibitors had no effect, indicating ERK function was dispensable. In keeping with these data, a dominant active AKT mutant was sufficient to induce 4E-BP1 phosphorylation but could not by itself activate p70 kinase activity. Prevention of IL-6-induced p70 activation and 4E-BP1 phosphorylation by the mammalian target of rapamycin inhibitors rapamycin and CCI-779 resulted in inhibition of IL-6-induced myeloma cell growth. These results indicate that both ERK and PI3-K/AKT pathways are required for optimal IL-6-induced p70 activity, but PI3-K/AKT is sufficient for 4E-BP1 phosphorylation. Both effects are mediated via mammalian target of rapamycin function, and, furthermore, these effects are critical for IL-6-induced tumor cell growth.
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PMID:Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. 1187 47

The aim of this study is to combine endocrine therapy [human prolactin (hPRL) antagonist, G129R] and immune therapy [interleukin 2 (IL2)] in the design of a fusion protein, G129R-IL2, to treat human breast cancer. This novel approach uses the specific interaction between the G129R and hPRL receptors (PRLRs), thus directly targeting the fusion protein to the malignant breast tissues that have previously been shown to contain high levels of PRLR. The localized bifunctional fusion protein is designed to block signal transduction induced by hPRL as well as to activate T lymphocytes near the tumor site. A bacterial expression system was used to produce G129R-IL2 fusion protein that maintained both G129R and IL2 activities as demonstrated by cell-based assays such as signal transducer(s) and activator(s) of transcription (STAT)5 phosphorylation, breast cancer cell proliferation, and T-cell proliferation. The antitumor activities of G129R-IL2 were demonstrated in vivo using a syngeneic model system with BALB/c mice and EMT6-hPRLR breast cancer cells. After daily injection (i.p.) of G129R-IL2 (100 microg/mouse) for 18 days, the tumor growth in the G129R-IL2-treated group was only one-third the size as compared with that of the control group. The growth rate in the G129R-IL2-treated group is also significantly slower than that of the group treated with G129R alone (200 microg/mouse/day). We hope that this novel bifunctional protein will contribute significantly to human breast cancer therapy.
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PMID:A novel design of targeted endocrine and cytokine therapy for breast cancer. 1194 33

Epidermal growth factor receptor (EGFR) inhibition with small molecule tyrosine kinase inhibitors results in antitumor activity in only a minority of patients whose tumors express EGFR. One hypothesis to explain this suboptimal clinical activity is that multiple growth regulatory pathways are abnormal in most EGFR-expressing cancers. Given the importance of Stat-3 signaling pathway in epidermoid tumors, we hypothesized that blocking complementary pathways in an epidermal growth factor (EGF)-driven model of proliferation in the A431 cell line would demonstrate improved antiproliferative activity. Exposure of A431 cells to the EGF results in a significant increase in EGFR and Stat-3 phosphorylation. However, inhibition of EGFR by AG1478 fails to decrease EGF-induced Stat-3 phosphorylation. This suggests that EGF continues to drive Stat-3 phosphorylation through other receptors. Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3. In this setting, combined exposure to an EGFR blocker and Stat-3 blocker (AG490) results in significantly greater tumor growth inhibition than either agent alone. We conclude that targeting multiple pathways (EGFR and JAK/STAT pathways) in EGF-driven tumors may result in greater antiproliferative activity than blocking EGFR alone.
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PMID:Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy. 1507 89

We demonstrated that enhanced expression of the costimulatory molecules CD80, CD54 and CD48 (designated rF-TRICOM) on target cells, as delivered via a recombinant fowlpox vector, results in an increased state of stimulation of CD8+ T cells, and consequent increased lysis of target cells. CTL studies in conjunction with antibody-blocking studies demonstrated that the enhanced effector activity of these CD8+ T cells is mediated mainly through CD54. Intracellular staining of CD8+ cells that interact with target cells infected with rF-TRICOM showed that they contain higher amounts of perforin and have a higher level of perforin message. Enhanced expression of costimulatory molecules (specifically CD54) on target cells using rF-TRICOM vectors also leads to the formation of stable conjugates/synapses between targets and T cells. The interaction of T cells with target cells that overexpress costimulatory molecules upon infection with rF-TRICOM leads to enhanced signaling through Lck, ZAP70, and STAT-1 in CD8+ T cells and heightened lytic activity of CD8+ cells through the formation of a greater number of immunological synapses. This, in turn, leads to enhanced signaling in T cells. Finally, studies were conducted in mice in which CEA is a self-antigen in an attempt to understand the potential clinical relevancy of intratumoral vaccine therapy. Mice were transplanted subcutaneously with CEA expressing tumors. Intratumoral (i.t.) vaccination was administered 8 days post tumor transplant. Mice vaccinated i.t. with rF-TRICOM demonstrated significantly reduced tumor growth and 40% of the mice had complete tumor regression. The antitumor effects were further improved by the addition of tumor antigen (CEA) in the vaccination by utilizing rF-CEA/TRICOM, with 80% of the mice experiencing complete tumor regression. These studies thus support the concept of intratumoral vaccination employing vectors expressing costimulatory molecules.
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PMID:Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy. 1535

Vascular endothelial growth factor (VEGF) upregulation is induced by many receptor and intracellular oncogenic proteins commonly activated in cancer, rendering molecular targeting of VEGF expression a complex challenge. While VEGF inducers abound, only two major transcription activators have been identified for its promoter: hypoxia inducible factor-1 (HIF-1) and signal transducer and activator of transcription (Stat3). Both HIF-1 expression and Stat3 activity are upregulated in diverse cancers. Here, we provide evidence that Stat3 is required for both basal and growth signal-induced expression of HIF-1. Moreover, induction of VEGF by diverse oncogenic growth stimuli, including IL-6R, c-Src, Her2/Neu, is attenuated in cells without Stat3 signaling. We further demonstrate that Stat3 regulates expression of Akt, which is required for growth signal-induced HIF-1 upregulation. Targeting Stat3 with a small-molecule inhibitor blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo. Furthermore, tumor cells' in vivo angiogenic capacity induced by IL-6R, which simultaneously activates Jak/STAT and PI3K/Akt pathways, is abrogated when Stat3 is inhibited. Activation of Stat3 signaling by various growth signaling is prevalent in diverse cancers. Results presented here demonstrate that Stat3 is an effective target for inhibiting tumor VEGF expression and angiogenesis.
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PMID:Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. 1600 14


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