UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER2 protooncogene encodes a 185-kDa transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor (EGF) receptor. Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma. These data also support the hypothesis that p185HER2 present on the surface of overexpressing tumor cells may be a good target for receptor-targeted therapeutics. The anti-p185HER2 murine monoclonal antibody (muMAb) 4D5 is one of over 100 monoclonals that was derived following immunization of mice with cells overexpressing p185HER2. The monoclonal antibody is directed at the extracellular (ligand binding) domain of this receptor tyrosine kinase and presumably has its effect as a result of modulating receptor function. In vitro assays have shown that muMAb 4D5 can specifically inhibit the growth of tumor cells only when they overexpress the HER2 protooncogene. MuMAb 4D5 has also been shown to enhance the TNF-alpha sensitivity of breast tumor cells that overexpress this protooncogene. Relevant to its clinical application, muMAb 4D5 may enhance the sensitivity of p185HER2-overexpressing tumor cells to cisplatin, a chemotherapeutic drug often used in the treatment of ovarian cancer. In vivo assays with a nude mouse model have shown that the monoclonal antibody can localize at the tumor site and can inhibit the growth of human tumor xenografts which overexpress p185HER2. Modulation of p185HER2 activity by muMAb 4D5 can therefore reverse many of the properties associated with tumor progression mediated by this putative growth factor receptor. Together with the demonstrated activity of muMAb 4D5 in nude mouse models, these results support the clinical application of muMAb 4D5 for therapy of human cancers characterized by the overexpression of p185HER2.
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PMID:Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. 167 63

In previous studies we showed that tumor-associated macrophages isolated from murine mammary tumors are mutagenic to bacteria and mammalian cells and thus may contribute to tumor progression. We reported previously, and confirm here, that inflammatory macrophages induce DNA strand breaks in cultured mammary tumor cells co-incubated at a 1:1 ratio for 1 h. This activity is prevented by inhibitors of arachidonate metabolism or the removal of H2O2 with catalase. In the present study, we show that two antibodies to recombinant murine tumor necrosis factor alpha (rMuTNFa)--a hamster monoclonal antibody (TN3-19.12) and a rabbit polyclonal antibody (Genzyme)--partially protect tumor cells from DNA strand breaks induced by elicited but not resident peritoneal macrophages. Antibody protection was reversed upon the addition of excess exogenous rMuTNFa. Purified rMuTNFa alone was unable to induce DNA strand breaks in the absence of macrophages, indicating that TNFa is necessary but not sufficient to mediate damage. Tumor target cells were completely resistant to the cytotoxic effects of rMuTNFa in the absence of actinomycin D and relatively resistant (in comparison to WEHI 164 clone 13 cells) in its presence. The incomplete protection seen with either catalase or anti-TNF suggests that macrophage-released TNFa, in the presence of other factors, induces non-cytotoxic DNA effects in tumor cells.
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PMID:The role of macrophage-derived TNFa in the induction of sublethal tumor cell DNA damage. 173 75

Monolayer cultures of the human melanoma cell lines StML-12, StML-11, StML-14 (third, respectively, twenty-fifth subculture), and SKMel-28 derived from specimens representing different stages of tumor progression were treated with 10-10,000 U/ml rTNF-alpha applied for 72 h. The effects of rTNF-alpha on cell proliferation, DNA synthesis, cell viability, cloning efficiency, cell division, cell morphology, and the immunophenotype were studied in triplicate experiments. The cell line StML-14(3) revealed a significantly dose-dependent reduction of growth due to both cytostatic and cytotoxic activities of rTNF-alpha as well as a decrease of CE. Increased numbers of cells in prophase were observed 24 h after addition of r-TNF-alpha. In addition, dislocation of chromosomes in the metaphase, formation of micronuclei, and dose-dependent increases of cells exhibiting micronuclei and the DNA amount per cell were detected at the end of treatment. On the other hand, only a slight sensitivity to the anti-proliferative effect of rTNF-alpha was observed with StML-14(25) and SKMel-28, whereas StML-12 and StML-11 were significantly resistant. The last four cell lines were serially subcultivated and presented common phenotypic patterns with more malignant characteristics than the cell line StML-14(3) before treatment. Overall, rTNF-alpha enhanced the malignant immunophenotype of the cell lines tested. It increased the expression of the "late" melanoma progression markers A.10.33 and A.1.43, and Ki67, and it decreased the expression of the "early" progression marker K.1.2. The expression of HLA-I, HLA-DR, and ICAM-1 was also enhanced after rTNF-alpha treatment, whereas in contrast to other cytokines, rTNF-alpha did not induce the de novo expression of HLA-DR in HLA-DR-negative melanoma cell lines. These findings indicate that rTNF-alpha induces cytostasis and decreases cell viability of certain rTNF-alpha-sensitive melanoma cells. These effects may result in selection of rTNF-alpha-non-sensitive human melanoma cell populations with higher proliferation rates and a more aggressive immunophenotype in vitro.
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PMID:Cytostatic and cytotoxic effects of recombinant tumor necrosis factor-alpha on sensitive human melanoma cells in vitro may result in selection of cells with enhanced markers of malignancy. 225 39

In vitro macrophage- or TNF-alpha-mediated selection procedures on 3LL tumor cells have led to the selection of 3LL variants manifesting a highly reduced sensitivity towards the cytotoxic effects of both TNF-alpha and tumoricidal macrophages, while retaining the parental sensitivity to the cytolytic activity of (i) H2O2, (ii) macrophage-ADCC reactions and (iii) NK cells. A correlation was observed between the TNF-alpha binding capacity of the 3LL cell lines and their susceptibility towards macrophage- and TNF-alpha-mediated cytotoxicity, indicating that macrophage and TNF-alpha sensitivity may partially be regulated at the TNF-alpha receptor level. Further, the selected 3LL variants are gene-regulatory variants rather than cellular mutants, as upregulation of the TNF-alpha receptor by interferon-gamma (IFN-gamma) or 5'-azacytidine treatment resulted in an increased vulnerability of the selected 3LL variants to the killing activity of macrophages and TNF-alpha. The resistance of the 3LL variants to macrophage- and TNF-alpha-mediated cytotoxicity in vitro was reflected by a higher tumorigenic and metastatic potential in vivo. Therefore, the generation of TNF-alpha- and macrophage-resistant variants through immunoselection may contribute to the basic mechanisms of tumor progression and metastasis.
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PMID:TNF-alpha mediated selection of macrophage-resistant gene-regulatory tumor variants. 247 62

Tumor necrosis factors (TNFs) are a class of cytokines secreted by activated effector cells involved in host defense against tumor progression. Epidermal growth factor (EGF) and recombinant human transforming growth factor-alpha (rHuTGF-alpha) were shown to interfere with the in vitro antiproliferative effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) and -beta on a human cervical carcinoma cell line, ME-180. The inhibitory effect could be observed at EGF or rHuTGF-alpha concentrations of 100 pg/ml, and was maximal between 1 and 10 ng/ml. This response was not due to down regulation of the TNF receptor or to alteration of the affinity of TNF-alpha for its receptor. Since the antiproliferative effect of recombinant human interferon-gamma was not significantly affected by the presence of EGF or rHuTGF-alpha, the inhibition was specific for recombinant TNFs and was not due solely to enhanced proliferation induced by the growth factors. Neither growth factor had a substantial protective effect on the synergistic cytotoxicity observed when tumor cells were exposed simultaneously to rHuTNF-alpha and recombinant human interferon-gamma. TGF-beta can also interfere with the antiproliferative effects of rHuTNF-alpha in vitro. At concentrations of less than 1 ng/ml, TGF-beta significantly antagonized the cytotoxic effects of rHuTNF-alpha on NIH 3T3 fibroblasts. Since EGF, platelet-derived growth factor, and TGF-beta all enhanced NIH 3T3 cell proliferation, but only TGF-beta interfered with rHuTNF-alpha cytotoxicity, the protective effects of TGF-beta were not related in a simple manner to enhanced cell proliferation. rHuTGF-alpha and TGF-beta did not have a significant protective effect against rHuTNF-alpha-mediated cytotoxicity on two other tumor cell lines, BT-20 and L-929 cells. Based upon these observations we suggest that growth factors might enhance tumor growth in vivo by a combination of distinct mechanisms: (a) by autocrine stimulation tumor cell growth; and/or (b) by interfering with normal effector mechanisms of host defense.
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PMID:Effects of growth factors on the antiproliferative activity of tumor necrosis factors. 380 82

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are involved in stimulation of acute-phase protein during inflammatory processes. We recently suggested that these two cytokines may play a role in human immune surveillance during tumor progression. The present study was designed to determine the capacity of OSM in modulating LIF production by human tumor cells and to provide a better definition of the interactions between these two molecules during inflammatory reaction due to neoplasia. LIF content in culture supernatants was assayed by a specific ELISA (sensitivity: 25 pg/ml). In vitro exposure to recombinant OSM increased LIF production 2 to 6-fold in all human melanoma cell lines tested. This effect was not limited to melanoma cell types since LIF production was also enhanced by an MDA breast undifferentiated adenocarcinoma line. Moreover, a synergistic effect was observed for OSM and TNF-alpha. LIF increase was apparently due to up-modulation through LIF synthesis since LIF transcript expression was also enhanced in these tumor cell lines. It is concluded that OSM can induce inflammatory reaction not only directly but also via LIF production by tumor cells.
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PMID:Modulation of LIF expression in human melanoma cells by oncostatin M. 759 Sep 43

In the present study, we demonstrate that TGF-beta is capable of enhancing macrophage ability to produce IL-10 in normal and EL4 tumor-bearing mice. We found the increase in IL-10 in ascitic fluid and IL-10 mRNA expression in macrophages in parallel with the TGF-beta level and tumor progression. The macrophage production of IL-10 in the tumor-bearing mice was significantly enhanced without LPS stimulation in vitro, compared with normal controls. To clarify the mechanism wherein increased IL-10 production was induced, anti-TGF-beta or anti-IL-10 Abs were administered to EL4-bearing mice. Administration of anti-TGF-beta Ab led to a reduction in the IL-10 contents in ascitic fluid of tumor-bearing mice; however, anti-IL-10 Ab administration did not prevent the increase in TGF-beta contents. Enhanced IL-10 production and mRNA expression of macrophages from the tumor-bearing mice were also reduced by anti-TGF-beta Ab administration. Both anti-TGF-beta and anti-IL-10 Ab administration restored the TNF-alpha production by macrophages in EL4-bearing mice. In normal macrophages, in vitro pretreatment with TGF-beta 1 potentiated IL-10 production, and when natural TGF-beta 1 was administered to normal mice, the recovered peritoneal macrophages showed enhanced IL-10 production. Based on the above findings it can be concluded that TGF-beta enhances macrophage ability to produce IL-10, which sheds a new light on the role of TGF-beta in the immune system.
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PMID:TGF-beta enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. 759 97

Most tumors grow progressively and overwhelm the host. The rare but documented cases of spontaneous regression of primary tumors are indicative of the potential of tumor-bearing hosts to develop a significant antitumor response. Because most tumors grow progressively in the host, it is not surprising that the majority of studies have focused on T lymphocytes that infiltrate these tumors. Although these studies have generated significant and useful information during the period of tumor growth, they can only speculate on the mechanisms that are involved in tumor rejection. We have used a well developed sponge model of concomitant tumor immunity that allows us to compare the immunologic events that occur during tumor progression vs rejection. In this model, an animal harboring a primary EMT6 mammary tumor is challenged with a secondary tumor implant through a pre-implanted gelatin sponge. During the manifestation of concomitant tumor immunity, the secondary tumor is rejected and the effector cells mediating the response are retained within the sponge matrix. Using this model we analyzed the TCR usage, cytotoxic activity of lymphocytes, and cytokine production at both tumor sites. The data revealed that tumor-rejecting lymphocytes isolated from the site of secondary tumor implant were cytotoxic toward EMT6 cells, whereas tumor-infiltrating lymphocytes isolated from the progressing primary tumor were not. Interestingly, the TCR-V beta repertoire of the tumor-infiltrating lymphocytes and tumor-rejecting lymphocytes were identical with V beta 1 and V beta 8 being predominant at both sites. Furthermore, the rejection site showed higher gene expression of IFN-gamma, TNF-alpha, and IL-10 whereas TGF-beta expression was slightly higher in the progressing tumors. These findings suggest that the disparate effector functions observed during tumor progression vs rejection are not caused by different T cell phenotypes but may be due instead to influences exerted by cytokines produced at the tumor sites.
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PMID:T lymphocytes infiltrating sites of tumor rejection and progression display identical V beta usage but different cytotoxic activities. 770 35

The molecular mechanisms of tumor invasion and metastasis are yet to be fully elucidated. A potential tumor-metastasis-suppressor gene nm23 has been described in certain rodent and human tumors. In the present study, we examined the potential anti-invasive and anti-metastatic effect of nm23 gene in B16F10 cells, a malignant murine melanoma cell line. Transfection of nm23 gene into B16F10 melanoma cells resulted in significant suppression of the invasiveness and metastatic ability of melanoma cells and significantly enhanced the survival of tumor-bearing mice. B16F10 melanoma cells transfected with nm23 produced significantly less soluble ICAM-I and were more susceptible to LAK-cell-mediated cytotoxicity. Co-culture of B16F10 melanoma cells with IL-2 had no effect on nm23 expression, whereas treatment with PGE2, TNF-alpha and IFN-gamma resulted in down-regulation of nm23 expression. Concomitantly, in vivo treatment with TNF-alpha or IFN-gamma in experimental mice increased pulmonary metastases and lowered the overall survival period, as compared with IL-2 treatment alone. These results provide evidence that nm23, in addition to its anti-metastatic function, could also be involved in modulating tumor-target-structure expression, in down-regulating invasive potential and in production of soluble intracellular adhesion molecules. The down-regulation of nm23 by TNF-alpha, IFN-gamma and particularly by PGE2 warrants re-examination of current immunotherapeutic protocols and of the role played by PGE2 in tumor progression.
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PMID:Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. 782 17

Peritoneal-exudate macrophages (PEM) from mammary-tumor-bearing mice have impaired cytotoxic activity against syngeneic and allogeneic tumor targets. The ability of PEM from normal and tumor-bearing mice to bind tumor targets was found to be similar in the presence or the absence of surrogate receptors, which enhanced the binding but not the killing of tumor targets by PEM from tumor-bearing mice, suggesting that other mechanisms are involved in their impaired cytolytic activity. Soluble and membrane-bound TNF-alpha, as well as H2O2, were found in higher amounts in PEM from tumor bearers upon stimulation with LPS, as compared with PEM from normal mice. However, tumor-bearers' macrophages displayed decreased capacity to produce and/or release nitric oxide, which could be reversed by the addition of increasing levels of IFN-gamma. These results indicate that the lack of macrophage cytotoxicity in mammary-tumor-bearing mice is related to impaired production and/or release of NO by these effector cells, possibly aggravated by the insufficient IFN-gamma production previously reported in these animals. Moreover, mammary-tumor progression results in dis-regulation of synthesis of macrophage-mediators, with over-production of molecules to which mammary-tumor cells are insensitive and deficient production of NO, the crucial molecule to which these cells appear to be highly sensitive.
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PMID:Decreased macrophage-mediated cytotoxicity in mammary-tumor-bearing mice is related to alteration of nitric-oxide production and/or release. 786 Jan 41

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