Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reactivity of four monoclonal antibodies (MAbs) directed against IFN-gamma inducible antigens with melanocytic cells was investigated in the course of local and systemic tumor progression of human malignant melanoma. Frozen sections of histologically defined melanocytic tissues at different stages of progression were stained with these MAbs using an indirect immunoperoxidase technique. The reactivity of MAbs Me15/B3 and Me15/F9, directed against two different epitopes of a 90-kDa molecule, was found to correlate with melanoma progression. Indeed, a significantly lower percentage of small than of advanced primary melanomas or metastases stained positively. A differential staining of nevocytic and dysplastic nevi was further observed for these two MAbs, which were also non-reactive with normal skin melanocytes. The reactivity of MAb Me14/D12, which identifies the intercellular adhesion molecule ICAM-1 and MAb Mel14/F12, directed against a 40-kDa molecule, was found to be independent of the Breslow thickness of primary melanomas. Both the latter MAbs stained a high proportion of nevocytic and dysplastic nevi. The co-expression of the surface molecules defined by MAbs Me14/D12, Me15/B3 and Me15/F9 in the course of melanoma progression was also analyzed. The frequency of this co-expression increased according to the Breslow thickness of primary melanomas. In addition, up to 100% of metastases, as opposed to 20% of dysplastic nevi, were found to be simultaneously stained by these three MAbs. It is therefore conceivable that high-risk melanocytic lesions might be identified by the use of a combination of MAbs directed against IFN-gamma regulated antigens.
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PMID:The differential reactivity of cells of the melanocytic lineage with four monoclonal antibodies against IFN-gamma inducible molecules. 134 19

Quantitative evaluation of the levels of endogenous gamma-interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the extracts of tumor, peritumoral and normal colorectal tissues resected surgically from 43 patients with colorectal adenocarcinoma was carried out using solid-phase, sandwich radioimmunoassay (RIA). The levels of both IFN-gamma and TNF-alpha detected in the tumor tissues were higher than those in the peritumoral and normal tissues obtained from each patient. A significant negative correlation was observed between the levels of IFN-gamma and TNF-alpha in each tumor tissue. The decrease of endogenous IFN-gamma in the tumors correlated with the advance of histopathological stages. Thirty seven patients were classified into three types according to the endogenous IFN-gamma distribution (intratumoral dominant type, peritumoral dominant type and nonreactive type). There was no significant difference concerning to the tumor diameters among them. However, the mean stage of the intratumoral dominant type was significantly earlier than that of the nonreactive types. On the other hand, the increase of endogenous TNF-alpha correlated with the maximum diameter of primary tumors. The production of endogenous TNF-alpha was localized in the tumor tissues, and the significant elevation of endogenous TNF-alpha was not observed in the peritumoral tissues. The immunohistochemical staining of IFN-gamma- and TNF-alpha-producing cells in tumor tissues represented that IFN-gamma was mainly produced by CD4+CD8-CD11c- lymphocytes and that TNF-alpha was mainly produced by CD4-CD8-CD11c+ cells with macrophage-like morphology. These results suggest that CD4+ lymphocytes producing IFN-gamma might play an important role in the anti-tumor response against cancer progression in human colorectal adenocarcinoma.
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PMID:[Detection of endogenous IFN-gamma and TNF-alpha in tumor-infiltrating mononuclear cells of human colorectal cancer]. 155 60

The murine skin multistage carcinogenesis model was used to characterize the co-promoting and tumor progressing activities of i.p. administered recombinant DNA-derived murine gamma interferon (rMuIFN-gamma). The dorsal skins of female SENCAR mice were topically initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted twice a week for 20 weeks with 1 microgram of 12-O-tetradecanoylphorbol-13-acetate (TPA). Doses of rMuIFN-gamma that had no effect on papilloma multiplicities when administered 1 day prior to TPA treatment increased the numbers of papillomas per mouse by 33-38% when administered immediately prior (zero time) to TPA application. A minimum of 6 weeks of co-treatment with TPA and rMuIFN-gamma (zero time) were necessary for demonstration of rMuIFN-gamma-dependent co-promotion. The ad libitum administration of either 0.25 or 1% (w/v) solutions of alpha-difluoromethylornithine (DFMO) in the drinking water inhibited by 90% the TPA-dependent elevation of epidermal ornithine decarboxylase activity but had minimal effect on papilloma multiplicities in TPA-promoted mice. However, both doses of DFMO completely suppressed rMuIFN-gamma-dependent co-promotion. Carcinoma incidence and multiplicities by weeks 46-48 of the promotion-progression period were statistically indistinguishable for initiated mice treated with TPA, TPA + DFMO, TPA + IFN-gamma or TPA + DFMO + IFN-gamma. Similarly, i.p. administration of rMuIFN-gamma to papilloma-bearing mice in a tumor progression study, with and without simultaneous topical TPA treatment, did not affect carcinoma latency or carcinoma multiplicities. C57BL/6 mice initiated with DMBA developed few papillomas (0.2 paps/mouse) after 19 weeks of TPA promotion. The i.p. administration of rMuIFN-gamma to C57BL/6 mice at the time of TPA treatment, at doses that were co-promoting in SENCAR mice, did not increase papilloma multiplicities. Collectively, our studies suggest that the co-promoting activity of rMuIFN-gamma is exceptionally sensitive to inhibition by DFMO and dependent upon the scheduling and duration of rMuIFN-gamma treatment, and the mouse strain/stock employed for the studies.
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PMID:Modulation of the co-promoting activity of gamma interferon in SENCAR and C57BL/6 mouse skin by difluoromethylornithine and the scheduling and duration of interferon treatment. 210 81

Herpes simplex virus (HSV) infections can enhance the progression of neoplastic diseases. Since macrophages can be activated to become tumorilytic and may figure prominently in host defense against cancer, the ability of HSV to modify macrophage-mediated tumoricidal functions was evaluated. Murine peritoneal macrophages treated with HSV could not be activated to a tumoricidal state by mouse recombinant gamma-interferon (IFN-gamma). Addition of HSV 4 h after treatment with IFN-gamma, at a time when the macrophages are fully committed to developing the cytotoxic phenotype, blocked macrophage-mediated lysis of syngeneic melanoma target cells. This inhibition of activation and cytotoxicity was not due simply to uptake of virus particles, because treatment with heat-inactivated HSV at 4-h posttreatment with IFN-gamma had no effect. In addition, HSV did not undergo a productive infection within macrophages, suggesting that the observed inhibitory activity might be due to a virus-induced product. In this regard, treatment of macrophages with recombinant alpha-interferon suppressed the activation of these cells by IFN-gamma, suggesting that virus-induced alpha-interferon may be mediating all or part of the suppressive activity. These studies suggest that enhancement of tumor progression following HSV infection may be related to the virus-induced suppression of macrophage-mediated tumoricidal activity.
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PMID:Herpes simplex virus-induced suppression of macrophage-mediated tumoricidal activity in murine macrophages. 243 19

The human breast cell line HBL100 acquires the capacity to invade normal tissues and to replace them by proliferation in vitro only at high passage levels (HPL). These cells therefore are a useful model for studying tumor progression in vitro. We have analyzed the expression of cell-surface markers supposed to be involved in the control of the neoplastic process. Quantitative flow cytometry has revealed that: (1) spontaneous expression of HLA class-I antigens strongly decreases in HPL HBL100 cells vs. LPL cells, which parallels amplification and over-expression of c-myc oncogene; (2) HLA DR antigens can be induced by IFN-gamma in LPL but not in HPL HBL100 cells; (3) HBL100 cells secrete a soluble protein factor which specifically inhibits HLA DR induction by IFN-gamma even in heterologous cell systems; (4) 50% of LPL HBL100 cells express integrin beta 3, whereas HPL HBL100 cells lose this antigen; (5) this cell line is myoepithelial in origin, since 100% of HBL100 cells exhibit the CD10 antigen. Our data stress a role of HLA antigens, of some integrins and of c-myc in the acquisition of malignant potential by myoepithelial mammary cells of the HBL100 line.
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PMID:Acquisition of tumorigenic potential in the human myoepithelial HBL100 cell line is associated with decreased expression of HLA class I, class II and integrin beta 3 and increased expression of c-myc. 249 51

ZME-018 monoclonal antibody (MAb, IgG2a subclass, 0.04 mg), recombinant human tumor necrosis factor-alpha (rHuTNF-alpha, 10(4) units), and recombinant human interferon-gamma (rHuIFN-gamma, 10(6) units) were injected intravenously into athymic nude mice bearing human malignant melanoma (Brown C5513) xenografts. Sixty-four animals were injected subcutaneously with 0.2 ml tumor chunks 4 days prior to administration of one or more of the treatments. The mice were randomized into eight groups so that mean tumor volume/group before initiation of treatment was similar (212-360 mm3); (a) saline, 2X; (b) rHuTNF-alpha, 1X; (c) rHuIFN-gamma, 1X; (d) ZME-018, 1X; (e) rHuIFN-gamma + rHuTNF-alpha, 1X each; (f) rHu-IFN-gamma + ZME-018 + rHuTNF-alpha, 1X each; (g) rHuTNF-alpha + ZME-018, 2X each; (h) rHuTNF-alpha + ZME-018, 3X each. The order of administration of the agents in those groups given more than one modality is as shown above and each injection was separated by a 24 h period. Tumor volume was measured daily for 9 days after the beginning of treatment. Compared to control mice, minimal suppression of tumor growth was noted when ZME-018, rHuTNF-alpha, or rHuIFN-gamma was used singly, but significantly (p less than or equal to 0.05) slower tumor progression occurred in animals given rHuIFN-gamma + rHuTNF-alpha or ZME-018 + rHuTNF-alpha when compared to controls. Histopathologic analyses of tumor biopsies obtained at 1 and 4 days after the last treatment for each group indicated that 15-95% necrosis was present. Necrosis was most striking in the animals given rHuIFN-gamma + rHuTNF-alpha or the ZME-018 MAb alone. However, the group receiving all three agents exhibited a tumor growth rate similar to that seen in the controls and demonstrated minimal necrosis. These results suggest that ZME-018, rHuIFN-gamma, and rHuTNF-alpha may be useful in the treatment of human melanoma. However, the effects of administration of all three of these agents in a single host needs to be evaluated further.
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PMID:Effects of monoclonal antibody, recombinant interferon-gamma, and tumor necrosis factor-alpha in the treatment of human melanoma xenografts. 251 78

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

Unregulated expression of epidermal growth factor receptor (EGF-R) is a common event in neoplastic transformation and has been shown to be associated with melanocytic tumor progression. Modulation of such a receptor by pharmacological agents could therefore be of clinical interest. We have studied EGF-R expression, its response to epidermal growth factor (EGF) and modulation effects by interferon gamma (IFN gamma) on human melanoma cells. Addition of EGF, anti-EGF and anti-EGF-R antibodies had no effect on proliferation of six melanoma cell lines tested. We report in this communication that EGF-R expression on human melanoma cells can be modulated by IFN-gamma. In the melanoma cell lines treated with IFN gamma, proliferative behavior was not affected; however, we demonstrate a downregulation of EGF-R expression on the protein level, by immunohistochemistry and flow cytometric analysis, and an accumulation of EGF-R mRNA by Northern blot analysis. The results suggest that IFN gamma downregulates EGF-R expression at a posttranscriptional level on human melanoma cells. This EGF/EGF-R interaction and its modulation by IFN gamma on human melanoma cells needs to be further clarified regarding its in vivo significance for the treatment and prognosis of malignant melanoma.
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PMID:Interferon-gamma downregulates epidermal growth factor receptors on human melanoma cells. 775 29

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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