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

Expression of the transmembrane isoform of Mucin 1 (MUC1/TM) in an aggressive murine mammary tumor line, DA-3, does not alter tumor development and metastasis, leading to death of the host. However, tumor cells expressing a secreted isoform of MUC1 (MUC1/sec) fail to develop tumors in immunocompetent mice. The rejection of MUC1/sec-expressing tumor cells is immunologically mediated, as, initially, innate cells and, ultimately, T cells are required. After gene array analysis, and confirmation at the protein level, it was discovered that MUC1/sec-expressing tumor cells (DA-3/sec) have a significant reduction in expression of urokinase-type plasminogen activator (uPA) relative to the parental tumor line and tumor cells expressing MUC1/TM. The serine protease uPA has been found to be involved in growth-promoting signaling, angiogenesis, and induction of matrix remodeling leading to metastasis. Although the tumor-promoting Stat3 transcription factor was unaltered in these tumor cells, the tumor-suppressive and IFN-responsive signal transducer and activator of transcription 1 (Stat1) is dramatically up-regulated in DA-3/sec cells. In addition, treatment of various murine and human cell lines with conditioned medium containing MUC1/sec results in up-regulation of Stat1. DA-3/sec tumor cells are also sensitized to the antiproliferative effects of IFN-gamma. Furthermore, transfection of the Stat1 gene into DA-3 tumor cells leads to a down-regulation of uPA and delays tumor progression. Thus, Stat1 up-regulation in DA-3/sec cells seems to play a significant role in the mechanism(s) by which rejection of tumor cells expressing MUC1/sec may be occurring.
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PMID:Antitumor effects of Mucin 1/sec involves the modulation of urokinase-type plasminogen activator and signal transducer and activator of transcription 1 expression in tumor cells. 1838 51

CpG are powerful drugs activating the innate immune system. In this study, the ability of their intramammary administration in impeding the devastating progression of carcinogenesis in all the mammary glands of female BALB/c mice transgenic for the rat neu transforming oncogene was assessed. Starting when in situ carcinomas were scattered over all their mammary glands (week 10), mice received CpG injections in the stroma of the fourth left gland. Local neoplastic progression was inhibited by six monthly administrations. CpG not only delayed the onset of carcinomas in the injected gland, but also hampered their progression. Extended latency was observed for tumors in glands both close to and far from the injection site. When the experiment ended (week 45), no tumors were palpable in 67% of the injected glands and a markedly impaired tumor growth was evident in the others. An impressive local infiltrate of CD11b(+) cells with the morphologic features of macrophages, plasma cells, B220(+) B cells, and CD4(+) and CD8(+) T cells was quickly recruited to the CpG-treated glands. High quantities of IFN-gamma producing cells were only present in the ipsilateral axillary draining lymph nodes of the treated glands. Enhanced natural killer (NK) lytic activity was also detected in the spleens. Inhibition of progression was weaker when only four injections were given, and abolished by in vivo depletion of NK cells. CpG monotherapy is thus effective in an aggressive model of autochthonous cancer. The results strongly support the administration of CpG as a local monotherapy of multiple invasive microscopic lesions.
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PMID:Intramammary application of non-methylated-CpG oligodeoxynucleotides (CpG) inhibits both local and systemic mammary carcinogenesis in female BALB/c Her-2/neu transgenic mice. 1847 36

CpG-oligonucleotides (CpG-ODN), which induce signaling through Toll-like receptor 9 (TLR9), are currently under investigation as adjuvants in therapy against infections and cancer. However, whether the CpG-ODN alone could enhance the anti-tumor immunity and the underlying mechanisms remains unclear. Here, we investigated that stimulation of peripheral blood mononuclear cells (PBMCs) from human lung cancer patients with CpG-ODN induced proliferation responses of the PBMCs, accompanied by the elevated cytokine secretion, including IFN-alpha, IL-12 and TNF-alpha. In addition, after treatment with CpG-ODN, the cytotoxic activity of the PBMCs and the production of IFN-gamma in CD8(+) T cells were dramatically enhanced. Furthermore, we found that adoptive transfer of CpG-ODN treated PBMCs significantly inhibited the tumor progression in nude mice, which were challenged with the autologuous tumor cells from human lung cancer patients. Finally, we demonstrated that the inhibitory CpG ODN or chloroquine could dramatically abrogate the enhanced anti-tumor responses of the CpG ODN treated PBMCs. Our findings suggest that the CpG-ODN is promising as a preventive and therapeutic anti-tumor measure against pulmonary carcinoma.
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PMID:Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances anti-tumor responses of peripheral blood mononuclear cells from human lung cancer patients. 1856 66

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.
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PMID:Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. 1863 51

We examined the merits of combinatorial hMUC1 vaccination and hNIS radioiodine gene therapy and evaluated its tumoricidal effects in an animal tumor model. CMNF (CT26 expressing hMUC1, hNIS, and firefly luciferase) cells were transplanted into 28 mice, and 4 and 11 days after tumor challenge, tumor-bearing mice were immunized i.m. with pcDNA3.1 or pcDNA-hMUC1 vaccine and subsequently administered PBS or (131)I i.p. [four groups (7 mice per group): pcDNA3.1 + PBS, phMUC1 + PBS, pcDNA3.1 + (131)I, and phMUC1 + (131)I groups]. Thirty-two days after tumor challenge, we rechallenged mice in the pcDNA3.1 + (131)I and phMUC1 + (131)I groups with CMNF cells. Tumor progression and tumor-free mice (%) were monitored by bioluminescence. We investigated hMUC1-associated immune response generated by combination therapy. Marked tumor growth inhibition was observed in the phMUC1 + (131)I group by bioluminescence at 32 days after tumor challenge. Mice in phMUC1 + (131)I group showed complete hMUC1-expressing tumor suppression after tumor rechallenge, whereas mice in the pcDNA3.1 + (131)I group did not. The tumor-free mice (%) were much higher in the phMUC1 + (131)I group than in the other three groups. Levels of hMUC1-associated CD8(+)IFN-gamma(+) T cells were higher in the phMUC1 + (131)I group than in the other three groups. hMUC1-loaded CD11(+) cells in the phMUC1 + (131)I group were found to be most effective at generating hMUC1-associated CD8(+)IFN-gamma(+) T cells. The activities of hMUC1-associated cytotoxic T cells in the phMUC1 + (131)I group were higher than in the other three groups. Our data suggest that phMUC1 + (131)I combination therapy synergistically generates marked tumoricidal effects against established hMUC1-expressing cancers.
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PMID:Synergistic tumoricidal effect of combined hMUC1 vaccination and hNIS radioiodine gene therapy. 1864 34

Suppression of tumor-specific T cell sensitization is a predominant mechanism of tumor escape. To identify tumor-induced suppressor cells, we transferred spleen cells from mice bearing progressive MCA205 sarcoma into sublethally irradiated mice. These mice were then inoculated subdermally with tumor cells to stimulate T cell response in the tumor-draining lymph-node (TDLN). Tumor progression induced splenomegaly with a dramatic increase (22.1%) in CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC) compared with 2.6% of that in normal mice. Analyses of therapeutic effects by the adoptive immunotherapy revealed that the transfer of spleen cells from tumor-bearing mice severely inhibited the generation of tumor-immune T cells in the TDLN. We further identified MDSC to be the dominant suppressor cells. However, cells of identical phenotype from normal spleens lacked the suppressive effects. The suppression was independent of CD4(+)CD25(+) regulatory T cells. Intracellular IFN-gamma staining revealed that the transfer of MDSC resulted in a decrease in numbers of tumor-specific CD4(+) and CD8(+) T cells. Transfer of MDSC from MCA207 tumor-bearing mice also suppressed the MCA205 immune response indicating a lack of immunologic specificity. Further analyses demonstrated that MDSC inhibited T cell activation that was triggered either by anti-CD3 mAb or by tumor cells. However, MDSC did not suppress the function of immune T cells in vivo at the effector phase. Our data provide the first evidence that the systemic transfer of MDSC inhibited and interfered with the sensitization of tumor-specific T cell responses in the TDLN.
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PMID:Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. 1871 1

Mycobacterial HSP70 protein coupled with ovalbumin is known to elicit antigen-specific CD8(+) T-cell response. We investigated whether anti-idiotype immunity can likewise be enhanced using a conjugate of recombinant mycHSP70 and the Ig Id in a murine lymphoma model, A20. Plasmids were constructed of A20 tumor to generate A20Id-HSP70 (scFv-H), unconjugated A20Id (scFv), and mycHSP70 (H) recombinant proteins. We evaluated their relative efficacy in activating anti-tumor immunity that can reduce the mortality of tumor-challenged BALB/c mice; significantly, a longer term protection (>50% of the population) was observed in mice vaccinated with scFv-H compared to those receiving the scFv or H proteins. Concomitantly a much higher-level activation in anti-A20 cytotoxic T-cell activity, IFN-gamma secretion and predominantly anti-A20 IgG2a response was also observed with the scFv-H group. Thus, conjugating HSP70 with the A20Id renders the latter significantly immunogenic and affords longer protection against A20 tumor progression.
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PMID:Mycobacterial HSP70 as an adjuvant in the design of an idiotype vaccine against a murine lymphoma. 1871 53

Inhibition of tumor growth by thrombospondin (TSP) 1 is generally attributed to its antiangiogenic activity, but effects on tumor immunity should also be considered. We show that overexpression of TSP1 in melanoma cells increases macrophage recruitment into xenograft tumors grown in nude or beige/nude mice. In vitro, TSP1 acutely induces expression of plasminogen activator inhibitor-1 (PAI-1) by monocytic cells, suggesting that TSP1-induced macrophage recruitment is at least partially mediated by PAI-1. Tumor-associated macrophages (TAM) can either promote or limit tumor progression. The percentage of M1-polarized macrophages expressing inducible nitric oxide synthase is increased in TSP1-expressing tumors. Furthermore, soluble TSP1 stimulates killing of breast carcinoma and melanoma cells by IFN-gamma-differentiated U937 cells in vitro via release of reactive oxygen species. TSP1 causes a significant increase in phorbol ester-mediated superoxide generation from differentiated monocytes by interaction with alpha(6)beta(1) integrin through its NH(2)-terminal region. The NH(2)-terminal domain of TSP2 also stimulates monocyte superoxide production. Extracellular calcium is required for the TSP1-induced macrophage respiratory burst. Thus, TSP1 may play an important role in antitumor immunity by enhancing recruitment and activation of M1 TAMs, which provides an additional selective pressure for loss of TSP1 and TSP2 expression during tumor progression.
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PMID:Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. 1875 24

In addition to the known function in the glycolytic pathway, phosphoglycerate kinase 1 (PGK-1) promotes reduction of plasmin disulfide bonds leading to angiostatin formation and inhibition of tumor angiogenesis. In this study, the effects of PGK-1 on anti- tumor immunity against lung cancer were evaluated using the Tet-Off control of PGK-1 expression in the Lewis lung carcinoma (LLC-1). There was no significant difference in cell proliferation between parental LLC-1 and LLC-1 transduced with PGK-1 (PGK-LLC-1). However, expression of PGK-1 was found to limit tumor growth in mice subcutaneously injected with the cell lines and tumor growth was restored after doxycycline treatment. In addition, the cell invasion ability of PGK-LLC-1 became weaker than that of LLC-1. Expressions of COX-2, TGF-beta1 and PGE2 were all found to be down-regulated in PGK-LLC-1. PGK-LLC-1 cells treated with doxycycline recovered their COX-2 protein expression. In the presence of conditioned medium from PGK-LLC-1, the endothelial cell migration was reduced. Moreover, PGK-LLC-1 also stimulated T lymphocytes to express higher levels of Th1 cytokine (IFN-gamma) and lower levels of IL-10 in comparison with parental LLC-1. PGK-LLC-1 cells restored the growth rate in immunodeficient mice when compared with the growth rate in normal mice. In the tissue sections, reduced COX-2 expressions and marked infiltrated CD3 T lymphocytes were observed in the PGK-LLC-1 injected group. These findings indicate that overexpression of PGK-1 in LLC-1 reduces the COX-2 expression, and, in turn, affect PGE2, cell invasion, angiogenesis, and the immune functions, and finally inhibit the tumor progression.
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PMID:Phosphoglycerate kinase 1-overexpressing lung cancer cells reduce cyclooxygenase 2 expression and promote anti-tumor immunity in vivo. 1881 80

The delivery of stimulatory signals to dendritic cells (DCs) in the tumor microenvironment could be an effective means to break tumor-induced tolerance. The work presented here evaluates the immunostimulatory properties of pathogen-associated molecular patterns (PAMPs), microbial molecules which bind Toll-like receptors and deliver activating signals to immune cells, when expressed in tumor cells using adenoviral (Ad) vectors. In vitro, transduction of A549 tumor cells with Ad vectors expressing either flagellin from Listeria monocytogenes or P40 protein from Klebsiella pneumoniae induced the maturation of human monocyte-derived DCs in co-cultures. In mixed lymphocyte reactions (MLRs), Ad-flagellin and Ad-P40 transduction of tumor cells stimulated lymphocyte proliferation and the secretion of IFN-gamma. In vivo, these vectors were used either as stand-alone immunoadjuvants injected intratumorally or as vaccine adjuvants combined with a tumor antigen-expressing vector. When Ad-PAMPs were administered intratumorally to mice bearing subcutaneous syngeneic B16F0-CAR (cocksackie-adenovirus receptor) melanomas, tumor progression was transiently inhibited by Ad-P40. In a therapeutic vaccine setting, the combination of Ad-MUC1 and Ad-PAMP vectors injected subcutaneously delayed the growth of implanted RenCa-MUC1 tumors and improved tumor rejection when compared with vaccination with Ad-MUC1 alone. These results suggest that Ad-PAMPs could be effective immunoadjuvants for cancer immunotherapy.
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PMID:Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy. 1894 16


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