Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of interleukin 10 (IL-10) mRNA in human malignant melanoma was investigated by reverse transcriptase polymerase chain reaction analysis. Selective expression of IL-10 mRNA in tissues of primary melanomas and melanoma metastases was found in comparison with normal skin. In addition, strong expression of IL-10 mRNA and of biologically active IL-10 was detected in 3 out of 13 melanoma cell lines. Normal melanocytes consistently expressed low levels of IL-10 mRNA but did not produce detectable IL-10 protein, nor did keratinocytes or fibroblasts. The production of biologically active IL-10 by melanoma cell lines suggests that IL-10 mRNA in melanoma lesions may derive at least in part from the tumour cells themselves. Tumour-infiltrating cells, however, could also be a source of IL-10 in melanoma tissues. The presence of IL-10 in melanoma lesions may contribute to the postulated 'paralysis' of an anti-melanoma immune response.
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PMID:Expression of interleukin 10 in human melanoma. 798 Oct 73

We have previously shown that a 78-kDa "invasion stimulating factor" (ISF) triggers collagenase IV (MMP-2) secretion and the invasive behavior of metastatic PC-3 ML subclones in modified Boyden chamber assays [Stearns, M. E.; Stearns, M. Autocrine factors, type IV collagenase secretion and prostatic cancer cell invasion. Cancer Metastasis Rev. 12:39-52; 1993. Wang, M.; Stearns, M.; Stearns, M. E. Identification of the receptor for a novel M(r) 78,000 "invasion stimulating factor" from metastatic human prostatic PC-3 ML clones. Cancer Res. 54:2492-2495; 1994.]. Recently, we have shown that interleukin 10 (IL-10) preferentially stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) production in these cells [Wang, M.; Stearns, M. E. Characterization of a novel TIMP-1 enhancer element. J. Biol. Chem., submitted.]. In this paper, we report that IL-10 (20-40 ng) can inhibit the invasion stimulatory effects of ISF (30-60 ng) on PC-3 ML cells. "Checkerboard analysis" with modified Boyden chambers (precoated with 10 and 100 micrograms collagen IV) shows that IL-10 inhibits the stimulatory effects of ISF on both cell motility and chemoinvasion processes. In support of these data, exogenously supplied TIMP-1 (10 micrograms/ml) and collagenase antibodies (1:200 dilution) both completely blocked invasion. Quantitative ELISAs comparing the molar ratios of TIMP-1:MMP-2 and TIMP-2:MMP-2 further demonstrate that IL-10 (10-40 ng) preferentially activates TIMP-1 secretion to increase the molar ratio of TIMP-1:MMP-2 in the presence of increasing amounts of ISF (0-60 ng). IL-10 did not elevate TIMP-2 secretion or influence the molar ratio of TIMP-2:MMP-2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-10 blocks collagen IV invasion by "invasion stimulating factor" activated PC-3 ML cells: upregulation of TIMP-1 expression. 855 49

Many studies show defective immune responses in patients diagnosed with cancer. Most of the diverse nonspecific approaches used to stimulate the immune system to recognize and destroy abnormal tumor cells have limited clinical utility. Attempts to identify tumor-specific antigens and to improve the antigen presentation were equally disappointing. It appears that some of these failures can be explained by tumor-induced immunosuppression. A large number of cytokines, hormones, and other molecules secreted by tumors were demonstrated to have immunomodulating properties. The most extensively studied immunosuppressive molecules secreted by tumors are transforming growth factor-beta (TGF beta), interleukin 10 (IL-10), and prostaglandin E2 (PGE2). TGF beta in particular may play a key role in tumor-induced immunosuppression. It is the most potent immunosuppressor described to date, and it has been consistently isolated from variety of tumor cell lines and detected in plasma of tumor-bearing hosts. Level of TGF beta production by tumor cells correlates with their metastatic potential, and TGF beta neutralization not only prevents development of metastases, but also inhibits growth or completely eradicates tumors as diverse as breast cancer, melanoma, and malignant gliosarcoma in animal models. PGE2 may play significant role in early stages of tumor development, promoting the process of tumorigenesis in some tumors. Research on reversal of tumor-induced immunosuppression promises new, more powerful, and less toxic approaches to cancer therapy. Existence of molecule(s) consistently secreted by different types of tumors and responsible for tumor progression raises the possibility of a single, universal assay to monitor progression and recurrence in many malignancies, including those that currently do not have reliable plasma markers.
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PMID:Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. 918 55

We compared the serum levels of several cytokines with established tumour markers in 24 patients with non-small cell lung cancer (NSCLC) and 31 patients with benign lung disease (BLD). Cytokine levels were measured using in-house double determinant sandwich ELISAs and tumour markers by a variety of established techniques. There was no correlation between serum cytokines and expression of cytokeratins 18 and 19, MUCI and carcinoembryonic antigen. While no significant difference was observed in any of the cytokines between patients with NSCLC and BLD, patients with metastatic tumour had a significantly higher level of serum tumour necrosis factor alpha and interleukin 10 than those with localised disease (P < 0.015 and P < 0.05 respectively). The serum levels of granulocyte macrophage colony stimulating factor and interferon gamma were no different between these groups. These results suggest immunological effects of NSCLC which tends towards impaired cell mediated immunity in patients with metastatic disease.
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PMID:Serum cytokines and tumour markers in patients with non-small cell carcinoma of the lung. 940 32

We have permanently transfected human prostate PC-3 ML tumor cells and examined the influence of interleukin 10 (IL-10) production on tumor growth and metastasis following orthotopic implantation in the prostate gland of severe combined immunodeficient mice. Measurements of tumor volume after 5, 8, and 12 weeks indicated that tumor volume was negatively correlated with the amount of IL-10 production. Likewise, the extent of metastasis was inversely related to the amount of IL-10 produced. Following i.v. injection, the IL-10-expressing clones also failed to metastasize to the bone marrow. Controls showed that PC-3 ML and PC-3 ML mock clones grew rapidly and metastasized when implanted orthotopically or injected i.v. via the tail vein. Mouse survival curves showed that all of the mice injected orthotopically with the PC-3 ML clones died by about 14-16 weeks, whereas the PC-3 ML-IL10a or PC-3 ML-ILl0b clones induced only 10-20% death after 23-24 weeks. Likewise, survival studies showed a high death rate by approximately 30 days with PC-3 ML mock cells but <10% death by 12 weeks with the IL-10-transfected clones injected i.v. via the tail vein. The data strongly suggest that IL-10 production blocks tumor growth and metastasis in severe combined immunodeficient mice.
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PMID:Antimestatic and antitumor activities of interleukin 10 in transfected human prostate PC-3 ML clones: Orthotopic growth in severe combined immunodeficient mice. 974 47

Transforming growth factor-beta (TGF-beta) and interleukin 10 (Il-10) are cytokines that have a strong immunosuppressive ability. Their secretion by tumor cells is able to suppress an immunological response against tumor. Both factors have been shown to enhance tumor growth in glioblastomas and carcinoma of the breast. We determined the expression pattern of TGF-beta and Il-10 in squamous cell carcinomas of the head and neck (HNSCC) and a possible association with tumor stage and their pre-treatment cytokine serum levels. Cytokine expression in primary tumors and metastases of 21 patients with HNSCC was investigated by immunohistochemistry. To assess the TGF-beta2 and Il-10 levels in tumor patients before therapy 49 serum specimens were analyzed by ELISA. TGF-beta2 was detected in 95% of all tumor tissues analyzed and Il-10 in 79% of all tumors. TGF-beta2 was localized in tumor cells and tumor borders, while Il-10 was preferentially found in peritumoral connective tissue. Metastasizing tumors showed elevated pretreatment serum levels for TGF-beta2 and Il-10. There was no correlation between TGF-beta2 and Il-10 expression in tumor tissue and pretreatment serum levels. Our data show that the majority of HNSCC analyzed express TGF-beta2 and Il-10. A correlation between pretherapy elevated cytokine serum levels and tumor grade was shown.
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PMID:[Cytokine expression of transforming growth factor-beta2 and interleukin-10 in squamous cell carcinomas of the head and neck. Comparison of tissue expression and serum levels]. 1055 Mar 71

Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an adoptive immunotherapy model. The number of pulmonary metastases was significantly reduced and survival was prolonged after the transfer of anti-CD3/anti-CD28/anti-4-1BB-activated TDLN cells compared with an equivalent number of cells activated without anti-4-1BB. The antitumor effect through 4-1BB involvement during CD28 costimulation was dependent on IFN-gamma production and abrogated after IFN-gamma neutralization. By contrast, interleukin 10 neutralization resulted in significantly enhanced tumor regression. These results indicate that costimulation of TDLN cells through newly induced 4-1BB and CD3/CD28 signaling can significantly increase antitumor reactivity by shifting T-cell responses toward a type 1 cytokine pattern while concomitantly decreasing type 2 responses.
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PMID:Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. 1275 Feb 78

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFbeta1 and TGFbeta2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT-PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor beta receptor 1 (TGFbetaR1), and are therefore susceptible to TGFbeta1 and TGFbeta2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.
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PMID:Mechanisms of local immunosuppression in cutaneous melanoma. 1756 41

Immunosuppression in a patient with malignant tumor is a major obstacle in cancer treatment. In this study, we investigated changes in the circulating level of all measured immunosuppressive cytokines in patients with malignancy before and after high intensity focused ultrasound (HIFU) treatment. Fifteen patients with solid malignancy were enrolled in this study and an enzyme-linked immunoabsorbent assay (ELISA) method was used to measure serum level of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), transforming growth factor-beta2 (TGF-beta2), interleukin 6 (IL-6) and interleukin 10 (IL-10), respectively before and 1 wk after HIFU treatment. Among them, seven patients had distant metastasis and the remaining eight had no metastasis. All patients received one-session HIFU treatment for primary cancer, including complete ablation in eight patients without metastasis, and partial ablation in seven patients with metastases. The results showed that serum immunosuppressive cytokine levels decreased after HIFU treatment, and there were significant decreases of VEGF, TGF-beta1, and TGF-beta2 before and after HIFU treatment. Compared with the values in the metastatic patients, serum levels of immunosuppressive cytokines were significantly lower in the nonmetastatic patients after HIFU treatment. It is concluded that HIFU can decrease tumor-secreted immunosuppressive cytokine production in addition to its direct tumor destruction. This change may lessen tumor-induced immunosuppression and renew antitumor immunity after HIFU in cancer patients.
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PMID:Changes in circulating immunosuppressive cytokine levels of cancer patients after high intensity focused ultrasound treatment. 1785 83

In this study, we assessed the effectiveness of a live, attenuated Salmonella enterica serovar Typhi (S. Typhi) vaccine strain as a cancer immunotherapy in a mouse model of metastatic T-cell lymphoma. EL4 tumor-bearing C57BL/6J mice immunized with S. Typhi strain CVD 915, by injection into the tumor and the draining lymph node areas, displayed a significant decrease in tumor growth, a reduction in the mitotic index (MI) of tumors, a delayed development of palpable lymph node metastases and most importantly improved survival, compared to untreated mice. Besides, complete tumor regression was achieved in a small number of bacteria-treated mice. A successful therapeutic response associated with a significant reduction of tumor mass was evident as early as 5 days after treatment. The administration of Salmonella to tumor-bearing mice promoted early cellular infiltration (mainly neutrophils) within the tumor, and was accompanied by a decreased intratumoral interleukin 10 production as well as by leukocyte expansion in tumor draining lymph nodes. A tumor-specific memory immune response was induced in most of cured animals, as evidenced by the lack of tumor growth after a rechallenge with the same tumor. EL4 cells cultured with live Salmonella failed to proliferate and underwent apoptosis in a dose-dependent, time-dependent, and contact-dependent manner. To our knowledge, these results demonstrate for the first time the efficacy of a S. Typhi vaccine strain as an oncolytic and immunotherapeutic agent against a highly malignant tumor and support the use of S. Typhi-based vaccine strains in cancer therapy.
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PMID:Therapeutic effects of Salmonella typhi in a mouse model of T-cell lymphoma. 2350 64


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