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)

Despite recent advances in treatment strategies, the overall 5-year survival rate for patients with common epithelial cancers is poor largely because of the difficulty in treating metastatic cancers. Therefore, therapeutic agents are urgently needed that can effectively inhibit both primary epithelial tumors and their metastases. One such agent that has shown promise in preclinical studies is the tumor suppressor/cytokine, melanoma differentiation associated gene-7 also known as interleukin-24 (mda-7/IL-24). Preclinical studies from our and other laboratories have shown that overexpression of MDA-7/IL-24 causes a strong tumor- suppressive effect in many human cancer cells but spares normal cells. This gene therapy also enhances the tumor-suppressive activity of radiotherapy and chemotherapy. Secreted MDA-7 protein that is glycosylated also has been shown to have potent antiangiogenic activity both in vitro and in vivo. Studies examining the immune properties of mda-7 have shown that MDA-7/IL-24 unlike the related IL-10, functions as a Th1 cytokine. Recently, an MDA-7 protein-mediated "bystander effect" on tumor cells has been documented. Building on these findings we successfully completed a Phase I clinical trial of adenovirus-based mda-7 cancer therapy that confirmed the safety of this gene therapy. Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted. The outcome of such ongoing mda-7-based gene therapy trials will allow us to better understand this therapy's clinical utility.
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PMID:MDA-7/IL-24-based cancer gene therapy: translation from the laboratory to the clinic. 1647 47

The hepatic immunological environment, dominated by NK and NKR(+) T cells, seems specialised to respond to malignant challenge. Ineffective immune responses to malignancy are likely determined by factors including alterations in the local cytokine profile. This study examines the cytokine milieu of normal and tumour-bearing liver, quantifying pro-/anti-inflammatory cytokines using modified ELISAs and real-time quantitative PCR. Cytokine protein was localised using immunohistochemistry. We demonstrate an active cytokine environment in normal liver, with high levels of inflammatory and regulatory cytokines. Inflammatory IFN-gamma was increased in tumour-bearing liver (p<0.0001). However, a much greater increase in anti-inflammatory IL-10, produced by non-parenchymal cells (p<0.0005), resulted in a reduced IFN-gamma:IL-10 ratio in tumour-bearing liver (p<0.02). In contrast, immunosuppressive TGF-beta and IL-13 were significantly downregulated (p<0.02). Furthermore, IL-2 was not increased and IL-15 was reduced (p<0.02). The IFN-gamma inducing cytokine, IL-18 was increased in tumour-bearing liver (p<0.02), while pro-inflammatory TNF-alpha was suppressed (p<0.05). These results suggest that, whilst there is a significant inflammatory immune response in tumour-bearing liver, evidenced by increased levels of IFN-gamma, disproportionate increase in IL-10 may be a key factor in facilitating tumour progression. Therapies aimed at antagonising IL-10-mediated immunosuppression may prove a useful strategy in the future treatment of metastatic disease.
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PMID:Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: implications for hepatic anti-tumour immunity. 1697 Nov 36

Tumors produce several factors, such as Prostaglandins (PGs), Interleukin (IL)-10, Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor (TGF)-beta, which may directly or indirectly inhibit the immune response and may hamper immunotherapy. Furthermore, cells of innate or adaptive immunity, recruited by tumor-derived factors, may contribute in immunosuppression. Regulatory T (Treg) cells such as the "naturally occurring" CD4(+)/CD25(+) Treg and the IL-10-induced Tr1 cells are major players in this arena. Paradoxically Treg cells are stimulated by IL-2, which is used in tumor immunotherapy. Treg cells suppress T cell responses through soluble factors or by contact-dependent mechanisms, such as the Cytotoxic T Lymphocyte Antigen (CTLA)-4-mediated induction of Indoleamine 2,3-Dioxygenase (IDO) in dendritic cells (DC). IDO inhibits T cell responses by depleting Tryptophan and producing Kynurenine, which is toxic to lymphocytes. Macrophages, granulocytes or myeloid suppressor cells (MSC) suppress immunity by other enzymatic mechanisms, involving Arginase and Nitric Oxide Synthase (NOS). Subversion of tumor immunosuppression is required for successful immunotherapy. Attempts to block or eliminate Treg cells have been made by the use of chemotherapy, anti-CD25 or anti-CTLA-4 antibodies, IL-2-toxin chimeric proteins or Glucocorticoid-induced TNF-like Receptor (GITR) and CD134/OX-40 ligands. Tumor cells genetically modified to secrete IL-21 (an immune-stimulatory "IL-2-like" cytokine, which is not involved in immune regulation) cured experimental metastases in combination with anti-CD25 monoclonal antibodies (mAbs). Also strategies aimed at blocking enzyme-based immune-suppressive mechanisms are suitable, as suggested by experimental evidences in mouse tumor models.
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PMID:Targeting tumor-related immunosuppression for cancer immunotherapy. 1701 74

Cancer immunotherapy by dendritic cell (DC)/tumor cell fusion hybrids (DC/TC hybrids) has been shown to elicit potent anti-tumor effects via the induction of immune responses against multiple tumor-associated antigens. In the present study, we compared the anti-tumor effects of vaccinating Balb/c mice (H-2(d)) with CT26CL25 colon carcinoma cells that had been fused with either syngeneic DCs from Balb/c mice, allogeneic DCs from C57BL/6 mice (H-2(b)) or semiallogeneic DCs from B6D2F1 mice (H-2(b/d)). Preimmunization with either semiallogeneic or allogeneic DC/TC hybrids induced complete protection from tumor challenge, whereas mice preimmunized with syngeneic DC/TC hybrids were only partially protected (75% tumor rejection). The average number of pulmonary metastases after intravenous tumor injection decreased significantly following immunization with semiallogeneic or allogeneic DC/TC hybrids (8.3 +/- 7.9 or 16.3 +/- 3.5, mean +/- SD) relative to syngeneic DC/TC hybrids (67.8 +/- 6.3). These data demonstrate that vaccination with semiallogeneic DC/TC hybrids resulted in the greatest anti-tumor efficacy. Anti-tumor effects showed by in vivo studies were virtually accomplished by the frequency of induced CTLs specific to both gp70 and beta-galactosidase assessed by using pentameric assay. Among the fusion vaccines tested, semiallogeneic DC/TC hybrids induced the highest ratio of Th1 cytokine IFN-gamma to Th2 cytokine IL-10. In addition, allogeneic or semiallogeneic DC/TC hybrids elicited a significantly stronger NK activity than syngeneic DC/TC hybrids. These findings suggest that in clinical settings, DCs derived from a healthy donor (which are generally characterized as more semiallogeneic than allogeneic) may be more capable than autologous DCs of inducing promising anti-tumor effects in vaccinations with DC/TC hybrids.
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PMID:Superior anti-tumor protection and therapeutic efficacy of vaccination with allogeneic and semiallogeneic dendritic cell/tumor cell fusion hybrids for murine colon adenocarcinoma. 1713 Nov 18

We have reported important benefits and survival with an immunotherapy schedule in patients with endocrine-dependent breast cancer and distant metastases. Here clinical outcome is updated and its correlation with new immunological data is shown. In 32 evaluated breast cancer patients with endocrine-dependent distant metastases treated with a new immunotherapy schedule (cyclic administration of beta-interferon and interleukin-2), cellular immunity, cytokines and CRP were related to the clinical course. Estimated and true 5-10 year overall survival rates from first line antiestrogen and distant metastases were higher than previously reported in a similar population. Interleukin-2 administration was followed by a significant increase in total lymphocytes, CD4+, CD8+, CD16+56+ (NK) cells, IL-6, IL-12, and CRP (from P<0.04 to P<0.000) but no change in IL-10 and TGFbeta1 during clinical benefit. During progressive disease no change was observed in the former parameters, concomitant with a significant increase in IL-10 (P=0.020) and a significant decrease in TGFbeta1 (P=0.023). These findings confirm that cellular immunity is significantly stimulated by IL-2 only during clinical benefit. Furthermore, these results demonstrate that different changes of proinflammatory cytokines, CRP and inhibiting factors are consistent with associated clinical benefit or with disease progression, respectively.
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PMID:Relationship of cellular immunity, cytokines and CRP with clinical course in breast cancer patients with endocrine-dependent distant metastases treated with immunotherapy. 1721 77

Tumor-associated macrophages (TAMs) play a major role in promoting tumor growth and metastasis and in suppressing the antitumor immune response. Despite the immunosuppressive environment created by the tumor and enforced by tumor-associated macrophages, treatment of tumor-bearing mice with IL-12 induces tumor regression associated with appearance of activated NK cells and activated tumor-specific CTLs. We therefore tested the hypothesis that IL-12 treatment could alter the function of these tumor-associated suppressor macrophages. Analysis of tumor-infiltrating macrophages and distal TAMs revealed that IL-12, both in vivo and in vitro, induced a rapid (<90 min) reduction of tumor supportive macrophage activities (IL-10, MCP-1, migration inhibitory factor, and TGFbeta production) and a concomitant increase in proinflammatory and proimmunogenic activities (TNF-alpha, IL-15, and IL-18 production). Similar shifts in functional phenotype were induced by IL-12 in tumor-infiltrating macrophages isolated from the primary tumor mass and in TAMs isolated from lung containing metastases, spleen, and peritoneal cavity. Therefore, although TAMs display a strongly polarized immunosuppressive functional profile, they retain the ability to change their functional profile to proinflammatory activities given the appropriate stimulus. The ability of IL-12 to initiate this functional conversion may contribute to early amplification of the subsequent destructive antitumor immune response.
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PMID:IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. 1723 82

Many immune therapeutic strategies are under development for melanoma to treat metastatic disease and prevent disease reoccurrence. However, human melanoma cells are often deficient in antigen processing and this appears to play a role in their expansion and escape from immunosurveillance. For example, expression of the transporters associated with antigen processing (TAP1 and TAP2) is down-regulated in the mouse melanoma cell line B16F10. This results in a lack of tumor-associated antigen processing, low surface expression of MHC Class I molecules and low immunogenicity. We observe that restoration of TAP1 expression by transfection resurrects the processing and presentation of viral antigens, and the melanoma-associated antigen, TRP-2. Immunization with irradiated B16F10/rTAP1 transfected cells generates CTLs that are capable of killing B16F10/rTAP1 transfected targets and B16F10 targets deficient in TAP1. Furthermore, B16F10/rTAP1 transfectants grow at a significantly slower rate in mice than B16F10 cells. In an experimental model that closely recapitulates the clinical situation, treatment of B16F10 tumors in mice with a vaccinia virus vector expressing TAP1 also significantly decreases tumor growth in vivo. Furthermore, tumors treated with vaccinia TAP1 had significantly reduced numbers of immunosuppressive, CD3(+)/IL-10 positive, tumor infiltrating lymphocytes. Therefore, TAP1 expression restores both antigen presentation and immunogenicity in B16F10 melanoma cells and concomitantly reduces immunosuppressive IL-10 production at the local tumor site, thereby increasing immunosurveillance mechanisms against tumors.
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PMID:TAP expression reduces IL-10 expressing tumor infiltrating lymphocytes and restores immunosurveillance against melanoma. 1727 2

Surgery may render patients susceptible to life-threatening complications, including infections and later metastases. Suppression of cell mediated immunity (CMI) and perturbations in the cytokine network were implicated in these outcomes. The current study assessed the effects of various surgeries on a wide array of immune indices, and compared patients' pre-operative immune status to that of control subjects. A total of 81 subjects (controls, moderate and major surgeries) provided up to five daily blood samples. Whole blood procedures were conducted within hours of blood withdrawal, assessing NK cell number and cytotoxicity, and plasma cytokine levels and induced production (IFNgamma, IL-6, IL-10, and IL-12). Our findings indicate that surgery reduced NK cell numbers/ml blood, and independently suppressed NK activity per NK cell and per ml blood. Among other perturbations in the cytokine network, pro-CMI cytokine production (IL-12 and IFNgamma) was reduced by surgery. Surprisingly, plasma levels of IFNgamma and IL-6 increased following surgery, while their in vitro induced production showed opposite effects. Patients awaiting surgery exhibited impaired IL-12 induced production and NK activity/ml, and reduced IFNgamma plasma levels. No significant associations were found between NK cytotoxicity and Th1 cytokines, although these indices showed high correlations with other variables. Overall, our findings indicate that patients exhibit impaired immune functions even before operation, which seem to contribute to the evident post-operative immune suppression. In the peri-operative context, induced cytokine production and plasma cytokines levels reflect different processes. Last, we suggest that peri-operative suppression of NK activity is mediated by neuroendocrine responses rather than Th1 cytokines.
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PMID:Immune suppression while awaiting surgery and following it: dissociations between plasma cytokine levels, their induced production, and NK cell cytotoxicity. 1729 81

Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity.
Clin Exp Metastasis 2007
PMID:Autocrine motility-stimulatory pathways of oral premalignant lesion cells. 1737 39

Interleukin (IL)-10 is expressed in many solid tumours and plays an ambiguous role in controlling cancer growth and metastasis. In order to determine whether IL-10 is involved in tumour progression and prognosis in nonsmall cell lung cancer (NSCLC), IL-10 expression in tumour cells and tumour-associated macrophages (TAMs) and its associations, if any, with clinicopathological features were investigated. Paraffin-embedded sections of surgical specimens obtained from 50 patients who had undergone surgery for NSCLC were immunostained with an antibody directed against IL-10. TAMs and tumour cells positive for IL-10 were subsequently quantified. IL-10-positive TAM percentage was higher in patients with stage II, III and IV NSCLC, and in those with lymph node metastases compared with patients with stage I NSCLC. High IL-10 expression by TAMs was a significant independent predictor of advanced tumour stage, and thus was associated with worse overall survival. Conversely, IL-10 expression by tumour cells did not differ between stages II, III and IV and stage I NSCLC. In conclusion, interleukin-10 expression by tumour-associated macrophages, but not by tumour cells, may play a role in the progression and prognosis of nonsmall cell lung cancer. These results may be useful in the development of novel approaches for anticancer treatments.
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PMID:Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer. 1790 81


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