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

Neoadjuvant immunotherapy with the combination of intratumoral IL-12 and TNF-alpha encapsulated in poly-lactic acid microspheres (PLAM) generate a greater systemic immune response than either cytokine alone. We sought to examine the effector cells responsible for this synergy using the poorly immunogenic B16 melanoma and MCA205 sarcoma cell lines. Splenocytes from MCA205 bearing mice treated with IL-12 and TNF-alpha PLAM contained significantly more tumor-specific IFN-gamma secreting cells than IL-12 alone. Adoptive transfer of lymphocytes from mice treated by the combination mediated significant tumor regression in mice bearing established pulmonary metastases. In mice bearing bilateral tumors, treatment of the primary with IL-12 and TNF-alpha PLAM, resulted in suppression of contralateral tumor growth. Both the local and distant effects were absent in mice depleted of CD8+ T-cells. In B16 bearing mice with established pulmonary disease, only the combination of intratumoral IL-12 and TNF-alpha resulted in a significant reduction of lung nodules. Both the local and distant effects were eradicated in mice depleted of either CD8+ T-cells or NK cells. The local and sustained release of IL-12 and TNF-alpha using PLAM synergistically activate both a cytotoxic T-cell and NK cell response, although their impact varies with MHC class I expression.
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PMID:Synergistic effect of intratumoral IL-12 and TNF-alpha microspheres: systemic anti-tumor immunity is mediated by both CD8+ CTL and NK cells. 1798 Nov 96

Overexpression of lysyl oxidase (LOX) is associated with the invasive potential of metastatic breast and head and neck cancer (HNC) cells and reduced metastasis-free and overall survival. Recently, we have demonstrated up-regulation of a new member of the LOX family, lysyl oxidase-like 4 (LOXL4), in invasive HNC revealed a significant correlation between LOXL4 expression and local lymph node metastases and higher tumour stages. The objective of this study was to examine whether cellular LOXL4 may provide an effective target for cell-meditated immunotherapy in invasive tumours associated with LOXL4 overexpression. As a feasibility study we expressed LOXL4 mRNA in immature dendritic cells derived from human peripheral blood mononuclear cells (PBMC). LOXL4 protein expression was ascertained using Western blotting and immunocytochemistry with polyclonal rabbit anti-LOXL4 antibody. The successfully transfected immature dendritic cells (DCs) were induced to mature with GM-CSF, IL-4, IL-1beta, TNF-alpha, IL-6, and PGE2, and then used to stimulate T cell enriched non-adherent fraction of PBMC. LOXL4 specific T cell stimulation induced cytotoxic T lymphocyte (CTL) response was monitored using IFN-gamma secretion from the non-adherent PBMC fraction exposed to mature, LOXL4 transfected DCs acting as the antigen presenting target cells. LOXL4-DC stimulated T cells produced higher IFN-gamma secretion compared to unstimulated T cells and T cells stimulated with untransfected DCs, in the presence of the pan-DR-epitope (PADRE). These initial results demonstrated the potential for LOXL4-transfected DCs to serve as efficient tumour vaccine and support their suitability as a vaccination strategy applicable to cancer patients with tumour specific up-regulation of LOXL4.
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PMID:Vaccination strategy to target lysyl oxidase-like 4 in dendritic cell based immunotherapy for head and neck cancer. 1820 53

Immunotherapy by vaccination represents a novel method for treatment of cancer. In this regard, vaccines with the broadest possible menu of relevant antigens stand the greatest chance of success. Tissue vaccines are composed of material harvested directly from tumors and contain not only antigens associated with neoplastic epithelium, but also those that may be unique to in vivo growth and antigens associated with the tumor stroma. To test the hypothesis that a tissue vaccine, produced by glutaraldehyde fixation of harvested syngeneic prostate tumors (GFT vaccine), could be used for treatment of prostate cancer, male Lobund-Wistar (LW) rats were treated with methylnitrosourea (MNU) and testosterone propionate to induce autochthonous prostate tumors. Tumor-bearing rats were randomly assigned to one of three treatment groups: no treatment (11 rats); vaccination with media (10 rats); or vaccination with the GFT vaccine (19 rats). Vaccination was given initially with Freund's complete adjuvant and booster doses were given with incomplete Freund's adjuvant every week until the time of euthanasia. There were no significant differences in mean tumor weight between groups; however, GFT-vaccinated rats had a prolonged survival time; and 4/19 (21%) GFT-vaccinated rats were found to be tumor-free compared to none of the untreated or media-treated controls. Further, pulmonary metastasis occurred in only 5/15 (33%) of GFT-vaccinated rats compared to 10/11 (91%) and 10/10 (100%) of untreated and media-vaccinated controls, respectively. Supernatants of cultured splenocytes from similarly media- and GFT-vaccinated rats demonstrated significant (P < 0.001) increases in IFN-gamma and TNF-alpha from splenocytes of GFT-vaccinated rats, suggesting that GFT vaccination stimulates a Th1 response. In summary, treatment of tumor-bearing rats with a tissue vaccine stimulated a protective immune response that resulted in complete tumor regression in 21% of animals and reduced the number of animals with any evidence of metastasis by nearly 70%. These results suggest that tissue vaccines may be useful for the treatment of prostate cancer.
Clin Exp Metastasis 2008
PMID:Inhibition of prostate cancer metastasis by administration of a tissue vaccine. 1882 Oct 60

EBV-induced gene 3 (EBI-3) codes for a soluble type I receptor homologous to the p40 subunit of IL-12 that is expressed by APCs following activation. In this study, we assessed the role of EBI-3 in a model of lung melanoma metastasis. Intravenous injection of the B16-F10 cell line resulted in a significant reduction of lung tumor metastasis in EBI-3(-/-) recipient mice compared with wild-type mice. The immunological finding accompanying this effect was the expansion of a newly described cell subset called IFN-gamma producing killer dendritic cells associated with CD8(+) T cell responses in the lung of EBI-3(-/-) mice including IFN-gamma release and TNF-alpha-induced programmed tumor cell death. Depletion of CD8(+) T cells as well as targeting T-bet abrogated the protective effects of EBI-3 deficiency on lung melanoma metastases. Finally, adoptive transfer of EBI-3(-/-) CD8(+) T cells into tumor bearing wild-type mice inhibited lung metastasis in recipient mice. Taken together, these data demonstrate that targeting EBI-3 leads to a T-bet-mediated antitumor CD8(+) T cell responses in the lung.
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PMID:Immunosurveillance of lung melanoma metastasis in EBI-3-deficient mice mediated by CD8+ T cells. 1894 Dec 5

This study evaluates the effects of gingival fibroblasts, type I collagen and autocrine/paracrine elements on cytokine expression in paired primary and metastatic human squamous cell carcinoma (HNSCC) cell lines. Additionally, the effects of IL-1alpha, IL-1beta, IL-6, TNF-alpha, TGF-beta and HGF on MMPs and cell invasion were investigated. RT-PCR results indicated the presence of mRNAs for IL-1alpha, IL-1beta, IL-6, TNF-alpha, and TGF-beta in primary and metastatic HNSCC cell lines but high expression of cytokines was not a prerequisite for metastatic cancer cells. HGF mRNA was not detected in the cancer cell lines. Co-culturing of HNSCC cells with fibroblasts caused increases in cytokine expression. Type I collagen and conditioned media derived from HNSCC cells or fibroblasts enhanced cytokine expression in the cancer cells. Cytokines also enhanced MMP-2 and MMP-9 enzymatic activities as well as HNSCC cell invasion. Our findings suggest that the interactions between cancer cells, the extracellular matrix and fibroblasts, as mediated by cytokines, play important roles in the progression of HNSCC.
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PMID:Tumor-stroma interactions influence cytokine expression and matrix metalloproteinase activities in paired primary and metastatic head and neck cancer cells. 1899 11

Engagement of endothelial protein C receptor (EPCR) by activated protein C (aPC) decreases expression of endothelial adhesion molecules implicated in tumor-endothelium interactions. We examined the role of the aPC/EPCR pathway on tumor migration and metastasis. In vitro, B16-F10 melanoma cells showed decreased adhesion to and transmigration through endothelium treated with recombinant human aPC (rhaPC). In murine B16-F10 metastasis models, transgenic EPCR overexpressing (Tie2-EPCR) mice exhibited marked reductions in liver (50%) and lung (92%) metastases compared with wild-type (WT) animals. Intravital imaging showed reduced B16-F10 entrapment within livers of Tie2-EPCR compared with WT mice. A similar reduction was observed in WT mice treated with rhaPC. Strikingly, rhaPC treatment resulted in a 44% reduction in lung metastases. This was associated with decreased lung P-selectin and TNF-alpha mRNA levels. These findings support an important role for the aPC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration.
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PMID:Role of activated protein C and its receptor in inhibition of tumor metastasis. 1918 68

Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-alpha, IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-alpha. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.
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PMID:CL097, a TLR7/8 ligand, inhibits TLR-4--dependent activation of IRAK-M and BCL-3 expression. 1933 35

Metastasis as a complex process involves loss of adhesion, migration, invasion and proliferation of cancer cells. Sulforaphane (SFN) is one of naturally occurring cancer chemopreventive isothiocyanates found in cruciferous vegetables, consumption of which has been associated with reduced risk of cancer. In this study, we describe effect of SFN on various aspects determining invasive behavior of MDA-MB-231 human breast carcinoma cells. We studied modulation of molecules associated with epithelial to mesenchymal transition (EMT), hypoxic marker CA IX and mitochondrially located peripheral benzodiazepine receptor (PBR) using flow cytometry, gene expression of matrix metalloproteinases MMP1, 3, 7, 9, 14, transcription factors POU5F1 and Twist1 mRNA by RT PCR, and cytokine production by multiplex bead assay. SFN downregulated PBR and vimentin expression in a dose dependent manner, but significantly affected neither HIF-1alpha, nor CA IX protein expression, nor VEGF and GLUT1 mRNA levels. Among studied MMPs, MMP7 and MMP14 mRNA were downregulated while no apparent effect on MMP1, MMP3 and MMP9 was observed. Further, we found significant down regulation of Twist1 and POU5F1, transcription factors that mediate EMT and the self-renewal of undifferentiated embryonic stem cells. SFN reduced also the production of pro-inflammatory cytokines IL-1beta, IL-6, TNF-alpha, IFN-gamma, immunomodulating cytokine IL-4 and growth factors involved in angiogenesis PDGF and VEGF. Our study shows that SFN efficacy is associated with the reversal of several biological characteristics connected with EMT or implicated in the matrix degradation and extracellular proteolysis, as well as with reduced production of pro-inflammatory cytokines and pro-angiogenic growth factors in MDA-MB-231 cells.
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PMID:Modulation of markers associated with aggressive phenotype in MDA-MB-231 breast carcinoma cells by sulforaphane. 1972 65

Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.
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PMID:Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer. 1980 95

Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor with poor outcome and increasing incidence. We examined by immunohistochemistry the expression of three novel matrix metalloproteinases (MMPs)-MMP-21, MMP-26, and MMP-28-in 44 primary MCC tumors and six lymph node metastases while MMP-10 served as a positive control. Their mRNA expression was also studied in the UISO MCC cell line basally and after various stimulations using quantitative real-time PCR. MMP-28 was observed in tumor cells of 15/44 samples especially in tumors <2 cm in diameter (p = 0.015) while 21/44 specimens showed MMP-28 in the tumor stroma. Expression of MMP-21 was demonstrated in tumor cells of 13/43 samples. MMP-26, instead, was positive in stromal cells (17/44) and its expression associated with tumors >or=2 cm in diameter (p = 0.006). Stromal expression of MMP-10 was the most frequent finding of the studied samples (31/44), but MMP-10 was detected also in tumor cells (17/44). Most of the metastatic lymph nodes expressed MMP-10 and MMP-26. MMP-10, MMP-21, and MMP-28 mRNAs were basally expressed by the UISO cells, and the corresponding proteins were detectable by immunostaining of cultured cells. IFN-alpha and TNF-alpha downregulated MMP-21 and MMP-28 expression. Our results suggest that novel MMPs may have a role in MCC pathogenesis: especially that MMP-26 expression in stroma is associated with larger tumors with poor prognosis. Expression of MMP-21 and MMP-28 seems to associate with the tumors of lesser malignant potential. We also confirm the previous finding on the role of MMP-10 in MCC pathogenesis.
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PMID:Expression of MMP-10, MMP-21, MMP-26, and MMP-28 in Merkel cell carcinoma. 1992 Dec 52


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