Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines affect inflammation and cancer through leukocyte attraction and angiogenesis. Here, we demonstrate that CXCL4L1/platelet factor-4 variant (PF-4var), a highly angiostatic chemokine, is poorly chemotactic for phagocytes and is inducible in monocytes by inflammatory mediators but remained undetectable in macrophages and neutrophils. In addition, CXCL4L1/PF-4var production by mesenchymal tumor cells was evidenced in vitro and in vivo by specific ELISA and immunohistochemistry. CXCL4L1/PF-4var, but not CXCL4/PF-4, was coinduced with the angiogenic chemokine CXCL6/granulocyte chemotactic protein-2 (GCP-2) by cytokines, e.g., IL-1beta and IL-17, in sarcoma cells, but not in diploid fibroblasts. Furthermore, the induction of CXCL6/GCP-2 in endothelial cells by IL-1beta was enhanced synergistically by TNF-alpha but inhibited by IFN-gamma, which synergized with IL-1beta to produce the angiostatic CXCL10/IFN-gamma-induced protein-10. These findings indicate that the equilibrium between angiostatic and angiogenic factors during inflammation and tumor progression is rather complex and differs depending on the chemokine, cell type, and stimulus. Selective intervention in the chemokine network may drastically disturb this delicate balance of angiogenesis and tissue repair. Application of angiostatic CXCL4L1/PF-4var without attraction of protumoral phagocytes may be beneficial in cancer therapy.
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PMID:Stimulation of angiostatic platelet factor-4 variant (CXCL4L1/PF-4var) versus inhibition of angiogenic granulocyte chemotactic protein-2 (CXCL6/GCP-2) in normal and tumoral mesenchymal cells. 1782 42

IFN regulatory factor 8 (IRF8) is a transcription factor that was originally identified in myeloid cells and has been shown to be essential for differentiation and function of hemopoietic cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of the granulocytic and monocytic lineages that progress into a phenotype resembling human chronic myelogenous leukemia. In human patients with chronic myelogenous leukemia, IRF8 transcript levels are frequently diminished. Therefore, IRF8 is a key regulator of myeloid tumor development. In this study, we report that IRF8 is a critical regulator of apoptosis in nonhemopoietic tumor cells. Disruption of IRF8 function with IRF8 dominant-negative mutants diminished Fas-mediated apoptosis in sarcoma tumor cells. Both constitutively expressed and IFN-gamma-activated IRF8 were involved in regulation of apoptosis. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFN-gamma-initiated induction of STAT1 phosphorylation, which in turn, blocked IFN-gamma-induced Fas up-regulation. Interestingly, the constitutively expressed IRF8 was also essential for TNF-alpha sensitization of Fas-mediated apoptosis because disruption of IRF8 function also inhibited TNF-alpha-sensitized and Fas-mediated apoptosis. Taken together, our data suggest that IRF8 is an essential mediator of Fas-mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas expression in nonhemopoietic tumor cells.
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PMID:IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression. 1787 76

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

Ganoderma lucidum (GL, Lingzhi) has been suggested as a candidate for immunomodulation and cancer treatment. The present study aimed at comparing the different parts of the fruiting body (whole fruiting body, pileus and stipe) of GL as well as Ganoderma spores (sporoderm-broken and -unbroken), with regard to their antitumor and immunomodulatory activities in S-180 sarcoma-bearing mice. The hot water extracts of different parts of GL or the Ganoderma spores were orally administered to the sarcoma-bearing mice. The results showed that GL whole fruiting body, stipe and sporoderm-broken spore possessed stronger inhibitory activities on sarcoma growth when compared with the pileus extract. Higher immunomodulatory activities in terms of enhancing the proliferative responses and the cytokines (IFN-gamma, IL-4 and IL-6) production of spleen lymphocytes were also found in GL stipe and sporoderm-broken spore treatment groups. The sporoderm-broken spores had higher stimulatory effects on mitogen-activated spleen lymphocytes of healthy mice than those of sarcoma-bearing mice. In addition, the immunostimulatory activities of GL hot water extracts and Ganoderma spores were shown to be comparable; hence the latter did not show superiority in efficacy. This is the first comparative study on the immunomodulatory activities of Ganoderma spores and the fruiting body extracts.
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PMID:Comparative studies on the immunomodulatory and antitumor activities of the different parts of fruiting body of Ganoderma lucidum and Ganoderma spores. 1857 Jan 98

The aim of this project was to investigate the anti-tumor effect of an IL-12 gene modified mammary sarcoma murine cell line, EMT6/IL-12, in mouse model. In this study, we transfected the recombinant eukaryotic plasmid encoding IL-12 gene (pcDNA6-p70) into EMT6 and obtained the IL-12 expressing EMT6/IL-12 cell line. Then EMT6/IL-12 cells were s.c. inoculated into mice. The recombinant vector treatment group was set as control. We then evaluated the inhibition of tumor growth and the anti-tumor immunity function in vivo such as cytotoxicity, proliferation of splenocytes and serial IFN-gamma level. And the percentage of IFN-gamma producing CD4 or CD8 T cells among splenocytes was also analyzed in tumor bearing mice. Our results showed that the growth of tumors was obviously inhibited in EMT6/IL-12 group. Moreover, the capacities of anti-tumor immunity were all significantly higher in EMT6/IL-12 group compared to the controls. The results of the present investigation support the notion that EMT6/IL-12 could exert gene therapy in tumor model by improving the anti-tumor cellular immunity.
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PMID:Interleukin-12 gene modification exerts anti-tumor effects on murine mammary sarcoma cell line in vivo. 1858 5

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

3-Methylcholanthrene (MCA)-induced sarcomas have been used as conventional tools for investigating immunosurveillance against tumor development. However, MCA-induced sarcoma is not always an ideal model for the study of the human cancer system because carcinomas and not sarcomas are the dominant types of human cancers. To resolve this problem, we established a novel and simple method to induce mouse squamous cell carcinomas (SCCs). As well known, the subcutaneous injection of MCA caused the formation of sarcomas at 100% incidence. However, we here first succeeded at inducing SCC at 60% of incidence within 2 months by a single intra-dermal injection of MCA. Using this primary SCC model, we demonstrated the critical role of interferon (IFN)-gamma-dependent type 1 immunity in immunosurveillance against SCC from the following results: (i) The incidence of SCC was accelerated in IFN-gamma-deficient mice compared with that in wild-type mice; (ii) In vivo injection of CpG-oligodeoxynucleotides (CpG-ODN) caused a marked reduction in the incidence of SCC in parallel with the activation of type 1-dependent antitumor immunity and (iii) The antitumor activity of CpG-ODN was significantly decreased in IFN-gamma-deficient mice. Thus, our established MCA-induced mouse SCC model could be a powerful tool for evaluating immunosurveillance mechanisms during the development of SCC and might result in a novel strategy to address immunosurveillance mechanisms of human cancer.
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PMID:IFN-gamma-dependent type 1 immunity is crucial for immunosurveillance against squamous cell carcinoma in a novel mouse carcinogenesis model. 1950 17

Thymic function decreases in line with tumor progression in patients with cancer, resulting in immunodeficiency and a poor prognosis. In the present study, we attempted to restore thymic function by BALB/c (H-2(d)) syngeneic (Syn), or B6 (H-2(b)) allogeneic (Allo) bone marrow transplantation (BMT) using intra-bone marrow-bone marrow transplantation (IBM-BMT) plus Syn-, Allo- or C3H (H-2(k)) 3rd-party fetal thymus transplantation (TT). Although the BALB/c mice with advanced tumors (Meth-A sarcoma; H-2(d), >4 cm(2)) treated with either Syn- or Allo-BMT alone showed a slight improvement in survival compared with non-treated controls, the mice treated with BMT + TT showed a longer survival. The mice treated with Allo-BMT + Allo-TT or 3rd-party TT showed the longest survival. Interestingly, although there was no difference in main tumor size among the BMT groups, lung metastasis was significantly inhibited by Allo-BMT + Allo-TT or 3rd-party TT. Numbers of CD4(+) and CD8(+) T cells, Con A response, and IFN-gamma production increased significantly, whereas number of Gr-1(+)/CD11b(+) myeloid suppressor cells and the percentage of FoxP3(+) cells in CD4(+) T cells significantly decreased in these mice. Furthermore, there was a positive correlation between survival days and the number of T cells or T cell function, while there was a negative correlation between survival days and lung metastasis, the number of Gr-1(+)/CD11b(+) cells, or the percentage of FoxP3(+) cells. These results suggest that BMT + TT, particularly Allo-BMT + Allo-TT or 3rd-party TT, is most effective in prolonging survival as a result of the restoration of T cell function in hosts with advanced tumors.
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PMID:Prolonged survival in mice with advanced tumors treated with syngeneic or allogeneic intra-bone marrow-bone marrow transplantation plus fetal thymus transplantation. 2022 83

Natural killer (NK) cells represent a promising cell type to utilize for effective adoptive immunotherapy. However, little is known about the important cytolytic molecules and signaling pathways used by NK cells in the adoptive transfer setting. To address this issue, we developed a novel mouse model to investigate the trafficking and mechanism of action of these cells. We demonstrate that methylcholanthrene-induced RKIK sarcoma cells were susceptible to NK cell-mediated lysis in vitro and in vivo following adoptive transfer of NK cells in C57BL/6 RAG-2(-/-)gammac(-/-) mice. Cytotoxic molecules perforin, granzymes B and M as well as the death ligand TRAIL and pro-inflammatory cytokine IFN-gamma were found to be important in the anti-tumor effect mediated by adoptively transferred NK cells. Importantly, we demonstrate that adoptively transferred NK cells could traffic to the tumor site and persisted in vivo which correlated with the anti-tumor effect observed. Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies.
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PMID:Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. 2037 39

We found that Aged Garlic Extract (AGE) could be a significant immuno-potentiator, and could exhibit anti-tumor activities through immune modulation. Consequently, AGE stimulated the proliferation of mouse spleen cells and the release of cytokines, such as IL-2, TNF-alpha and IFN-gamma, increased NK activities, and enhanced phagocytosis of peritoneal macrophages. AGE treatment also stimulated the reactivity of lymphocytes in response to cytokines or mitogens. AGE was far superior to PSK in IL-2 induction, but slightly inferior to PSK in nitric oxide induction. AGE, as effectively as PSK (Krestin), significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in NK and killer activities of spleen cells were observed in Sarcoma-180 bearing mice treated with AGE. These results strongly suggest that AGE is as effective as PSK, and could serve as a potent biological response modifier on NK cells and T lymphocytes, and subsequently inhibit the growth of transplanted tumors.
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PMID:Immunomodulation and antitumor activities of Aged Garlic Extract. 2319 97


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