Fibrosarcoma News Headlines

Flavonoid glycosides isolated from Salicornia herbacea inhibit matrix metalloproteinase in HT1080 cells.

Toxicol In Vitro. 2008 Jul 31;

Authors: Kong CS, Kim YA, Kim MM, Park JS, Kim JA, Kim SK, Lee BJ, Nam TJ, Seo Y

Flavonoid glycosides, isorhamnetin 3-capital O, Cyrillic-beta-D-glucoside, and quercetin 3-O-beta-D-glucoside were isolated from Salicornia herbacea and their inhibitory effects on matrix metalloproteinase-9 and -2 (MMP-9 and -2) were evaluated in human fibrosarcoma cell line (HT1080). In zymography experiments, these flavonoid glycosides led to the reduction of the expression levels and activities of MMP-9 and -2 without any significant difference between these flavonoid glycosides. Protein expression levels of both MMP-9 and MMP-2 were inhibited and TIMP-1 (tissue inhibitor of metalloproteinase-1) protein level was enhanced by these flavonoid glycosides. Moreover, a transfection study carried out with AP-1 reporter construct revealed that the reporter activity was suppressed by treatment with isorhamnetin 3-capital O, Cyrillic-beta-D-glucoside. Therefore, these results suggested that these flavonoid glycosides have a potential as valuable natural chemopreventive agents for cancer.

PMID: 18715546 [PubMed - as supplied by publisher]

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Antitumor mechanism of intratumoral injection with IL-12-expressing adenoviral vector against IL-12-unresponsive tumor.

Biochem Biophys Res Commun. 2008 Aug 8;372(4):821-5

Authors: Kanagawa N, Gao JQ, Motomura Y, Yanagawa T, Mukai Y, Yoshioka Y, Okada N, Nakagawa S

Interleukin-12 (IL-12) has potent antitumor activities through the activation of natural killer cells and cytotoxic T lymphocytes. Some tumors, however, are resistant to IL-12; for example, in murine Meth-A fibrosarcoma, an IL-12-unresponsive tumor model, tumors do not regress following IL-12 administration due to the fact that few T cells migrate to tumor sites. Transduction of IL-12 genes into preexisting Meth-A tumors using RGD fiber-mutant adenoviral vectors (AdRGD), however, enhances tumor infiltration by T cells, thereby inducing tumor regression due to enhanced tumor infiltration by T cells. Here, we demonstrated the mechanism underlying the anti-tumor effect induced by intratumoral injection of AdRGD encoding IL-12 (AdRGD-IL12). The anti-tumor activity of the IL-12 treatment was T cell-dependent, requiring mainly CD8(+) cytotoxic T lymphocytes in the effector phase, as confirmed by analysis using BALB/c nude mice and an in vivo depletion assay. Additionally, intratumoral injection of AdRGD-IL12 promoted cellular immunity, as determined by the frequency of interferon-gamma-positive cells in regional lymph nodes, and changed the tumor microenvironment to an immunologic activation state with enhanced expression of lymphocyte activation markers and cell adhesion molecules. The present data provide evidence that the antitumor effect of IL-12 gene transduction in a local tumor site is dependent on induced alterations of the tumor microenvironment and systemic immunity.

PMID: 18519033 [PubMed - indexed for MEDLINE]

In vivo induction of necrosis in mice fibrosarcoma via intravenous injection of type B staphylococcal enterotoxin.

Biotechnol Lett. 2008 Jul 24;

Authors: Fooladi AA, Sattari M, Hassan ZM, Mahdavi M, Azizi T, Horii A

The bacterial superantigen staphylococcal enterotoxin B (SEB) is a potent inducer of cytotoxic T-cell activity and cytokine production in vivo. We investigated the possibility of the therapeutic application of SEB in patients with fibrosarcoma. The anti-tumor effect of SEB in mice with inoculated fibrosarcoma (WEHI-164) was examined by intravenous (IV) and intratumoral (IT) injection and the sizes of the inoculated tumors, IFN-gamma production, and CD4+/CD8+ T cell infiltration were determined. The inoculated tumors were also examined histologically. In the mice in the IV-injected group, a significant reduction (P < 0.02) of tumor size was observed in comparison with mice in the IT-injected and control groups. Furthermore, the mice in the IV-injected group showed significantly higher levels of IFN-gamma (P < 0.009) and CD4+/CD8+ T cell infiltration when compared with the other groups (P < 0.02). A significantly higher frequency of necrosis in tumor tissues was also observed in mice in the IV-injected group (P < 0.05). Our present findings suggest that tumor cell death is caused by increased cytotoxic T-cell activity and cytokine levels in response to the IV injection of SEB and that SEB may be a good option for use as a novel therapy in patients with fibrosarcoma.

PMID: 18651228 [PubMed - as supplied by publisher]

Congenital fibrosarcoma with a novel complex 3-way translocation t(12;15;19) and unusual histologic features.

Hum Pathol. 2008 Jul 24;

Authors: Mariño-Enríquez A, Li P, Samuelson J, Rossi MR, Reyes-Múgica M

Congenital mesenchymal tumors are diagnostically challenging as they are rare and may feature overlapping patterns between several benign, low-grade, and tumors of intermediate malignancy, including myofibromatosis, myofibroma/hemangiopericytoma, congenital fibrosarcoma, and inflammatory myofibroblastic tumor. Their immunophenotype is either silent or minimally expressive, and their ultrastructural features are generically consistent with "fibroblastic/myofibroblastic" differentiation. Cytogenetic analysis allows refined diagnoses, improved classifications, and bettering of our therapeutic armamentarium. However, genotype/phenotype correlations continue rendering novel findings that must be examined for their potential value in diagnosis and treatment. We describe a retroperitoneal congenital fibrosarcoma with an unusually bland histopathology and novel 3-way t(12;15;19) translocation involving chromosome bands 12p13.2, 15q25.3, and 19p13.1, associated with trisomies 8, 11, and 20. Fluorescence in situ hybridization showed one fusion signal in the normal chromosome 12p13.2 and break-apart 3'ETV6 and 5'ETV6 signals in the rearranged 12p13.2 and 15q25.3, respectively. The importance of molecular diagnosis and genotype-phenotype correlations is emphasized.

PMID: 18657299 [PubMed - as supplied by publisher]

Mapping local matrix remodeling induced by a migrating tumor cell using 3-D multiple-particle tracking.

Biophys J. 2008 Jul 18;

Authors: Bloom RJ, George JP, Celedon A, Sun SX, Wirtz D

Mesenchymal cell migrating through a three-dimensional (3-D) matrix typically involves major matrix remodeling. The direction of matrix deformation occurs locally in all 3 dimensions, which cannot be measured by current techniques. To probe the local, 3-D, real-time deformation of a collagen matrix during tumor cell migration, we develop a new assay where matrix-embedded beads are tracked simultaneously in all 3 directions with high resolution. To establish a proof of principle, we investigate patterns of collagen I matrix deformation near fibrosarcoma cells in the absence and the presence of inhibitors of matrix metalloproteinases and acto-myosin contractility. Our results indicate that migrating cells show patterns of local matrix deformation towards the cell, which are symmetric in magnitude with respect to the axis of cell movement. In contrast, patterns of matrix release from the cell are asymmetric: the matrix is typically relaxed first at the back of the cell allowing forward motion, and then at the cell's leading edge. Matrix deformation in regions of the matrix near the cell's leading edge is elastic and mostly reversible, but induces irreversible matrix rupture events near the trailing edge. Our results also indicate that matrix remodeling spatially correlates with protrusive activity, a correlation mediated by myosin II and Rac1 and eliminated following inhibition of pericellular proteolysis or ROCK. We have developed an assay based on high-resolution 3-D multiple-particle tracking that allows us to probe local matrix remodeling during mesenchymal cell migration through a 3-D matrix and simultaneously monitor protrusion dynamics.

PMID: 18641063 [PubMed - as supplied by publisher]

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Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in Rheumatoid Arthritis.

Mol Med. 2008 Jul 10;

Authors: Liu C, Batliwalla F, Li W, Lee A, Roubenoff R, Beckman E, Khalili H, Damle A, Kern M, Plenge RM, Coenen M, Behrens TW, Furie R, Carulli JP, Gregersen PK

The prediction of response (or non-response) to anti-TNF treatment for Rheumatoid Arthritis is a pressing clinical problem. We conducted a genome wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 weeks. We used a two part analysis that treated the change in DAS28 as a continuous trait and then incorporated into a dichotomous trait of "good responder" and "nonresponder" by EULAR criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using Eigenstrat. Multiple SNP markers showed significant associations near or within loci including the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20, the type I interferon gene IFNk on chromosome 9, and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene A SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets are clearly required. We provide a reference list of candidate SNPs (p<0.01) that can be investigated in future pharmacogenomic studies.

PMID: 18615156 [PubMed - as supplied by publisher]

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Rottlerin induces autophagy and apoptotic cell death through a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells: the protective role of autophagy in apoptosis.

Autophagy. 2008 Sep-Oct;4(5):650-8

Authors: Song KS, Kim JS, Yun EJ, Kim YR, Seo KS, Park JH, Jung YJ, Park JI, Kweon GR, Yoon WH, Lim K, Hwang BD

Rottlerin is widely used as a protein kinase C-delta inhibitor. Recently, several reports have shown the possible apoptosis-inducing effect of rottlerin in some cancer cell lines. Here we report that rottlerin induces not only apoptosis but also autophagy via a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells. Rottlerin treatment induced a dose- and time-dependent inhibition of cell growth, and cytoplasmic vacuolations were markedly shown. These vacuoles were identified as acidic autolysosomes by electron microscopy, acidic vesicular organelle (AVO) staining and transfection of green fluorescent protein-LC3. The LC3-II protein level also increased after treatment with rottlerin. Prolonged exposure to rottlerin eventually caused apoptosis via loss of mitochondrial membrane potential and translocation of AIF from mitochondria to the nucleus. However, the activities of caspase-3, -8 and -9 were not changed, and PARP did not show signs of cleavage. Interestingly, the pretreatment of cells with a specific inhibitor of autophagy (3-methyladenine) accelerated rottlerin-induced apoptosis as revealed by an analysis of the subdiploid fraction and TUNEL assay. Nevertheless, the knockdown of PKC-delta by RNA interference neither affected cell growth nor acidic vacuole formation. Similarly, rottlerin-induced cell death was not prevented by PKC-delta overexpression. Taken together, these findings suggest that rottlerin induces early autophagy and late apoptosis in a PKC-delta-independent manner, and the rottlerin-induced early autophagy may act as a survival mechanism against late apoptosis in HT1080 human fibrosarcoma cells.

PMID: 18424913 [PubMed - in process]

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Autophagy plays a protective role during zVAD-induced necrotic cell death.

Autophagy. 2008 Jul-Aug;4(4):457-66

Authors: Wu YT, Tan HL, Huang Q, Kim YS, Pan N, Ong WY, Liu ZG, Ong CN, Shen HM

The aim of this study is to examine the role of autophagy in cell death by using a well-established system in which zVAD, a pan-caspase inhibitor, induces necrotic cell death in L929 murine fibrosarcoma cells. First, we observed the presence of autophagic hallmarks, including an increased number of autophagosomes and the accumulation of LC3-II in zVAD-treated L929 cells. Since the presence of such autophagic hallmarks could be the result of either increased flux of autophagy or blockage of autophagosome maturation (lysosomal fusion and degradation), we next tested the effect of rapamycin, a specific inhibitor for mTOR, and chloroquine, a lysosomal enzyme inhibitor, on zVAD-induced cell death. To our surprise, rapamycin, known to be an autophagy inducer, blocked zVAD-induced cell death, whereas chloroquine greatly sensitized zVAD-induced cell death in L929 cells. Moreover, similar results with rapamycin and chloroquine were also observed in U937 cells when challenged with zVAD. Consistently, induction of autophagy by serum starvation offered significant protection against zVAD-induced cell death, whereas knockdown of Atg5, Atg7 or Beclin 1 markedly sensitized zVAD-induced cell death in L929 cells. More importantly, Atg genes knockdown completely abolished the protective effect of serum starvation on zVAD-induced cell death. Finally, we demonstrated that zVAD was able to inhibit lysosomal enzyme cathepsin B activity, and subsequently blocked autophagosome maturation. Taken together, in contrast to the previous conception that zVAD induces autophagic cell death, here we provide compelling evidence suggesting that autophagy serves as a cell survival mechanism and suppression of autophagy via inhibition of lysosomal function contributes to zVAD-induced necrotic cell death.

PMID: 18253089 [PubMed - in process]

Tetrahydrocurcumin inhibits HT1080 cell migration and invasion via downregulation of MMPs and uPA.

Acta Pharmacol Sin. 2008 Jul;29(7):853-60

Authors: Yodkeeree S, Garbisa S, Limtrakul P

Aim: Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells. Methods: The effect of THC on HT1080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting. Results: Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis. Conclusion: Our findings revealed that THC reduced HT1080 cell invasion and migration. The inhibition of cancer cell invasion is associated with the downregulation of ECM degradation enzymes and the inhibition of cell adhesion to ECM proteins.

PMID: 18565284 [PubMed - in process]

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Global and focused transcriptional profiling of small molecule aminopeptidase N inhibitor reveals its mechanism of angiogenesis inhibition.

Biochem Biophys Res Commun. 2008 Jun 20;371(1):99-103

Authors: Shim JS, Park HM, Lee J, Kwon HJ

We recently developed a specific small molecule inhibitor of aminopeptidase N (APN), named as HNSA, through a high throughput screening. In the present study, we investigated the major cellular phenotypes of HNSA in comparison with those of APN knock-down in human fibrosarcoma cells and the mechanism of angiogenesis inhibition by the compound using DNA microarray analyses. Global gene expression analyses showed that HNSA signatures are significantly correlated with those of APN knock-down in HT1080 cells, suggesting that APN is a primary target of HNSA in the cells. Using the angiogenesis-focused DNA microarrays, nine of angiogenesis-related genes were identified as crucial mediators of angiogenesis inhibition by HNSA. These data demonstrate that HNSA can be used as a valuable tool to decipher the APN function in angiogenesis.

PMID: 18413233 [PubMed - indexed for MEDLINE]

Tumorigenicity of IL-1alpha- and IL-1beta-deficient fibrosarcoma cells.

Neoplasia. 2008 Jun;10(6):549-62

Authors: Nazarenko I, Marhaba R, Reich E, Voronov E, Vitacolonna M, Hildebrand D, Elter E, Rajasagi M, Apte RN, Zöller M

Analyzing the growth of fibrosarcoma lines derived from IL-1alpha-, IL-1beta- , or IL-1alphabeta-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1alpha and IL-1beta exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1-deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1-deficient fibrosarcoma lines grow in immunocompromised mice. However, IL-1alpha(-/-)beta-competent (comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1beta(comp) lines, IL-1alpha strengthens anchorage-independent growth, but both IL-1alpha and IL-1beta support drug resistance. Corresponding to the aggressive growth, IL-1beta(comp) cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated alpha(v)/beta3 and matrix metalloroteinase expression. Recruitment of myeloid cells requires IL-1beta but is regulated by IL-1alpha, because inflammatory chemokine and cytokine expression is stronger in IL-1alpha(-/-)beta(comp) than in IL-1(wt) lines. This regulatory effect of tumor-derived IL-1alpha is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1beta. Both sarcoma cell-derived IL-1alpha and IL-1beta promote tumor growth. However, IL-1alpha exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1beta initiates systemic inflammation.

PMID: 18516292 [PubMed - in process]