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A 2-week-old northern fur seal female pup (Callorhinus ursinus) found dead in the Pribilof Islands had an irregular mass at the anterior pole of the right kidney. Histopathological examination revealed a fibrosarcoma.
A large, rapidly growing subcutaneous fibrosarcoma was observed on the head of an aged male white-tailed deer (Odocoileus virginianus) from Frederick County, Maryland. Although there was no evidence of distant metastasis, the large neoplastic mass had extensively invaded the osseous supraorbital process, and had several small satellite nodules nearby.
An 8-yr-old male capybara (Hydrochoerus hydrochaeris), a resident of an urban zoological collection in upstate New York (USA), had a mass posteroventral to its left stifle; it was of unknown duration. The mass was a fibrosarcoma based on invasive sheets of interwoven spindle-shaped neoplastic cells with moderate associated extracellular matrix composed of collagen fibers. Supportive immunohistochemical staining was positive for vimentin but negative for cytokeratins, desmin, and myoglobin. The animal subsequently died of unknown causes. This is the first known report of a neoplasm in a capybara.
Syndecan-1 is a transmembrane heparan sulfate proteoglycan which plays pivotal role in cell-cell and cell-extracellular matrix interactions. However, its implication in the establishment of malignant phenotype is still controversial. Its expression indicates differentiated phenotype in certain tumors, while it confers invasive nature for others. For the better understanding of the role of syndecan-1 in cancer we transfected HT-1080 fibrosarcoma cell line with the full and a truncated construct of syndecan-1 and established stable cell lines with them. We studied the in vitro and in vivo growth capacity and metastatic potential of the transfectants in comparison with the cell line bearing only the EGFP expression vector. Our results showed that the growth rate of syndecan transfectants increased and they developed more lung metastases than the control cells. As local growth of the full transfectant was faster than that of the 78sig we presume that the full protein and maybe the shedding is needed for the local development of the tumor, but the intracellular and transmembrane domain is sufficient to promote metastasis formation.
The establishment and cultivation of two human neoplastic cell lines is described. The cell line B-5GT was derived from bone giant cell tumor and B-6FS from poorly differentiated fibrosarcoma. In comparison to the normal skin fibroblasts both cell lines have a potential for "indefinite" multiplication in vitro and they exhibit growth properties which are associated with malignant transformation. The parameters investigated included cell morphology, chromosome characteristics, terminal cell density, growth pattern, residual DNA synthesis and growth in soft agar. Both cell lines exhibited human karyotype with aneuploidy and differed in their karyotype from each other.
A new strategy in anticancer gene therapy uses stress-responsive cellular promoters that offer the advantage of enhanced gene expression in a variety of tumors. Although the feasibility of their selective expression has been demonstrated, functional evidence of their ability to activate therapeutic agents within the tumor environment leading to tumor eradication has not been established. Glucose deprivation, chronic anoxia, and acidic pH known to persist in poorly vascularized solid tumors strongly induce the transcription of the glucose-regulated protein 78 (grp78) gene, which encodes an Mr 78,000 stress-inducible protein. In this report, we tested directly the efficacy of the grp78 promoter in a retroviral system to drive the expression of the herpes simplex virus-thymidine kinase (HSVtk) suicide gene, using a murine fibrosarcoma model, in the context of their syngeneic, immunocompetent hosts. Our results showed that under glucose starvation conditions, the expression of HSVTK was enhanced in tumor cells where the HSVtk gene was driven by the internal grp78 promoter, in contrast to the Moloney murine leukemia virus long terminal repeat, where suppression was observed. We further demonstrated that in vivo, HSVTK expression was elevated to much higher levels inside tumors when driven by the internal grp78 promoter, resulting in complete eradication of sizable tumor mass, with no recurrence of tumor growth. Our study suggests that the glucose starvation-inducible grp78 promoter could be useful for enhanced expression of a variety of therapeutic agents within the solid tumor environment.
Steric exclusion of molecules in the extravascular space of tissues can be quantified by the available volume fraction (K(AV)). Despite its clinical importance, however, there is a paucity of data in the literature regarding the available volume fraction of macromolecules in the extravascular space of tumor tissues. In this study, we quantified K(AV) of inulin, BSA, and dextran molecules of Mr 10,000-2,000,000 in polymer gels and fibrosarcoma tissues. The measurement involved: (a) sectioning of gels or tumor tissues into thin slices (approximately 600 microm) using a Vibratome, (b) ex vivo incubation of the slices in solutions containing fluorescently labeled tracers, and (c) quantification of the equilibrium tracer concentrations in both slices and solutions. We found that K(AV) in gels decreased monotonically when the Mr of dextran was increased from Mr 10,000 to 2,000,000. However, K(AV) in tumor tissues was insensitive to the molecular weight of dextran in the range between Mr 10,000 and 40,000. There was a sharp decrease in K(AV) from 0.28 +/- 0.14 to 0.10 +/- 0.06 when the molecular weight was increased from Mr 40,000 to 70,000. In addition to the molecular weight dependence, K(AV) was heterogeneous in tumors, with intertumoral difference being greater than intratumoral variation. The interstitial fluid space, which was quantified by K(AV) of inulin, was 50% of the total tissue volume. These data indicate that the fraction of the extravascular volume in tumors that is accessible to large therapeutic agents is heterogeneous and depends on the size of agents.
An unusual case of primary fibrosarcoma of the liver in a cow is described. The most prominent pathological findings were severe abdominal haemorrhage and neoplastic masses confined to the liver only. Histologically, spindeloid cells arranged in interlacing bundles running in various directions and numerous areas of necrosis and ossification were randomly scattered in the neoplasm.
The overexpression of manganese superoxide dismutase (MnSOD), an enzyme that catalyzes the removal of superoxide (O2*-) from the mitochondria, has been shown to be closely associated with tumor regression in vivo and loss of the malignant phenotype in vitro. To investigate the mechanism by which MnSOD overexpression mediates this reversal, we have established 29 independent, clonal MnSOD-overexpressing HT-1080 fibrosarcoma cells. MnSOD activity is inversely correlated with cell proliferation in our cell lines. Incubating cells in 3% oxygen can prevent the inhibition of cellular proliferation mediated by MnSOD, suggesting that oxygen is a prerequisite component of the MnSOD-dependent proliferative inhibition. Confocal laser microscopy was used in combination with the oxidant-sensitive fluorescent dyes dihydrorhodamine-123, dihydroethidium, and 2',7'-dichlorodihydrofluorescein diacetate to determine the oxidizing capacity of the MnSOD-overexpressing cells. When compared with parental or control cell lines, there was a significant decrease in the rate of oxidation of the fluorophores in the MnSOD-overexpressing cell lines. Thus, an increase in the oxidizing capacity of the cells does not appear to mediate the inhibition of proliferation associated with MnSOD overexpression. Superoxide dismutase has also been shown to enhance the cytotoxic activity of NO* toward tumor cells. In this study, we have shown that MnSOD overexpression enhances the cytostatic action of the NO* donors, sodium nitroprusside, 3-morpholinosydnonomine, and (Z)-1-[2-aminethyl)-N-(2-ammonioethyl)amino]diazen-1-+ ++ium-1,2-diolate in a dose-dependent manner. In addition, the NO* toxicity is blocked by oxyhemoglobin, a NO* scavenger. Our findings suggest that NO* may play a role in the reversal of tumorigenicity associated with MnSOD overexpression.
Recombinant tumor necrosis factor alpha (rTNF-alpha)-induced release of endogenous fatty acids was examined in WEHI 164 clone 13 fibrosarcoma cells using a highly sensitive HPLC method. The initial rTNF-alpha-induced extracellular release of endogenous fatty acids was dominated by 20:4n;-6, 22:4n;-6, 24:4n;-6, and 18:1n;-9 showing relative rates of 2.9, 0.9, 1.1, and 1.0, respectively. Release of endogenous AA and DNA fragmentation occurred simultaneously and preceded cell death by approx. 2 h. Methyl arachidonoyl fluorophosphonate and LY311727, specific inhibitors of Ca(2+)-dependent cytosolic PLA(2) (cPLA(2)) and secretory PLA(2) (sPLA(2)), respectively, neither blocked rTNF-alpha-induced cytotoxicity or endogenous AA release. However, both inhibitors reduced rTNF-alpha-induced release of other endogenous fatty acids. In comparison, the antioxidant butylated hydroxyanisole (BHA) completely inhibited the rTNF-alpha-induced cytotoxicity as well as AA release mediated through the TNF receptor p55, while the very similar antioxidant butylated hydroxytoluene had no effect. BHA did not inhibit recombinant cPLA(2) or sPLA(2) enzyme activity in vitro. Furthermore, stimulation of cells with rTNF-alpha for 4 h did not increase cPLA(2) enzyme activity. The data indicate that neither cPLA(2) or sPLA(2) mediate rTNF-alpha-induced apoptosis and extracellular AA release in WEHI cells. The results suggest that a BHA-sensitive signaling pathway coupled to AA release is a key event in TNF-induced cytotoxicity in these cells.
Meso-substituted cationic porphyrins were examined for binding dsDNA. Subcellular localization time studies used Confocal Laser Scanning Microscopy of radiation-induced fibrosarcoma (RIF) cells incubated with porphyrins. Binding studies revealed a reversible interaction between porphyrin and dsDNA that is a function of DNA shape. Binding was inhibited at high salt concentrations, and enhanced by heat and DNA denaturants such as dimethyl formamide (DMF). Trans dicationic porphyrin required more stringent binding conditions than cis dicationic and tetracationic porphyrins. Phenol extraction of porphyrin from the DNA-porphyrin complex demonstrates that cationic porphyrins do not damage dsDNA at high concentrations. Localization studies within a 24-hour range reveal different distribution patterns. Metal chelates of tetracationic porphyrin exhibited a cytoplasmic localization with the exception of the zinc chelate. Localization of other metal chelates appears to be redistributed to lysosomes and mitochondria between 3 and 6 hours post-incubation. HPPH used in PDT clinical trials localizes to the cytoplasmic compartment.
Mouse monoclonal antibody (mAb) BCD-F9, which recognizes an unknown antigen found on the surface of many tumor cells, was used to screen a phage display library expressing random peptide decamers. The phage that was selected encoded the unique sequence GRRPGGWWMR, representing the peptide capable of binding to the BCD-F9 mAb. The peptide was synthesized and found to specifically inhibit the binding of mAb to HT-1080 fibrosarcoma cells. Alanine mutagenesis of the sequence encoding this peptide indicated that three residues, PXXWW, were critical for its binding to the BCD-F9 mAb. Polyclonal antibodies generated by immunization of rabbits with the synthetic peptide GRRPGGWWMR (anti-mimotope antiserum or AM-F9) bound specifically to HT-1080 cells and inhibited the binding of the BCD-F9 mAb to these cells. Using an experimental animal model in which CD-1 nude mice are inoculated i.v. with HT-1080 cells, develop lung metastasis, and die within 30 days, we have shown that AM-F9 could significantly prolong the life span of these animals. Our results suggest that a peptide mimotope can potentially be used as a novel immunotherapy to induce a beneficial antitumor response.
This is a case presentation of a young patient with an intracranial space-occupying lesion following multiple episodes of generalised tonic clonic seizures for the last 20 years. Such a long latency period between the onset of fits and the discovery of an intracranial lesion is highly unusual in malignant brain tumours. This lesion was excised completely and proved to be a primary lesion of the brain - fibrosarcoma. These rare tumours of mesenchymal origin in the central nervous system are very rare.
Radiation-induced alterations in the levels of p53 and lactate dehydrogenase activities were studied in fibrosarcoma, following exposure to different doses of gamma-irradiation (2-10 Gy). The levels of p53 were elevated in the cytoplasm, while the lactate dehydrogenase activity in tumor tissue was considerably decreased.
A 9-year-old, female guinea pig was diagnosed with a subcutaneous fibrosarcoma overlying the ventral thorax. The mass was invasive within the subcutis without extension into surrounding structures or organ systems. Other findings included cystic ovaries, renal cortical cysts, nodular hyperplasia of the liver, and myocardial fibrosis with pulmonary hypertension.
Uridine/cytidine kinase which converts uridine and cytidine to their corresponding monophosphates is a rate-limiting enzyme involved in the salvage pathway of pyrimidine synthesis. We isolated cDNA encoding the enzyme from human fibrosarcoma cells, then determined its nucleotide sequence by the 5'-RACE method followed by confirmation employing the human genome DNA library. The isolated uridine/cytidine kinase cDNA (UCK cDNA) consisted of 786 nucleotides encoding 261 amino acids and was found to have approximately 70% homology with mouse UCK cDNA. Northern blot analysis of human leukemia RNAs with labeled UCK gene showed a single band at 1.6 kb to be UCK mRNA, and southern blot analysis of the UCK cDNA after digestion with BamHI, SacI and XbaI enzymes showed four band signals, suggesting the UCK gene to have at least 4 exons. A truncated form of UCK cDNA was expressed as the His-tag conjugated protein in Escherichia coli. The expressed and purified protein specifically converted uridine and cytidine to their corresponding monophosphates and also phosphorylated antitumor nucleosides such as 5-fluorouridine, cyclopentenyl-cytosine and 3'-C-ethynylcytidine. The present results suggest that our cloned human UCK cDNA encodes the correct amino acid sequence for UCK protein, showing high intracellular phosphorylation activity forward natural and synthetic pyrimidine nucleosides.
A fibrosarcoma of the right thenar eminence is presented. It is interesting that this lesion covered an area larger than the hand before presenting for definite treatment. The tumour was completely excised with minimum functional defect of the affected thumb. Many patients in the African subregion present when their tumours have reached enormous sizes just like this patient. The reason for this late presentation is that the patient prefers to visit herbalists, patent medicine dealers or private hospitals with minimum experience in specialised surgery. The patient's primary reason, apart from superstition, is the high cost of orthodox medical care. Our patients in Nigeria need a lot of health education which will enable them present early and the government should be able to identify their citizens who cannot pay their hospital bills, should be assisted so that operations will be promptly attended to.
OBJECTIVE: To investigate the effects of genistein on cancer invasion and associated cellular characteristics and explore the possibility of developing protein tyrosine kinase inhibitors as anti-metastasis drugs. METHODS: HT1080 human fibrosarcoma cells were exposed to 20 mumol/L or 40 mumol/L genistein for 3 days. The abilities of the genistein-treated cells to invade through reconstituted matrigel or migrate through polycarbonate filters in transwell chambers were then investigated. Northern blot and laser densitometry were used to estimate the relative mRNA amounts of MMP-2, MMP-9 and TIMP-1 in the cells. RESULTS: The ability of the genistein-treated HT1080 cells to invade the reconstituted basement membrane was decreased significantly (P < 0.01). In consistent with the lowered invasive potential, migration rates of the drug-treated cells decreased dramatically. genistein did not, however, significantly affect attachment of HT1080 cells on fibronectin, laminin or Matrigel. Though exposure to genistein led to a small increase in MMP-2 and MMP-9 gene expression, a much greater increase in the amount of TIMP-1 mRNA was observed. Imbalanced enhancement of gene expression between matrix metalloproteinases and their inhibitors in favor of the latter may imply that matrix degradation is impaired in the genistein-treated cells. CONCLUSION: Genistein suppresses invasion of HT1080 cells at relatively low concentrations. genistein and other protein tyrosine kinase inhibitors might be valuable candidate drugs for the treatment of invasion and metastasis of cancer.