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PubMed1995

Quantitative distinction of cisplatin-sensitive and -resistant mouse fibrosarcoma cells grown in multicell tumor spheroids.

As a suitable model to study the growth behavior and therapeutic response of drug-resistant and -sensitive cells in three-dimensional coculture we have established multicellular spheroids generated from both cisplatin-sensitive and -resistant cells of a murine fibrosarcoma cell line. A drug resistant clone was derived from the parent cisplatin-sensitive cells by intermittent drug exposure in vitro. As a prerequisite for analysis of differential growth and treatment response of spheroid subpopulations, two efficient methods to discriminate between the two morphologically indistinguishable subpopulations in mixed spheroids were established. In the cisplatin-resistant cell line chosen for the present study, resistance is mainly due to an increased cellular metallothionein content and is therefore associated with increased resistance to CdCl2. Exposure of colonies to high concentrations of CdCl2 thus allowed selective elimination of sensitive colonies. Permanent labeling of either resistant or sensitive cells was achieved by introduction of the Escherichia coli beta-galactosidase marker gene with a retroviral vector system. The transformation of an uncolored galactose derivative by this enzyme into an indigo stain allowed detection of cells carrying and expressing the marker gene. The marker gene and CdCl2 method led to identical results when used simultaneously to distinguish quantitatively between resistant and sensitive colonies grown from plated cells of untreated or irradiated mixed spheroids. The retroviral labeling method was also used successfully in the study of intact spheroids, showing that in 1:1 mixed spheroids, cisplatin-sensitive parent cells accumulate in the spheroid periphery, outgrowing resistant cells and displacing them into the metabolically restricted spheroid center. Only when sensitive and resistant cells are initially mixed at a ratio of 1:9 are the resulting spheroids composed of equal proportions of the 2 cell types throughout 10-20 days after spheroid initiation.

Animals↗
PubMedDate not supplied

Studies regarding a fibrosarcoma induced in Sprague-Dawley rats by a murine cytomegalovirus. Note I. Aspects related to the character and reproduction of the tumor.

Through passages on Sprague-Dawley rats (performed during seven years) the serial transmissibility of a fibrosarcoma type tumor, with a tendency to local recurrence and locoregional metastasis formation, is demonstrated. The tumor was initially obtained by in vitro transformation of primary total rat embryonic cultures under the influence of a murine cytomegalovirus (M-CMV). In the course of passages, susceptible (S) and resistant (R) animal lines to the respective tumor could be obtained. The R and S crossings demonstrated the dominant transmission of S.

Animals↗
PubMed1994

Soluble urokinase receptor from fibrosarcoma HT-1080 cells.

A soluble form of urokinase-binding protein has been isolated from the human fibrosarcoma cell line HT-1080 and cell lines derived from it. Conditioned media of these cells were collected after overnight incubation under serum-free conditions, and were concentrated and passed through a column of Sepharose 4B to which high-molecular-weight urokinase had been attached. After thorough washing, a polypeptide could be eluted from the column with 1 M acetic acid. This material appeared to be a single band of approximately 60 kDa on SDS polyacrylamide gel. It cross-reacted with commercial antibodies made against urokinase receptor, and could be chemically cross-linked to the amino terminal fragment of urokinase. This material was similar to the urokinase receptor that was cleaved from HT-1080 cells by means of phosphatidylinositol-specific phospholipase C.

Chromatography, Affinity↗
PubMed1994

Okadaic acid-elicited transcriptional activation of collagenase gene expression in HT-1080 fibrosarcoma cells is mediated by JunB.

Okadaic acid (OA) is a novel, non-phorbol ester-type tumor promoter, which is a specific inhibitor of protein phosphatases 1 and 2A. Treatment of human fibrosarcoma HT-1080 cells with OA resulted in induction of collagenase and stromelysin-1 mRNA levels, while mRNA levels for tissue inhibitor of metalloproteinases-1 were enhanced to a lesser extent. Induction of collagenase and stromelysin-1 mRNA levels was dependent on protein synthesis. Exposure of HT-1080 cells to OA resulted in marked and persistent induction of junB, junD, and c-fos mRNA levels up to 24 h, while c-jun mRNA levels were only slightly elevated. In transiently transfected HT-1080 cells, OA-elicited activation of a 3.8-kilobase collagenase promoter/reporter gene construct was entirely dependent on junB expression, as determined by cotransfection with a junB antisense expression construct. Overexpression of JunB in HT-1080 cells enhanced collagenase promoter activity by 10-fold, and OA augmented trans-activation of collagenase promoter by c-Jun and JunB. The results indicate that induction of collagenase gene expression by OA is mediated by enhanced JunB expression, as well as enhanced trans-activating capacity of AP-1 complexes containing c-Jun and JunB. These results also suggest that selective overexpression of junB may enhance invasive and metastatic potential of neoplastic cells.

Collagenases↗
PubMed1995

Characterization of defectiveness in endogenous antigen presentation of novel murine cells established from methylcholanthrene-induced fibrosarcomas.

Three cell lines (4A1, 4C2 and 6D1 cells) derived from fibrosarcoma induced by the inoculation of 3-methylcholanthrene into C3H/HeN (H-2k) mice were examined for their ability to present antigens to CD8+ cytotoxic T lymphocytes (CTL). 6D1 and 4C2 cells were deficient in presenting endogenously synthesized influenza virus antigens to CTL, but they were able to present antigens when they were sensitized with a synthetic epitope peptide. The expression of the H-2 Kk gene in 4C2 and 6D1 cells was much reduced and was detectable only with Northern blot hybridization. The expression of two transporter genes (TAP1 and TAP2), examined by Northern hybridization, was also reduced in both cells, and negligible particularly in 4C2 cells. Interferon-gamma (IFN-gamma) treatment of these cells induced expression of Kk, TAP1 and TAP2 genes and rescued the defect of class I-restricted antigen presentation in 4C2 and 6D1 cells. Even after this treatment, however, antigen-presentation capability of 4C2 cells was still much lower than that of normal 4A1 cells. This finding suggests that 4C2 cells might have an additional defective gene(s), whose products are involved in the processing of class I-restricted antigen, besides the Kk and TAP genes, and this may explain the difficulty of 4C2 cells to induce tumour-specific immunity, as described previously. To our knowledge, the 4C2 cell is the first tumour cell postulated to have more than three defective genes involved in class I-restricted antigen presentation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Transfection of tissue transglutaminase into a highly malignant hamster fibrosarcoma leads to a reduced incidence of primary tumour growth.

Reduced expression of the tissue transglutaminase in both murine and human tumours has been consistently associated with tumour growth and progression. To investigate the functional effects of transglutaminase expression we have transfected a constitutive human tissue transglutaminase expression construct into a highly malignant hamster fibrosarcoma cell line Met B. Met B clones expressing the exogenous tissue transglutaminase exhibited a reduced incidence of primary tumour formation and an increased adherence to tissue culture plastic and fibronectin coated surfaces when compared to transfected and non transfected control cells. Transglutaminase transfected clones exhibited no significant differences in their growth rates measured in vitro, cell morphology or levels of spontaneous apoptosis measured by the determination of detergent insoluble apoptotic envelopes. The data demonstrates a suppressive effect of tissue transglutaminase on tumour growth and confirms its importance in the phenotypic changes associated with the cancer process.

Animals↗
PubMed1994

Inactivation of human anaphylatoxin C5a and C5a des-Arg through cleavage by the plasminogen activator activity of a human fibrosarcoma cell line.

The HT-1080 human fibrosarcoma cell line exhibited a plasminogen-dependent ability to inactivate recombinant anaphylatoxin C5a or zymosan-activated serum. The inactivation was obtained at physiological levels of both plasminogen (2 microM) and C5a (1-5 nM). Inactivated C5a and zymosan-activated serum were no longer able to induce chemotaxis and degranulation of neutrophils. Inactivation of C5a paralleled the emergence of plasmin activity, assayed by cleavage of the synthetic substrate H-D-valyl-L-leucyl-L-lysine-p-nitroanilide (S-2251). Both C5a inactivation and S-2251 cleavage were inhibited by the plasmin inhibitor alpha 2-antiplasmin, the urokinase inhibitor amiloride, and by anti-urokinase antibodies. In a cell-free system, inactivation of C5a was shown to depend on the simultaneous presence of urokinase and plasminogen and was inhibited by alpha 2-antiplasmin and by anti-urokinase antibodies. SDS-polyacrylamide electrophoresis demonstrated the cleavage of C5a by the plasminogen activation system and inhibition of the cleavage by amiloride. Amino acid sequencing of the band corresponding to the C5a degradation product revealed that C5a was cleaved at positions Lys14-His15 and Arg40-Ile41; cleavage at position Arg40-Ile41 seemed to be responsible for the loss of activity. Since neoplastic cells extensively produce and exhibit plasminogen activator activity, the present observations suggest that plasminogen activation may, by inactivation of C5a, reduce the anti-tumor immune response and support the immunological escape phenomenon of tumors.

Amino Acid Sequence↗
PubMed1994

Tumorigenic and metastatic properties of two ras-oncogene transfected rat fibrosarcoma cell lines defective in c-jun.

We here report the spontaneous loss of both homologues of the c-jun gene in two cell lines, isolated after transfection of rat embryo fibroblasts with single ras-oncogenes. These cells lines (designated A14 and B25) grow rapidly in vitro, have transformed morphologies and are invasive through reconstituted basal membranes. Both c-jun defective cell lines were found to be tumorigenic and metastatic in athymic mice. Loss of c-jun was paralleled by a dramatic decrease in interstitial collagenase expression, whereas stromelysin mRNA expression in c-jun- A14 and B25 cells was similar to that observed in c-jun+ transformed cell lines. Transient transfection experiments using reporter plasmids showed that stromelysin promoter activity in A14 cells was severely impaired by a point mutation in the -71 to -65 AP-1 motif, and was inhibited by a Jun dominant negative mutant. Gel mobility shift studies demonstrated the presence of a factor in A14 nuclear extracts capable of binding the stromelysin TRE. This factor bound JunB, JunD and Fos antibodies. Our findings suggest that c-Jun is not required for the tumorigenic and metastatic potential of ras-transformed fibrosarcoma cells, and that AP-1 protein(s) lacking c-Jun are capable of activating the stromelysin gene promoter.

Animals↗
PubMedDate not supplied

The effects of ketoconazole on the human fibrosarcoma cell line HT-1080.

In light of the reported cytotoxic effects of the antifungal agent ketoconazole on several malignant cell lines, we investigated the in vitro and in vivo effects of this drug on the human fibrosarcoma cell line HT-1080. Utilizing an anchorage dependent in vitro assay, we demonstrated an IC90 of 10.0 micrograms/ml at 72 hours and a decreasing IC90 with increasing exposure (IC90 = 6.2 micrograms/ml at 12 days). In vivo investigation utilizing the subcutaneous growth of this tumor in athymic mice and the oral, subcutaneous or intraperitoneal administration of ketoconazole at doses of 5-50 mg/kg/day demonstrated no consistent activity. Ketoconazole appears to have significant in vitro activity for HT-1080 but this does not translate into significant in vivo activity and its clinical relevance in sarcoma remains uncertain.

Administration, Oral↗
PubMed1994

Development and characterization of suramin-resistant Chinese hamster fibrosarcoma cells: drug-dependent formation of multicellular spheroids and a greatly enhanced metastatic potential.

Suramin-resistant DC-3F/SU 1,000 Chinese hamster fibrosarcoma cells were obtained by continuous exposure of parental DC-3F cells to increasing concentrations of suramin (1 mg/ml final concentration). These cells are 10-fold more resistant to suramin compared to the parental cell line as determined by colony formation in the continuous presence of drug; the 50% effective dose for DC-3F is 35 micrograms/ml whereas the 50% effective dose for DC-3F/SU 1,000 is 380 micrograms/ml. The resistance is not due to reduced drug accumulation and is stable for at least 10 months in the absence of drug. Sensitive and resistant cells show comparable growth rate, cell size, and DNA content. In the presence of suramin, DC-3F/SU 1,000 cells form big multicellular spheroids which regrow as monolayer cultures when the drug is removed. Similar morphological changes are not observed for sensitive DC-3F cells exposed to isotoxic doses of suramin but appeared early on during the development of resistance. Inoculation of DC-3F or DC-3F/SU 1,000 cells s.c. into nude mice results in 100% tumor take within 1 week for both groups. Although the tumor size increases at the same rate, only animals given injections of DC-3F/SU 1,000 cells show extensive and persistent s.c. hemorrhages around the tumor. By 3 weeks, 30% of DC-3F-injected mice (9 of 30) show approximately 5 metastases/lung compared to -262 metastases/lung in 100% of DC-3F/SU 1,000-inoculated mice (30 of 30). These findings have several important implications: (a) given the fact that suramin is currently used clinically, special precaution may be warranted in patients undergoing suramin treatment; (b) the drug may possess an unusual potential to interfere with processes essential to invasion and metastasis which, when properly used, may result in the development of antimetastatic therapies; and (c) suramin may serve as a model compound for other molecules of the antiangiogenic and/or antimetastatic type.

Animals↗
PubMed1994

Suppression of fibrosarcoma metastasis by elevated expression of manganese superoxide dismutase.

A mouse fibrosarcoma cell line (FSa-II), which exhibits low endogenous levels of manganese superoxide dismutase, was transfected with a human manganese superoxide dismutase complementary DNA. Fifty clones were screened for manganese superoxide dismutase activity by the superoxide dismutase activity gel assay. Activity of the positive clones was measured by the nitro blue tetrazolium-reduction assay in the presence of cyanide. Three cell lines exhibiting a range of activity were chosen to be transplanted into syngeneic mice. The results indicated that the metastasis rate for all transfected cells was significantly less than that of control cells.

Animals↗
PubMedDate not supplied

Interaction between vinblastine and ionizing radiation in the mouse MO4 fibrosarcoma in vivo.

The effect of combining vinblastine (VLB) and ionizing radiation (IR) on tumor response was investigated in CDF1 mice bearing the MO4 mouse fibrosarcoma. Favorable interactions were assumed to occur if VLB treatment caused accumulation of cells in metaphase (M-)phase at the time of IR. High pressure liquid chromatography (HPLC) measurements showed that VLB administered at 2.0 mg/kg (0.4 maximal tolerated dose, MTD) was taken up rapidly by the tumor in vivo, and that sufficient concentrations of VLB were achieved to cause blocking of tumor cells in M-phase. However, different treatment schedules of the combination of 2.5 mg/kg VLB (0.5 MTD) and 10 Gy IR resulted in additive tumor responses. The best therapeutic response was observed when IR was given 6 hours after intravenous injection of VLB. In order to increase the therapeutic response, we attempted to enhance the accumulation of cells in M-phase by treating mice with VLB at the MTD. The maximum percentage of tumor cells that could be accumulated in mitosis by a single intravenous bolus of VLB at the MTD was around 13%. The results show that this will probably be insufficient for significant IR enhancement.

Animals↗
PubMed1993

Autoreactive and heat shock protein 60-recognizing CD4+ T-cells show antitumor activity against syngeneic fibrosarcoma.

A CD4+ heat shock protein (hsp) 60-recognizing autoreactive T-cell line (BASL1) and clone (BASL1.1) were examined for their antitumor activity against major histocompatibility complex class II- syngeneic Meth A fibrosarcoma (Meth A), which was immunofluorescently stained with monoclonal antibody specific for hsp 60. In in vitro proliferative assay, BASL1.1 was suggested to recognize Meth A-derived hsp 60 presented by syngeneic antigen-presenting cells in a major histocompatibility complex class II-restricted manner. This cell line and clone showed antitumor activity in tumor-neutralizing (Winn) assay. BASL1 and BASL1.1 cells produced gamma-interferon, tumor necrosis factor, and interleukin 2 but not interleukin 4 by the stimulation with syngeneic spleen cells. In cytolytic assay, these cell lines and clones showed neither direct nor indirect (bystander) cytolysis against Meth A. In cytostatic assay, these cells inhibited the proliferation of Meth A in the presence of syngeneic macrophages, and this activity was abrogated by the addition of anti-gamma-interferon monoclonal antibody. Recombinant gamma-interferon could induce cytostatic activity only in the presence of macrophages, and tumor necrosis factor synergized this activity. Antitumor activity induced by BASL1 was abrogated by the administration of anti-CD8 monoclonal antibody in vivo, suggesting that CD8+ cytotoxic T-lymphocytes are essential and final effector cells for BASL1-mediated Meth A rejection. These findings indicate that CD4+ autoreactive and hsp 60-recognizing T-cells show two types of antitumor activity: cytostasis and induction of tumor-specific cytotoxic T-lymphocytes. Furthermore, these results imply that tumor-specific immunity could be elicited by CD4+ helper T-cells which recognize hsp.

Animals↗
PubMed1994

Histologically low-grade, yet biologically high-grade, fibrosarcomas of the mandible and maxilla in dogs: 25 cases (1982-1991).

Medical records of 25 dogs with histologically low-grade fibrous masses of the maxilla and mandible were reviewed. Most of the dogs had extensive clinical histories and had had previous biopsies of the affected regions, from which specimens were often interpreted as benign fibrous connective tissue. The most common breed represented was Golden Retriever (13/25 dogs, 52%). Skull radiographs were evaluated for 22 dogs, and 16 dogs (72%) had evidence of bone lysis. At admission, none of the dogs had radiographic evidence of pulmonary metastasis. On subsequent examinations and necropsy, prevalence of pulmonary metastasis was 12% (3/25 dogs) and of regional lymph node metastasis, 20% (5/25 dogs). Histologic appearance of all specimens was similar and was characterized by proliferation of fibrous connective tissue, with moderate to low cellularity, that aggressively infiltrated adjacent normal tissue. Treatment modalities varied considerably. Surgical excision in combination with radiation therapy, surgery alone, radiation therapy alone, and radiation therapy used adjunctly with localized hyperthermia prolonged survival times in some dogs. The clinical signs, tumor behavior, and histologic characteristics of these lesions were distinctive from those in previously described oral fibrosarcomas in dogs. Comparatively, these tumors most closely resembled aggressive fibromatoses in human beings in regard to clinical signs, local invasive behavior, and histologic appearance, but differed in the prevalence of metastasis.

Animals↗
PubMed1993

Lethal fibrosarcoma complicating radiation therapy for benign glomus jugulare tumor.

Radiation therapy for temporal bone paragangliomas has been advocated by many authors, but remains controversial. Radiation has little direct effect on the tumor cells, and diminution in tumor size is seldom seen. The main reason radiation therapy is recommended over surgical management of glomus tumors is its purported lower complication rate. We report a case of a lethal radiation-induced fibrosarcoma presenting 15 years following irradiation for a benign glomus jugulare tumor. Radiation-induced malignancies are rare, but are lethal when they occur. In experienced hands, surgical removal of glomus jugulare tumors carries a limited morbidity and virtually no mortality. In our opinion, the possibility of inducing a secondary life-threatening malignancy must be seriously considered when discussing therapeutic options with otherwise healthy individuals who are expected to survive 10 or more years after treatment.

Adult↗
PubMed1994

Isolation and identification of fresh tumor-derived endothelial cells from a murine RIF-1 fibrosarcoma.

Tumor vasculature is anatomically heterogeneous and distinct from the vasculature found in normal mature tissues. Examination of the differences between tumor and normal vasculature is critical to the future design of therapeutic modalities which either target tumor vasculature or potentially enable more efficient delivery of tumor cytotoxic agents. Such efforts to date have been hampered due to the inability to isolate live endothelial cells from solid tumors. We report here the isolation of fresh, noncultured endothelial cells from a C3H/HeJ RIF-1 murine fibrosarcoma through the use of fluorescence-activated cell sorting based on antibody staining for angiotensin-converting enzyme with further characterization by uptake and metabolism of acetylated low-density lipoprotein, factor VIII staining, and electron microscopy.

Animals↗
PubMedDate not supplied

Antitumor effects of local hyperthermia on a mouse fibrosarcoma.

Local hyperthermia at 41-43 degrees C for 40 min prior to transplantation of a fibrosarcoma reduced its growth on the heated as well as the unheated contralateral legs of mice. The growth retardation was most pronounced in the unheated leg at 16 days interval between hyperthermia and tumor cell inoculation and was noticeable even at 22 days while in the heated leg it disappeared by the time. Inhibition of tumor growth was also independent of temperature and of the heating time at 43 degrees C. These results thus indicate that local hyperthermia induces both direct and abscopal antitumor effects which may probably be the result of a systemic effect of hyperthermia in the host animal.

Animals↗
PubMed1993

[Insulin-like growth factor II/mannose-6 phosphate receptors in a rat fibrosarcoma cell line].

Insulin-like growth factor II (IGF II)/mannose 6-phosphate (Man-6-P) receptor, which has two binding sites, was efficiently purified using a phospho-pentamannan affinity column. The molecular mass of the receptor purified from rat fibrosarcoma cells (KMT-17) was 240,000 (240K), whereas that of the receptor from normal rat liver and fibroblasts (NRK-49F) was 250K. However, when the receptor was subjected to deglycosylation by treatment with tunicamycin, the receptors of the KMT-17 and MRK-49F cells gave the same molecular mass of 225K, indicating that the difference in molecular mass between two cell lines resulted from the different oligosaccharide sizes. Analysis of the number of receptor site and binding affinity with IGF II on cell surface showed that KMT-17 cells expressed about 10 times more sites than in NRK-49F cells, whereas the binding affinity of KMT cells was lower than that of NRK-49F cells. Since it is known that asparagine-linked oligosaccharides in the IGF II/Man-6-P receptor are essential for IGF II binding, the types of oligosaccharides in the receptor were investigated by concanavalin A affinity chromatography. It was revealed that a ratio (38%) of tetra- and triantennary (multiantennary) complex-type oligosaccharides in the receptor of KMT-17 cells was lower than that (61%) in NRK-49F cells. These results indicate that the receptor of KMT-17 cells possesses predominantly less branched complex-type oligosaccharides and that multiantennary complex-type oligosaccharides of the receptor are most likely to contribute to higher affinity binding of IGF II. To determine whether IGF II activates phosphatidyl inositol-specific phospholipase C (PLC) in KMT-17 cells, the production of inositol trisphosphate (IP3) was measured. Treatment with IGF II increased the level of IP3 in a concentration-dependent manner. The level of IP3 reached the maximum after 15 seconds of incubation. When the cells were pretreated with anti-receptor antibody, no activation of the PLC was observed. These findings suggest that IGF II stimulates PLC through binding to the IGF II/Man-6-P receptor.

Animals↗