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Metastatic behavior of the RIF-1 murine fibrosarcoma: inhibited by hypophysectomy and partially restored by growth hormone replacement.

BACKGROUND: We recently demonstrated that hypophysectomy profoundly inhibits metastatic behavior in the MGH-OGS murine osteosarcoma model and speculated that this effect is related at least in part to ablation of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. PURPOSE: In this study, we determined whether the administration of GH to animals rendered GH and IGF-I deficient by hypophysectomy attenuates the inhibitory effects of hypophysectomy on metastatic behavior. METHODS: Metastatic behavior was assayed by counting visible metastases in lungs 3 weeks after tail vein injection of RIF-I fibrosarcoma cells to control mice (n = 29), hypophysectomized mice (n = 19), and hypophysectomized mice administered 0.05 microgram/g body weight recombinant human GH twice daily (n = 21). RESULTS: Twenty of 21 hypophysectomized mice receiving GH, eight of 19 hypophysectomized mice not receiving GH, and 26 of 29 controls had grossly visible pulmonary metastases 3 weeks after intravenous injection of 5 x 10(5) cells; mean numbers +/- SD of gross metastases were 38.4 +/- 11.3, 6.4 +/- 2.2, and 13.1 +/- 2.8 in the three groups, respectively. The presence (P < .005, chi-square test) and number (P = .0003, Mann-Whitney U test) of metastases were significantly reduced in hypophysectomized hosts compared with control hosts and were significantly higher in hypophysectomized, GH-replaced hosts compared with hypophysectomized hosts (P < .001, chi-square test; P = .011, Mann-Whitney U test), while the difference in presence and extent of metastases between control and hypophysectomized, GH-replaced hosts was not statistically significant. CONCLUSIONS: These data support the hypothesis that the status of the host with respect to GH and/or GH-dependent factors such as IGF-I influences the metastatic behavior of certain neoplasms. IMPLICATIONS: Our results raise the possibility that compounds that reduce GH output or interfere with GH action, such as somatostatin analogues, GH antagonists, IGF antagonists, and GH-releasing hormone antagonists, may suppress metastatic behavior of certain neoplasms.

Animals↗

p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells.

The defining characteristic of a tumor cell is its ability to escape the constraints imposed by neighboring cells, invade the surrounding tissue, and metastasize to distant sites. This invasive property of tumor cells is dependent on activation of proteases at the cell surface. Most cancer cells secrete the urokinase-type plasminogen activator, which converts cell-bound plasminogen to plasmin. Here we address the issue of whether the plasminogen binding protein, p11, plays a significant role in this process. Transfection of human HT1080 fibrosarcoma cells with the human p11 gene in the antisense orientation resulted in a loss of p11 protein from the cell surface and concomitant decreases in cellular plasmin production, ECM degradation, and cellular invasiveness. The transfected cells demonstrated reduced development of lung metastatic foci in SCID mice. In contrast, HT1080 cells transfected with the p11 gene in the sense orientation displayed increased cell surface p11 protein and concomitant increases in cellular plasmin production, as well as enhanced ECM degradation and enhanced cellular invasiveness. The p11 overexpressing cells showed enhanced development of lung metastatic foci. These data establish that changes in the extracellular expression of the plasminogen receptor protein, p11, dramatically affect tumor cell-mediated pericellular proteolysis.

Animals↗

Radiation resistance in a doxorubicin-resistant human fibrosarcoma cell line.

In clinical practice, cancers refractory to chemotherapy can appear relatively radioresistant. Recent work in multidrug-resistant cell lines has yielded conflicting results concerning the relationship between drug resistance and radiation resistance. The current study examines the radiation response of a human fibrosarcoma (HT1080) and a doxorubicin-resistant subline (HT1080/DR4). Using soft-agar colony formation after graded doses of x-rays as an endpoint, HT1080/DR4 had an increased D0 (D0 = 2.1 Gy) and a broader initial shoulder (n = 2.7, Dq = 2.1 Gy) than the parental HT1080 line (D0 = 0.7, Gy, n = 1.2, Dq = 0.3 Gy), suggesting that HT1080/DR4 has an increased capacity to repair radiation-induced DNA damage. This possibility was tested by comparing the cell lines' ability to accumulate sublethal damage. In split-dose recovery experiments, HT1080/DR4 demonstrated increased ability to repair sublethal radiation damage following fractionated irradiation, compared with the HT1080 parental line. The mechanism for this radiation resistance is not clear, but a variety of cellular alterations seen in drug-resistant cell lines are discussed with reference to areas of further study.

Cell Cycle↗

Low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes): report of a case that metastasized.

"Hyalinizing spindle cell tumor with giant rosettes" is a tumor recently described by Lane et al. and thought by them possibly to represent a form of low-grade fibromyxoid sarcoma. Proof of a metastatic potential was lacking. We report an example of this tumor on the arm of a 28-year-old woman. The ultrastructural study of the tumor confirmed the fibroblastic nature of the lesion, which subsequently metastasized to the lung. Histologically, the giant rosettes simulated palisaded granulomas. Our findings warrant classifying the tumor as a sarcoma, and we suggest the designation low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes).

Adult↗

Decreases in histamine forming enzyme activity of non-metastasizing fibrosarcomas in hamsters with progressive tumor growth.

A marked and progressive decrease in the activity of the histamine forming enzyme, histidine decarboxylase (HDC), of tumors was found to be associated with the progressive growth of SV-40 virus induced and transplanted syngeneic non-metastasizing fibrosarcomas in inbred LSH Syrian hamsters. Histamine forming enzyme activity was highest in the smallest tumors (p < .005) and in the tumors with the slowest growth rate (p < .005, r - 0.84). Tumor histamine forming enzyme activity was highest for each interval of animal exposure to inoculated tumor cells in those animals which had limited their tumor growth to the smallest tumor size. These findings suggested a local anti-inflammatory effect of progressive tumor growth. Induced local inflammation by repeated intratumor injections of bradykinin markedly elevated tumor histamine forming enzyme activity above expected levels for tumors of the same size in a small group of individual animals which were sampled at random from a larger group of animals which were being studied for the tumor growth kinetics effects of repeated intralesional injections of bradykinin. Tumor histamine forming enzyme activity was highest in those animals which were managed by the frequency of injection and dose schedules which were found in the tumor growth kinetics study to be most effective in limiting tumor growth. These findings suggested that the observed anti-inflammatory effects of progressive tumor growth may be reversed by locally induced inflammation at the tumor site with beneficial effects on tumor growth.

Animals↗

Alpha-tocopherol ameliorates cyclophosphamide-induced hyperlipidemia in fibrosarcoma-bearing rats.

Cyclophosphamide, an alkylating agent, is currently being used for the treatment of various types of cancer, either alone or in combination with other cytostatic drugs. However, cyclophosphamide has a detrimental effect on lipid metabolism and causes hyperlipidemia in patients. Since alpha-tocopherol is known to reduce hyperlipidemia, we have investigated the effects of adding alpha-tocopherol to the cyclophosphamide treatment. Our study, carried out on fibrosarcoma-bearing rats, shows that alpha-tocopherol markedly reduces cyclophosphamide-induced hyperlipidemia and brings lipid metabolism down to values observed in untreated controls.

Animals↗

Giant fibrosarcoma of the ovary.

An unusual case of a huge primary ovarian fibrosarcoma, the largest tumor of its type reported to date, is presented. The gross, light microscopic, and ultrastructural features are described. The tumor was unique in three aspects: (a) its massive bulk; (b) the prompt relief of symptoms after debulking; and (c) most significantly, the lack of extensive abdominal metastasis in spite of its high grade, large size, and 6-month delay in resection.

Female↗

31P magnetic resonance spectroscopy detection of response-predictive adenosine triphosphate decrease in irradiated radiation-induced fibrosarcoma-1 tumors.

RATIONALE AND OBJECTIVES: In previous phosphorus-31 (31P) magnetic resonance (MR) spectroscopy studies of radiation-induced fibrosarcoma (RIF-1), tumor model single-dose x-ray irradiation was applied at subcurative doses. A more effective x-ray does was used in this study, allowing correlation of treatment efficacy with the early changes observed in the 31P MR spectra of RIF-1 tumors. METHODS: Subcutaneous RIF-1 tumors of 60 mice were examined by 31P MR spectroscopy shortly before a single localized x-ray dose of 40 Gy and at eight times (2, 12, 24, 48, 72, 120, 168, and 216 hours) thereafter. RESULTS: Early increases in the relative concentration of inorganic phosphate and decreases in adenosine triphosphate (ATP), most notably at 2 and 12 hours (each P < 0.00001), were observed that lasted up to 48 hours after irradiation. Phosphomonoester and tumor pH showed decreases that reversed even earlier. Reduction of ATP measured at 48 hours after irradiation was, however, correlated with percent tumor shrinkage observed during the subsequent weeks (r = -0.59; P < 0.00001). CONCLUSIONS: Sustained loss of RIF-1 tumor ATP is predictive of treatment efficacy. Temporary depression of high-energy phosphate in favor of inorganic phosphate does not necessarily lead to cell death.

Adenosine Triphosphate↗

Fibrosarcoma in a girl with celiac disease and IgA deficiency.

A case of abdominal wall fibrosarcoma in a 17-year-old girl with celiac disease and IgA deficiency is described. Celiac disease was putatively diagnosed with intestinal biopsy at the age of 15 years when she came for hospital investigations because of IgA deficiency and recurrent respiratory infections. The tumor occurred at the age of 17 years during the gluten challenge performed for final diagnosis of celiac disease. Surgical excision, irradiation, and chemotherapy were initially successful. After 7 months, however, the tumor recurred. Reoperation and a new course of irradiation therapy coinciding with the reinstitution of a gluten-free diet proved to be effective in tumor eradication. Nine years after the cessation of cancer treatment she is well and has two healthy children.

Abdominal Muscles↗

Sclerosing epithelioid fibrosarcomas involving the neuraxis: report of three cases.

OBJECTIVE AND IMPORTANCE: Sclerosing epithelioid fibrosarcoma (SEF) is a rare mesenchymal neoplasm composed of rounded, vimentin-immunoreactive tumor cells disposed in nests and cords within a hyalinized collagenous matrix. Most examples arise in the deep skeletal muscles of adults. The cases recorded to date have been characterized by protracted clinical evolutions with a tendency for stubborn local recurrence, followed by late metastasis. Accordingly, SEF has been regarded as a low-grade sarcoma. A single instance of brain and vertebral metastasis has been described. We report three examples of SEF distinguished by primary involvement of the neuraxis at initial presentation. CLINICAL PRESENTATION: Two tumors had intracranial, calvarial and extracalvarial, soft-tissue components, whereas the third tumor manifested as a paraspinal mass with extension into the T12-L1 neural foramen and invasion of the T12 nerve root. INTERVENTION: All three affected patients experienced local recurrence and distant metastasis after resection of the primary site. These complications appeared early in the disease course in two cases. In no case was there a response to adjuvant chemotherapy or radiotherapy. CONCLUSION: Our experience indicates that SEFs arising along the neuraxis may demonstrate unexpectedly aggressive clinical behavior, compared with those arising in the more typical location of deep skeletal muscles.

Adolescent↗

Primary bronchopulmonary fibrosarcoma of the trachea in a child.

We have reported the unusual case of a 7-year-old boy who was admitted with respiratory symptoms of several months' duration. He was found to have a tumor of the trachea, which proved to be a low-grade fibrosarcoma with smooth muscle differentiation.

Bronchial Neoplasms↗

Heterogeneity of tumorigenicity phenotype in murine tumors. Characterization of tumor clones isolated from primary 3-methylcholanthrene-induced fibrosarcomas.

In this study we have characterized three series of clonal populations isolated from primary murine fibrosarcomas induced with three different doses of the chemical carcinogen, 3-methylcholanthrene (3-MCA). Clones were evaluated fro their in vivo growth rates after transplantation into normal syngeneic animals, and for immunological cross-protection toward clones derived from the same tumor. A pattern of reactivity emerged from these studies which supports, at the single-cell level, existing theories regarding the correlation between the inducing dose of chemical carcinogen and the antigenicity of the resulting tumors. Clones from tumors induced with 10 mg of 3-MCA were found to be less tumorigenic than clones from tumors induced with 5 mg of 3-MCA. The 5-mg clones were in turn less tumorigenic than the 1-mg clones, all of which grew rapidly in normal animals. Related clones from each tumor were found for the most part to be immunologically noncross-reactive with other clones from the same tumor, suggesting that subpopulations of tumor cells expressing different tumor-specific transplantation antigens (TSTAs) may reside within single primary tumors. We have used these observations to formulate an hypothesis for the origin of antigenic heterogeneity in 3-MCA-induced tumors and as the basis for a discussion of the relationship between cell transformation and the appearance at the cell surface of tumor-specific transplantation antigens.

Animals↗

Superoxide dismutase activity of murine ultraviolet radiation-induced fibrosarcoma cell strains.

The average superoxide dismutase (SOD) activity of seven cell strains from mouse skin fibrosarcoma induced by ultraviolet (UV) irradiation was 5.78 +/- 0.81 (mean +/- SE) unit/mg protein, while that of seven normal mouse skin fibroblasts was 5.36 +/- 1.58. Although tumor cells have been previously reported to exhibit reduced SOD activity, the present study demonstrates that there is comparable SOD activity between tumor cells and normal cells of the same tissue origin.

Animals↗

Paraneoplastic pemphigus associated with pelvic inflammatory fibrosarcoma: a case report.

A 36-year-old African-American woman presented with an extensive stomatitis and pigmented cutaneous macules on the neck, axillae and hands. Subsequently she developed violaceus papules on the dorsa of the hands, histologically consistent with an interface dermatitis. After 18 months of progressive disease, paraneoplastic pemphigus was suspected and a search for an underlying neoplasm was initiated. An exploratory laparotomy revealed a pelvic mass and the histologic examination showed an inflammatory fibrosarcoma. The evidence of acantholysis on new cutaneous lesions and the positivity of indirect immunofluorescence with rodent urinary bladder epithelium reinforced the diagnostic criteria for paraneoplastic pemphigus, which is confirmed by the identification of strong protein bands at 210, 190 and 170 kd by immunoprecipitation. Paraneoplastic pemphigus should be considered when investigating atypical mucocutaneous manifestations of pemphigus vulgaris and lichen planus. Diagnostic screening for paraneoplastic pemphigus and a search for an underlying tumor should be performed.

Adult↗

Increased tumor control rates in murine fibrosarcoma by combined therapy with L-alanosine and radiation.

L-Alanosine, an analog of L-aspartic acid, was investigated as one of a series of chemical compounds that may have inhibitory effects on the repair of potentially lethal damage caused by radiation using an in vivo murine fibrosarcoma (Meth-A tumor) in BALB/cBy male mice. The combined treatment of single administration of L-alanosine (600 mg/kg) and single dose of X-irradiation (20 Gy) on Meth-A tumors produced 62% tumor control, while the radiation alone resulted in less than 5% tumor control. The potentiating effect by L-alanosine was higher when the drug was administered 8 h prior to X-irradiation. The dose modification factor of the drug is estimated to be 1.4 for Meth-A tumor. The increased tumor control rates with combined alanosine and radiation were highly dependent upon the time and sequence of the combined treatment. The reason for reduced efficacy at treatment times of less than 8 h prior to X-irradiations appears to be related in part to the modulation of the body temperature by L-alanosine when combined with Ketamine, an anesthetic agent.

Alanine↗

The tumor rejection antigen separated from Rous sarcoma virus-induced murine fibrosarcoma exhibits a molecular weight of approximately 60 kD but differs from functional pp60src.

The tumor antigen capable of inducing tumor resistance (tumor rejection antigen; TRA) was obtained in a solubilized form by sodium dodecyl sulfate (SDS) extraction of plasma membrane fraction from Rous sarcoma virus (RSV)-induced CSA1M fibrosarcoma cells (BALB/c origin). Analyses by Sephacryl S-300 gel filtration and SDS-polyacrylamide gel electrophoresis revealed that TRA activity was recovered in the fraction with a molecular weight of approximately 60 kD. Unfractionated crude SDS-solubilized preparation contained gp70 as detected by rabbit anti-gp70 antiserum, whereas such reactivity was lost in the fraction exhibiting the molecular weight of about 60 kD. Since this fraction retained pp60src activity, the relation of TRA to pp60src was further investigated. pp60v-src was also obtained from the lysate of v-src-expressing yeast transformant. Immunization of BALB/c mice with such pp60v-src-containing lysate failed to induce any significant tumor protection. The above 60 kD fraction of CSA1M solubilized antigens was allowed to bind to Sepharose beads coupled with anti-pp60src monoclonal antibody and separated into the bead-bound and bead-unbound fractions. The bead-bound fraction that was recovered from pp60src-binding beads (pp60src-positive fraction) did not exhibit the TRA activity. In contrast, immunization with the fraction depleted of pp60src activity (bead-unbound fraction) resulted in potent tumor protection. These results indicate that the solubilized membranous component(s) of CSA1M with a molecular weight of approximately 60 kD, which is distinct from functional pp60src, functions as the TRA against RSV-induced CSA1M tumor cells.

Animals↗

Active specific chemoimmunotherapy of lymph-node metastasis from a poorly immunogenic murine fibrosarcoma.

The fibrosarcoma MCA-SP, which was recently induced with methylcholanthrene (MCA) in C3H/HeJ mice, displays poor immunogenicity in in vivo prophylaxis. A cell variant MCA-SPN1, which bears a tumor-specific transplantation antigen (TSTA) cross-reactive with the parental line MCA-SP, was selected because of its proclivity for axillary lymph-node metastases. Although these lymph-node metastases were resistant to sinecomitant (post-excisional) immunity, they were susceptible to combined active and passive specific chemoimmunotherapy, using tumor-specific, 1-butanol-extracted, preparative isoelectric focusing-purified, TSTA (1 microgram weekly sc injections), cyclophosphamide (CY, a single intraperitoneal 20 mg/kg dose), and adoptive transfer of immune splenic T lymphocytes, which had been re-stimulated in vitro with extracted TSTA and interleukin-2. This triple regimen both reduced the incidence of spontaneous lymph-node metastases, and prolonged the survival of tumor-bearing, as well as tumor-resected hosts. The results from local adoptive transfer assay using T-lymphocyte subpopulations of spleen and lymph nodes in these treated hosts suggested that Lyt 2+ cytotoxic T-lymphocytes (CTL) mediated in vivo tumor-neutralization. Thus TSTA/CY/CTL therapy activates tumoricidal host responses effective against the poorly immunogenic MCA-SP tumor and its lymph-node metastases.

Animals↗

Analysis of clonal evolution in a tumor consisting of pSV2neo-transfected mouse fibrosarcoma clones.

The process of clonal evolution was analyzed in a line of methylcholanthrene-induced mouse fibrosarcomas. The tumor cells were transfected with pSV2neo gene and 22 clones were randomly isolated. Genetically tagged clones were mixed and inoculated into syngeneic mice. Southern blot analysis revealed that one of the clones, no. 11, dominated both in tumors in situ and in lung metastatic nodules. No. 11 clone and other clones were similar in growth rates in vitro and in vivo, in spontaneous and experimental metastatic abilities, in immunogenicity, and in the capacity of intercellular communication in vitro. Although no. 11 clone overgrew other clones in vivo, this was not the case when clones were mixed and maintained in vitro. We conclude that clonal interactions in vivo may be responsible for the dominance of no. 11 clone in the tumor. It is likely that the preferential metastasis of no. 11 clone to the lung may be a simple reflection of the proliferative advantage of the dominant clone in the tumor in situ.

Animals↗