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Malignancies have been described in association with various connective tissue disorders. While such associations may be relatively common in some disorders, such as polymyositis, the relationship between scleroderma and malignancy is more controversial. A case of fibrosarcoma of the tibia in a patient with scleroderma is presented, with correlation of conventional radiography, computed tomography, and histopathology.
In this study, we have used the T-10 fibrosarcoma tumor cells to further analyze the relationship between metastatic competence, expression of H-2K antigens and susceptibility to lysis by virus augmented NK cells in vitro. Our results show an inverse correlation between metastatic properties of the original T-10 clones, IC9 and IE7, and susceptibility in vitro to lysis by virus-augmented NK cells. Restoration by transfection of expression of H-2K genes (H-2Kb or H-2Kk) led to the alteration of the metastatic phenotype of the tumors cells, yet had minor influence on the putative susceptibility of these clones to NK. These observations suggest that expression of MHC gene products, while affecting metastases, does not exclusively determine sensitivity to NK cells.
The tumor stem line of a soft tissue fibrosarcoma, histologic malignancy grade III, had 43 chromosomes with several clonal chromosome aberrations, including the three balanced translocations t(X;18)(p11;q11), t(2;15)(p23;q26), and t(7;22)(q11;q13), two partly identifiable marker chromosomes, der(3)dic(3;?)(p11;?) and der(5), one small marker of unknown origin, and loss of one chromosome #11, #18, #19, and #21.
Cytogenetic studies were performed on a fibrosarcoma of a newborn. Only numerical chromosome changes (+8, +11, +20) were identified in this rare but distinct soft tissue sarcoma that occurs in children less than 5 years old.
Cytogenetic reports of soft tissue sarcomas in children, other than rhabdomyosarcomas, are rare. We report the second cytogenetic analysis of a congenital fibrosarcoma. The tumor had a monoclonal karyotype of 49.XX,+7,+15,+del(17)(p12).
Chromosome studies in a 7-week-old female infant with an intraabdominal malignant fibrosarcoma showed a hyperdiploid karyotype of 50,XX, +der(6)del(6)(p23)add(6)(q11), +8, +10, +11,add(12)(p13). Trisomy 11 appears to be a nonrandom primary cytogenetic abnormality in the congenital or infantile form of this mesenchymal tumor and is also a nonrandom gain in congenital mesoblastic nephroma. A possible developmental link between these two mesenchymal tumors, mediated by a gene or genes on chromosome 11 is postulated.
Clonal chromosome changes of a complex nature were found in a case of adult fibrosarcoma. Few studies on this tumor have been published, all showing complex changes without characteristic anomalies.
Functionally active (high-Mr) and inactive (low-Mr) plasminogen activator inhibitor 1 (PAI) have been purified from fibrosarcoma cell-line HT 1080 conditioned medium, containing 1% fetal calf serum. The two forms were first purified by affinity chromatography on heparin-Sepharose and then separated from each other by gel filtration on Sephadex G-150. The final purification was achieved by affinity chromatography on insolubilized monoclonal antibodies towards human PAI. Alternatively, the low-Mr form was purified by chromatography on carboxymethyl-cellulose. Low-Mr PAI purified in this way, could be almost fully reactivated by treatment with guanidinium chloride. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis followed by immunoblotting revealed that the low-Mr form contained nothing but PAI at an Mr of about 50,000. In addition to PAI, the high-Mr form contained a component, which was not antigenically related to PAI. This compound had a molecular weight of about 75,000 and its NH2-terminal amino acid sequence corresponded to that of human vitronectin. We conclude that the high-Mr form of PAI constitutes a complex between 50,000 Mr PAI and vitronectin from fetal calf serum.
An unusual case of fibrosarcoma of the right ventricle is described in a 25-year-old man. The diagnosis of a right ventricular tumour was made on the basis of echocardiographic and radionuclide studies and was confirmed by angiocardiography. The surgical management and postoperative course are described together with a brief review of the literature.
We report a case of primary fibrosarcoma of the heart which presented with features of obstruction to the tricuspid valve and superior caval vein. It was correctly diagnosed by cross-sectional echocardiography.
Growth and dose-response curves were established for a subcutaneously implanted isogenic fibrosarcoma in BD9 rats after treatment with photochemotherapy (PCT), using Photofrin II or polyhaematoporphyrin with superficial or interstitial 630 nm light, cyclophosphamide or gamma-irradiation. Tumour response to PCT increased with dose up to 200 J.cm-2 for superficial light or 200 J for interstitial light but no further response occurred after higher light doses. The maximum response after interstitial treatment was significantly greater than after superficial treatment where only a small margin of normal tissue was treated. The incidence of necrosis in the overlying skin was significantly less after interstitial than superficial light suggesting a better therapeutic ratio after interstitial than superficial PCT. Tumour response increased with the diameter of the treatment field after superficial light supporting the possibility of a tumour bed effect associated with PCT. The largest tumour that could be effectively treated with a single optical fibre was 12 mm. The dose-response curves for interstitial PCT and cyclophosphamide were similar but ionizing irradiation produced increasing tumour response throughout the range of doses used (5 to 30 Gy) and the maximum response was greater after radiotherapy than after PCT or chemotherapy suggesting that in this tumour model interstitial PCT is as effective as cyclophosphamide but less effective than radiotherapy.
Blood flow measurements following i.v. infusion of iodo-antipyrine labelled with 14C(14C-IAP) and blood volume measurements following i.v. injection of 125I human serum albumin and 51Cr-labelled red blood cells were made in a transplanted rat fibrosarcoma for comparison with various normal tissues. The tumour-blood partition co-efficient for 14C-IAP was found to be 0.79 +/- 0.07 which is similar to most of the normal tissues studied. The solubility of 14C-IAP in plasma was found to be higher than that in whole blood. Blood flow to tumours less than 1000 mm3 was found to be 17.9 +/- 4.0 ml blood 100 g tissue-1.min-1. These values were considered to be primarily measurements of nutritive flow. Blood in the tumours was found to occupy around 1% of the tissue space which was similar to that found for normal muscle and skin. There was no direct correlation between % blood volume and blood flow for the different tissues studied. The haematocrit of blood contained in tumour tissue was calculated to be significantly lower than that of blood contained in the normal tissues. It was suspected that permeability of tumour blood vessel walls to 125I-HSA could have accounted for this difference.
OK-432, a streptococcal preparation with potent biological response modifying activities, had the ability to cure mice bearing BAMC-1 (fibrosarcoma) ascites when it was injected intraperitoneally five times, 2, 4, 6, 8, and 10 days after the tumor inoculation. Previously, it was shown that the OK-432 injection on day 2 was indispensable since only a minimal antitumor effect was obtained when an inflammation-inducing agent such as thioglycolate instead of OK-432 was injected on day 2, followed by four OK-432 injections on days 4, 6, 8 and 10. In the present study, the injection of OK-432 on day 2 and a subsequent injection of either IL-2 or IFN-gamma on day 4 or 6 showed a significant antitumor effect, achieving a complete cure in approximately 50% of mice treated, although none of the mice could be cured by a single injection of either OK-432, IL-2, or IFN-gamma on day 2. Interestingly, however, the mice treated with an injection of a lymphokine (IL-2 or IFN-gamma) on day 2 followed by OK-432 on day 4 were not cured either. Peritoneal cells on day 12 in mice treated with OK-432 and either of the lymphokines contained pantropic killer cells, which were Thy-1+ and asialo GM1+ (AsGM1+). Moreover, the antitumor effect of the combined treatment was abolished when mice were pre-treated with anti-AsGM1. No significant antitumor effect was observed in athymic nu/nu mice. Together with our previous findings, these results indicate that lymphokines induced by OK-432 administration may account for some of its therapeutic effects and that these lymphokines may also facilitate the subsequent induction of specific killer cells. These results warrant further investigation on possible effective therapeutic protocols with the combined use of OK-432 and lymphokines.
Tumor necrosis factor-alpha (TNF alpha) is recognized as a principal mediator of a variety of inflammatory conditions. In animal models, pentoxifylline attenuates the morbidity and mortality of bacterial sepsis, an effect which has been attributed to its ability to suppress the induction of TNF alpha. To determine whether pentoxifylline also directly inhibits the effects of TNF alpha, the ability to inhibit cytotoxicity on the TNF alpha-sensitive murine fibrosarcoma cell line, L929, was examined. Cell viability was assessed by crystal violet staining and cell proliferation was assessed by [3H]-thymidine uptake assay. TNF alpha induced dose-dependent cytotoxicity. At concentrations of TNF alpha of 1000 U/ml, viability at 3 days was approximately 35% of control. When L929 cells were co-incubated with TNF alpha (1000 U/ml) and pentoxifylline (1 mM), cell viability increased to approximately 75% of control (P = 0.001). At concentrations of TNF alpha of 10,000 U/ml, cell viability which was 11% of control with TNF alpha alone increased to 53% in the presence of pentoxifylline (P = 0.002). TNF alpha at 1000 and 10,000 U/ml concentrations decreased [3H]-thymidine uptake to approximately 5% of control values. Co-incubation with pentoxifylline significantly increased uptake to 13% of control at both TNF alpha concentrations (P = 0.002). Pentoxifylline did not affect the level of type I TNF alpha receptor--ligand cross-link product. However, in TNF alpha receptor binding assays, incubation with pentoxifylline 1 mM for 4 h was associated with an increase in the receptor affinity (control: KD = 0.42 nM vs pentoxifylline-treated: KD = 0.21 nM, P = 0.006), without significant change in number of type I TNF alpha receptors, suggesting that pentoxifylline affects post-receptor signalling events. We have observed that pentoxifylline prevents the TNF alpha-mediated activation of sn-2 arachidonic acid-specific cytosolic phospholipase A2, an important component of the signal transduction pathway of TNF alpha cytotoxicity. Because pentoxifylline does not inhibit all activities mediated by the type I TNF alpha receptor, its selective inhibition of post-receptor signalling may facilitate further study into the mechanisms underlying the diverse effects of TNF alpha.
Growth of BN175, a malignant fibrosarcoma, was correlated with high plasma TXB2 and PGE2 levels. This statistically significant increase was first detected 17 days after inoculation of the tumor, at which time the tumors were 20 mms in diameter. A further increase in tumor size was associated with still higher PGE2 and TXB2 values. At the same time, progressive alterations in platelet function, as measured by ADP-induced platelet aggregation, were observed. 6-keto-PGF1 alpha levels remained normal throughout the whole experiment. It was concluded that tumor growth was associated with changes in PG synthesis and platelet function, although it remains unclear whether these changes were caused by some host immunological response towards the tumor or were predominantly the result of tumor PG-synthesis.
Inhibition of the invasiveness of MO4 mouse fibrosarcoma cells by the vinca alkaloid, vinblastine (VLB), vincristine (VCR) and vindesine (VDS), has been examined in vitro. At doses between 0.006 microgram/ml (minimal effect) and 0.1 microgram/ml (complete inhibition) these drugs interfered with the invasion of MO4 cells from an aggregate confronting a fragment of embryonic chick heart in three-dimensional culture. We have also examined the effect of these drugs on the following activities of MO4 cells: growth, directional migration and assembly of the cytoplasmic microtubule complex. Growth and directional migration were affected by the same doses of vinca alkaloids as invasion. In contrast with the vinca alkaloids, 5-fluorouracil at 1 microgram/ml inhibited growth but allowed directional migration and invasion. At a dose of 0.3 microgram/ml VLB, VCR and VDS interfered with the assembly of cytoplasmic microtubules, as visible after immunocytochemical staining with tubulin antiserum. Ultrastructural analysis demonstrated that inhibition of invasion in three-dimensional culture corresponds with abolishment of the cytoplasmic microtubule complex. Anti-invasive concentrations of VLB, VCR and VDS represent clinically achievable plasma concentrations. We concluded that the anti-invasive effect of the vinca alkaloids may contribute to their antitumor activity.
Vitamin K deficiency, either dietary or pharmacologically induced by warfarin, was unable to affect the metastatic capacity of cells from a benzopyrene-induced fibrosarcoma in C57BL/6J mice. The same cells had a procoagulant activity, of tissue thromboplastin type, which was also completely unaffected by vitamin K antagonism or deficiency. In another murine model of spontaneous metastasis we previously suggested that depression of a particular procoagulant such as a direct factor X activator might contribute to the antimetastatic activity of warfarin. The failure of vitamin K deficiency to affect both the procoagulant and the metastatic capacity of the model reported here offers strong negative support to the same concept.
We have studied the effect of the adenylate cyclase-stimulating agent forskolin on expression of components of the plasminogen activation system in the human fibrosarcoma cell line HT-1080. By enzyme-linked immunosorbent assays, forskolin was found to cause a 2 to 4-fold decrease in intracellular and culture medium levels of type-1 inhibitor of plasminogen activators (PAI-1) and tissue-type plasminogen activator (t-PA). This was true for cells not treated with other agents and for cells, in which the PAI-1 and t-PA levels had been increased 5 to 10-fold by treatment with dexamethasone. This down-regulation could be traced back to corresponding decreases in the cellular levels of PAI-1 and t-PA mRNAs. Of the two PAI-1 mRNAs, the 2.4 kb species was 5-fold decreased by forskolin in cells treated with dexamethasone, while the 3.4 kb transcript was unaffected; in cells not treated with dexamethasone, forskolin affected the two PAI-1 transcripts in parallel. These studies show that in addition to the many inducers of PAI-1, PAI-1 gene expression is also subject to negative modulation by cyclic AMP. They also show that t-PA gene expression, in contrast to the induction by cyclic AMP observed in many other cell lines, may also be subject to negative regulation by cyclic AMP. Thus, hormonal agents acting with cyclic AMP as a second messenger may be involved in down-regulating PAI-1 and t-PA expression in vivo.