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Cytogenetic analysis of an infantile fibrosarcoma showed the presence of a t(12;13) and numerical changes of chromosomes 15 and 20. Until now only non-random gain or loss of total chromosomes as well as one case with a deletion at 17p have been reported for this kind of tumor. This report represents the first cytogenetic description of an aggressive infantile fibrosarcoma with a translocation.
Loss or inactivation of tumor suppressor genes has been implicated by indirect methods in the etiology of most human cancers. In the functional studies presented here, tumor suppressors on human chromosome 1 were investigated using microcell-mediated chromosome transfer. Translocated chromosomes from normal human cells representing most of 1q, or all of 1p and a small portion of 1q translocated onto the region of the X chromosome encoding HPRT, were transferred into human fibrosarcoma cell line HT1080. Analysis of HT1080 microcell hybrids showed a tumor suppressor activity associated with 1q. All HT1080 cells carrying transferred 1q in a ratio of 1:1 with the HT1080 genome showed a more flattened morphology and a reduced ability to form tumors in nude mice compared to parental HT1080 cells. Diploid HT1080 cells carrying a single extra 1q also had a longer population doubling time and showed a loss of ability to clone in soft agar. Tumors arose from 1q-containing clones with a longer latency period, and a large majority of the cells comprising these tumors had lost the transferred chromosome. These results indicate the presence on chromosome 1q23-qter of a tumor suppressor gene or genes that can act to suppress transformation of a human fibrosarcoma cell line.
The combined effects of the synthetic glucosaminylmuramyl dipeptide (GMDP) on the antitumor activity of chemically synthesized lipid A analogs, compound A-103 (glucosamine-4-phosphate with (R)-3-tetradecanoyloxytetradecanoyl group at the C-2 and C-3 positions), Escherichia coli-type lipid A (506), Salmonella typhimurium LT-2 lipopolysaccharide (LPS) against Meth A fibrosarcoma in mice were examined. Meth A fibrosarcoma cells (5 x 10(5) were inoculated intradermally into BALB/c mice on day 0, and compound A-103 and/or GMDP was administered intravenously (i.v.) on days 7 and 9. Two i.v. injections of A-103 (50 micrograms) alone or GMDP (10 micrograms) alone induced 42.8 or 51.8% inhibition of the rate of tumor growth, however, A-103 (100 micrograms) with GMDP (10 micrograms) exhibited a high 68.7% inhibition rate 19 days after tumor inoculation. The inhibition of the tumor growth rate by the combination A-103 (100 micrograms) or 506 (50 micrograms) with GMDP (10 micrograms) was stronger than that of A-103 or 506 with MDP (10 micrograms). The combination of LPS (1 or 10 micrograms) with GMDP (10 micrograms) exhibited a higher inhibition rate than that of LPS with MDP, and three or four tumor-free mice out of five mice were observed, suggesting that the combined effect of GMDP is more potent than that of MDP. With the addition of GMDP, A-103 did not enhance the production of tumor necrosis factor (TNF) on the basis of L929 cell lysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Fibrosarcoma is a rare malignancy in the oral cavity. Tumours of fibrous connective tissue are sometimes difficult to classify as benign or malignant. The literature is reviewed and three cases of oral fibrosarcoma are presented.
Maxillary fibrosarcoma of a 31-year-old female is described with special reference to immunofluorescent characterization of the extracellular matrix. Following extractions, endodontic treatment and occlusal adjustment the tumour was operated on. The spindle-shaped tumour cells displayed a herring-bone pattern. The tumour was diagnosed as a fibrosarcoma and graded as poorly differentiated. Immunostaining for the specific type I collagen was positive throughout the tumour matrix, whereas staining for type III collagen was faint and occasional, and did not definitely codistribute with reticulin. Staining for type IV collagen and fibronectin in the tumour matrix was negative.
The growth of primary subcutaneous fibrosarcomas and their pulmonary metastases was studied in normal and athymic Swiss mice. The metastases tended to develop more rapidly than did the primary tumors. However, when growth rates of tumors of small volumes (up to 1 cm3) were compared, the tumor and metastases exhibited similar rates of development in both strains indicating the growth rate of pulmonary metastases was related to that of the tumor of origin. Modified immune reactivity, as in athymic mice, influenced the growth of the same tumor in that the subcutaneous fibrosarcoma exhibited a faster rate of development, while the growth rate of pulmonary metastases decreased, when compared with growth in Swiss mice. Therefore, it appears that growth characteristics of the primary tumor from which metastases originated and the reactivity of the host must be included among the factors determining metastatic growth rates.
The activated oncogenes in rat fibrosarcomas induced by subcutaneous injection of 1,6-dinitropyrene (1,6-DNP), an environmental mutagen-carcinogen, were examined by NIH3T3 cell transfection assay and Southern blot analysis. DNAs from two of eleven fibrosarcomas, 1,6-DNP6 and 1,6-DNP9T, induced transformants which contained rat specific repetitive sequences. Three primary transformants, obtained with DNA from 1,6-DNP6, and two secondary transformants of one of these primary transformants tested, contained rat H-ras. DNA from 1,6-DNP9T; a fourth transplant of 1,6-DNP9, also induced transformants. All the primary transformants with DNA from 1,6-DNP9T, and three secondary transformants of one of them, contained rat N-ras. The DNA from the original tumor, 1,6-DNP9, however, did not give any transformants by several transfection assays. Activation of N-ras oncogene during serial transplantations is discussed.
Antitumor activity of Leuconostoc mesenteroides, Streptococcus cremoris and Streptococcus lactis was investigated in solid mouse fibrosarcoma. Intratumor administration of lyophilised bacterial cells at a dose of 20 mg/kg body wt resulted in the regression of tumors in a maximum number of animals. Intraperitoneal injection at the same dose resulted in a significant increase in the survival time but was ineffective in curing the animals. Intratumor injection of Streptococcus thermophilus at a dose of 20 mg/kg body wt also inhibited the growth of fibrosarcoma accompanied by an increase in the survival time while intraperitoneal administration of S. thermophilus prolonged only the survival time and did not result in cure. In mice bearing the ascitic form of sarcoma-180 or Ehrlich ascites carcinoma, intraperitoneal administration of S. thermophilus resulted in complete cure in a very significant proportion of tumor-bearing mice. S. thermophilus was more effective in sarcoma-180 than in Ehrlich ascites carcinoma. The cured tumors did not recur.
Antitumor activity induced by a heat-killed preparation of S. thermophilus against mouse fibrosarcoma was investigated. The treatment of Swiss mice with S. thermophilus prior to transplantation could not prevent tumors. However, animals cured by treatment with a S. thermophilus preparation failed to take up the tumor when rechallenged with fibrosarcoma. S. thermophilus did not induce antitumor activity in animals immunosuppressed by sublethal whole body gamma-irradiation (4 Gy) or hydrocortisone treatment prior to transplantation. Suppression of activity of macrophages by carrageenan had no effect on antitumor activity of the heat inactivated preparation of S. thermophilus. The intravenous administration of sera from cured animals was ineffective in curing the tumours. Spleen cells from cured animals could effectively transfer the antitumor activity to recipients transplanted with the tumor. This effect was abolished when the T-lymphocyte population in the inoculum was specifically depleted. The results thus suggest the involvement of T-lymphocytes in antitumor activity exhibited by S. thermophilus.
We have previously reported that phytic acid (inositol hexaphosphate or InsP6), a natural constituent of cereal diet, when administered in drinking water exerts a consistent antitumor effect on experimental colon cancer in vivo. The objective of this study was to determine whether InsP6 has similar anti-neoplastic effect on other tumor models, such as murine fibrosarcoma. We report that intraperitoneal injection of InsP6 reduces growth of subcutaneously transplanted fibrosarcoma (FSA-1) in mice, prolongs survival of tumor-bearing mice and reduces the number of pulmonary metastases. Since InsP6 is a common constituent of our diet and has very little or no toxic effects, in addition to being chemopreventive, it could have potential use in therapy of cancer as well.
There is evidence that mast cells and their degranulation products are involved in resistance against tumours. Previously, we have shown that tumour incidence and growth were inversely correlated with basal histamine levels, i.e. mast cell numbers, in tissues of W/Wv (mast cell-deficient), Wv/+ (partially mast cell-depleted), and +/+ (mast cell-sufficient) mice, and that histamine levels were increased in numerous tissues of tumour-bearing animals, including C57BL/6 and C3H mice, Sprague-Dawley and Commentry rats. The aim of this work was to analyse the incidence and growth of a grafted tumour (fibrosarcoma MC-B6-1) in W/+ mice, as compared with W/Wv, Wv/+ and +/+ mice, and to study the modifications in tissue histamine levels in W/+, W/Wv, Wv/+ and +/+ tumour-grafted mice, in order to determine whether or not these modifications were correlated with resistance to tumours. We report confirmation that tumour incidence and growth are inversely correlated with basal tissue histamine levels in W/Wv, Wv/+, and +/+ fibrosarcoma-bearing mice. However, in W/+ mice (normal tissue histamine levels), tumour incidence was the same as in Wv/+ mice. Histamine levels in tissues of W/Wv, Wv/+, W/+ and +/+ tumour bearing mice were not significantly different from those in controls. They were higher in some tissues of Wv/+ mice rejecting the tumour than in Wv/+ mice not rejecting the tumour. However, in W/+ and +/+ mice, histamine levels were not significantly different, and even tended to be lower in most tissues of mice rejecting the tumour than in mice accepting the tumour. Overall, these results suggest that resistance to tumours cannot be ascribed solely to mast cells, and that other mechanisms may also be involved. Thus, further experiments are needed to clarify the exact role of mast cells and mast cell-derived mediators and cytokines in the defence against tumours.
Endogenous opioids play a role in carcinogenic events by serving as inhibitory growth factors that alter cell proliferative events by interaction with opioid receptors. The present study addresses the question of whether endogenous opioid systems function tonically in tissue culture. Using S20Y neuroblastoma, a cell line that produces a growth-related opioid peptide (i.e.[Met5]enkephalin) and contains the zeta receptor known to be associated with growth, the effects of opioid receptor blockade by naltrexone, a potent opioid antagonist, was examined. Drug concentrations of 10(-4) to 10(-8) M naltrexone stimulated cell proliferation, with 32-86% more cells found in the naltrexone groups than control from 12 to 48 h after initiating drug exposure; drug concentrations of 10(-9) to 10(-13) M had no effect on growth. Evaluation of labeling and mitotic indices revealed that both DNA synthesis and mitosis were increased by naltrexone, as were the number of cells with process lengths greater than 40 microns. Naltrexone (10(-6) M) also stimulated the growth of N115 murine neuroblastoma, SK-N-MC human neuroblastoma, and HT-1080 human fibrosarcoma. These results indicate that endogenous opioids function in vitro to regulate growth by inhibitory mechanisms, and do so actively. This autocrine mechanism in tissue culture also occurs in other animal neuroblastoma cell lines, as well as for human neuroblastoma and fibrosarcoma cell lines.
In this study we used alkaline elution to examine DNA damage produced in two murine fibrosarcomas after hyperthermia (42 degrees C), with or without preinduced hyperglycemia. The work was stimulated by a recent report that pretreatment of mice with glucose prior to hyperthermia decreased the growth rate in a similar fibrosarcoma tumor. The intercellular tumor pH dropped from its resting value of 7.1 to a value of 6.6 at 1.5 hr after a single injection of glucose. While treatment with either glucose alone or heat alone produced very little detectable damage, the combination of these two agents resulted in marked degradation of tumor DNA isolated immediately after treatment. DNA degradation was accompanied by a simultaneous decrease in cell viability; thus, direct cell killing and subsequent nuclease or lysosomal enzyme activity are probably involved. We also tested whether hyperglycemia combined with hyperthermia influenced the DNA-DNA crosslinking induced by subsequent cyclophosphamide (Cy) treatment. Because of the extensive degradation caused by the pretreatment alone under the conditions used in these initial experiments, we were not able to quantitate with validity the amount of Cy-induced crosslinking. However, damage in viable cells may presumably interact with the subsequent Cy treatment to produce further selective cell killing in the tumor.
In Vivo murine tumor experiments were carried out to determine whether 6-thioguanine (6-TG) could enhance the cytotoxic effects of radiation on tumors. The combined effects of single and fractionated x-irradiation were evaluated on the transplanted methylcholanthrene induced fibrosarcoma (Meth-A) in BALB/c mice, a moderately radioresponsive tumor and on the radiation induced fibrosarcoma (RIF) in C3H/He mice, a highly radioresistant tumor. The combined treatment of single administration of 6-TG (25 mg/kg) and of x-irradiation (20 Gy) on Meth-A tumors produced more than 90% tumor control, whereas the radiation alone resulted in less than 5% tumor control. The radiosensitizing effect by 6-TG was higher when the drug was administered either 1 to 8 hr prior to or 24 hr after x-irradiation. The dose modification factor of single dose 6-TG (10 mg/kg) is estimated to be 1.47 for Meth-A tumor and 1.25 for RIF tumor. The tumor control rates of fractionated irradiation alone and with concomitant 6-TG in Meth-A tumors were 14% and 59%, respectively. Based on the studies reported here and well documented pharmacokinetics in humans, it is suggested that combined radiation therapy and 6-TG may provide an enhanced therapeutic effect even in tumor varieties where the drug has no apparent anti-tumor activity on non-irradiated cells.
Transforming growth factor (TGF-beta) is a family of multifunctional signalling molecules that play a fundamental role in both normal and malignant cell behavior. Procedures that alter mouse TGF-beta 1 gene expression provide an important approach for analyzing the complex regulatory processes associated with this member of the growth factor family. Therefore, we have designed oligodeoxyribonucleotides (oligos) in an antisense orientation, which are complementary to regions of the TGF-beta 1 message, in an attempt to obtain an oligo sequence that specifically reduces TGF-beta 1 synthesis. We observed that oligos containing a mixture of phosphorothioate and phosphodiester linkages were less toxic and more specific when compared to those only containing phosphorothioate. A non-toxic sequence was identified that markedly reduced the levels of TGF-beta 1 in oligo-treated malignant mouse fibrosarcoma cells. The invasive and metastatic properties of these fibrosarcoma cells were also significantly decreased following treatment with the antisense oligo. The results indicate an important role for altered TGF-beta 1 expression in the regulation of malignant cell proliferation, invasion and metastasis. These results also indicate that this oligo sequence is a useful tool for studies directed towards understanding the complex relationships between TGF-beta 1 and cellular regulation.
Proliferating invaginations of the sinonasal epithelium, simulating inverted papillomas, have been mentioned once in the literature as a reactive phenomenon overlying sinonasal fibrosarcomas. These proliferations may be so marked as to make the distinction from inverted papilloma virtually impossible. The possible result is that the examining pathologist's attention might be drawn exclusively to the epithelial component, thus causing him to overlook, especially in a small biopsy, a rather bland but distinctive sarcomatoid component which is located underneath. We report such a case of marked endophytic proliferation of sinonasal epithelium which was interpreted, in the preoperative biopsy, as an inverted papilloma with dense fibrous stroma which later, in the surgical specimen, was found to be a part of a submucosal fibrosarcoma. The diagnostic pitfall is discussed.
Cytokine-encoding viral vectors are considered to be promising in cancer gene immunotherapy. Interleukin 12 (IL-12) has been used widely for anti-tumor treatment, but the administration route and tumor characteristics strongly influence therapeutic efficiency. Meth-A fibrosarcoma has been demonstrated to be insensitive to IL-12 treatment via systemic administration. In the present study, we developed an IL-12-encoding fiber-mutant adenoviral vector (AdRGD-IL-12) that showed enhanced gene transfection efficiency in Meth-A tumor cells, and the production of IL-12 p70 in the culture supernatant from transfected cells was confirmed by ELISA. In therapeutic experiments, a single low-dose (2 x 10(7) plaque-forming units) intratumoral injection of AdRGD-IL-12 elicited pronounced anti-tumor activity and notably prolonged the survival of Meth-A fibrosarcoma-bearing mice. Immunohistochemical staining revealed that the IL-12 vector induced the accumulation of T cells in tumor tissue. Furthermore, intratumoral administration of the vector induced an anti-metastasis effect as well as long-term specific immunity against syngeneic tumor challenge.
Peripheral-type benzodiazepine receptor (PBR) is a 18-kDa high-affinity drug and cholesterol binding protein, that has been implicated in several physiological processes, such as cholesterol transport and mitochondrial respiration. Specific PBR ligands regulate cell proliferation, although their action is controversial and probably cell-type specific. The aim of the present study was to examine the expression of PBR in cells of mesenchymal origin, i.e. human fibroblasts and fibrosarcoma cells, as well as its role in the regulation of their proliferation. Both mesenchymal cell types express high levels of PBR, localized exclusively in mitochondria. PBR-specific drug ligands, the isoquinoline carboxamide PK 11195 and the benzodiazepine Ro5-4864, at relative high concentrations (10(-4)M), exert a strong inhibitory effect on cell proliferation by arresting the cells at the G0/G1 phase of the cell cycle, while no apoptotic cell death was observed. In normal fibroblasts, this inhibition was correlated with a decrease in the activation of the cell cycle markers ERK and c-Jun. PBR knockdown by RNA inhibition did not affect the proliferation of either cell type and did not influence the inhibitory effect of PK 11195 and Ro5-4864 on cell growth. These data suggest that in fibroblasts and fibrosarcoma cells PBR drug ligands inhibit cell proliferation in a PBR-independent manner. These results are in contrast to data reported on cells of epithelial origin, suggesting that the origin of the cells is crucial in defining the role of PBR in their proliferation, and raise caution in the commonly made assumption that PBR mediates cell functions affected by PBR drug ligands.