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A fibrosarcoma of the penis is an infrequent finding. This paper contributes one case found in the perineo-scrotal region emphasising some aspects of local staging procedures, as well as the differential diagnosis with other mesenchymal tumours; there is no validated treatment protocol, although there is widespread agreement that extensive surgical excision should be performed, such as was performed in this patient.
Effect of propargylglycine (2-Amino-4-pentynoic acid, PPG) on invasive property of human fibrosarcoma HT-1080 cell was investigated. PPG treatment of HT-1080 significantly reduced the total cellular metallothioneins (MTs) contents, and the resistance of HT-1080 against heavy metals toxicity decreased with the decrease of the MTs contents. The HT-1080 cell invasion to reconstituted basement membrane Matrigel (MG) was inhibited by the PPG treatment in a PPG concentration-dependent fashion. The inhibition was due to the lowering of HT-1080 cells attachment to MG and degradation activity of matrix metalloproteinases (MMPs) secreted from HT-1080 by the PPG treatment. However, the chemotactic ability of the PPG treated HT-1080 was enhanced. Our results suggest that MTs concentration levels in a malignant tumor cell are closely related to its invasiveness, and if MTs level of tumor cell can be controlled, cancer metastasis may be able to be controlled.
Two strains of feline fibrosarcoma virus (ST-FeSV and GA-FeSV) were found to induce tumors in cats and marmosets, and to transform feline and marmoset cells in vitro after primary inoculation. A third strain (SM-FeSV) failed to induce tumors or transform marmoset cells after primary inoculation; however, when SM-FeSV-injected marmoset cultures were passed 26 times in vitro, the cell cultures released infectious virus which transformed marmoset fibroblasts but still failed to induce tumors in marmosets. ST-FeSV induced mainly round-cell type transformation (r foci), GA-FeSV induced predominantly mixed round-fusiform cell type transformation (fr foci), and SM-FeSV induced r and fr type foci with a higher proportion of fusiform cells in the fr foci than seen with GA-FeSV. Transforming virus was obtained from r or mixed r/fr foci of ST-FeSV but not from fr foci; heat treatment changed the virus from producing almost exclusively r type foci to inducing an increased number of fr foci. Passage of FeSV in cat cells yielded viruses with a higher ratio of infectivity for feline vs marmoset cells, while passage of FeSV in marmoset cells yielded virus with a relatively higher infectivity ratio for marmoset cells; the three strains differed in the degree of change in the infectivity ratio. Despite the alteration of host range of SM-FeSV propagated in marmoset fibroblasts, the virus retained feline P-30 antigen by CF and FA assays. Neutralization tests did not indicate but also did not exclude an alteration of the surface antigens of ST-FeSV or SM-FeSV propagated in marmoset fibroblasts. The alteration of the relative infectivity of FeSV during passage in marmoset cells may be due to: (1) the selection of a variant present in the original heterogenous uncloned population; (2) mutation; or (3) recombination with some marmoset genetic material, possibly an as yet unidentified endogenous marmoset virus.
In the peptide-targeted therapy for cancer, peptides are used to reach a selective and specific target in cancer cells. Peptides are used free or coupled to chemotherapeutic drugs, phagues, proteins, polymers, liposomes, and polymer-grafted liposomes. Using this latter approach, the pentapeptide YIGSR was coupled to the distal end from carboxyl groups of liposome-grafted polyethyleneglycol (PEG) chains (YIGSR-PEG-liposome). As a control, the peptide PEAGD coupled to PEG-liposome was used. The biological activity of YIGSR-PEG-liposome was tested using HT-1080 human fibrosarcoma cells. In adhesion assays, the YIGSR-PEG-liposome coated to plastic plates promoted 30% of the specific cell attachment. In competition assays, YIGSR-PEG-liposome inhibited the specific attachment of cells to laminin-1-coated plates by 25%. Following this, we prepared peptide-PEG-liposomes encapsulating adriamycin (ADR). In vitro cytotoxicity assays against HT-1080 cells gave IC(50) values 2.1 times lower for YIGSR-PEG-liposomal ADR in comparison to PEAGD-PEG-liposomal ADR. The free peptide added in excess increased the IC(50) value of YIGSR-PEG-liposomal ADR by 72%, while the IC(50) value of control liposomal ADR was unaffected, supporting a receptor-mediated mechanism of targeting. In addition, the lower IC(50) value is correlated with a higher total of ADR accumulation in the cells.
Hyaluronidase counteracts the growth inhibitory function of transforming growth factor beta (TGF-beta), whereas secretion of autocrine TGF-beta and hyaluronidase is necessary for progression and metastasis of various cancers. Whether hyaluronidase and TGF-beta1 induce resistance to staurosporine in L929 fibrosarcoma cells was investigated. When pretreated with TGF-beta1 for 1-2 h, L929 cells resisted staurosporine apoptosis. In contrast, without pretreatment, hyaluronidase protected L929 cells fromstaurosporine apoptosis. Hyaluronidase rapidly activated p42/44 MAPK (or ERK) in L929 cells and TGF-beta1 retarded the activation. Nonetheless, TGF-beta1 synergistically increased hyaluronidase-mediated inhibition of staurosporine apoptosis. Hyaluronidase rapidly activated c-Jun N-terminal kinase (JNK1 and JNK2) in L929 cells in 20 min. Dominant negative JNK1, JNK2, and JNK3 abolished the hyaluronidase inhibition of staurosporine apoptosis, but not the TGF-beta1 protective effect. Unlike the resistance to staurosporine, pretreatment of L929 cells with hyaluronidase is necessary to generate resistance to other anticancer drugs, including doxorubicin, daunorubicin, actinomycin D, and camptothecin, and the induced resistance was also blocked by dominant-negative JNKs. Together, hyaluronidase-mediated JNK activation is necessary to generate resistance to various anticancer drugs in L929 cells.
The antitumor effect of recombinant human tumor necrosis factor (rH-TNF) on two clones of rat fibrosarcoma with different metastatic potential to lymph nodes was examined. The colony formation of clone A, which has high metastatic potential, was completely inhibited by continuous exposure to rH-TNF at 50 U/ml. In contrast, colony formation of clone G, which has low metastatic potential, was not inhibited by high concentrations of rH-TNF (10,000 U/ml). The inhibitory effect of rH-TNF on colony formation by clone A was also observed with a 1-h exposure to rH-TNF. This effect was time and concentration dependent, as determined by the colony assay, 3H-thymidine uptake assay, and 51Cr-release assay. 3H-thymidine and 3H-uridine uptake per cell of clone A exposed to rH-TNF was not decreased. This suggests that the mechanisms of the antitumor effect of rH-TNF were not due to inhibition of DNA and RNA synthesis of tumor cells. In vivo growth and lymph node metastases of clone A inoculated i.p. to Donryu strain rats were completely suppressed by 14 consecutive i.p. injections of 10(5) or 10(6) U/kg per day of rH-TNF. On the other hand the growth of clone G was not influenced by rH-TNF administration.
BALB/c mice were immunized with the syngeneic 3-methylcholanthrene-induced fibrosarcoma CA-2 by the growth and excision method. When lymphoid cells from different organs of these tumor-free mice were tested in a direct 51Cr-release assay, peritoneal exudate cells but not spleen cells displayed specific cytotoxicity against the syngeneic tumor target. A cytotoxic response could be obtained by tumor-immune spleen cells when cultured in a mixed lymphocyte tumor cell culture (MLTC) at high but not low density although at the same effector/stimulator ratio. Lack of cytotoxic activity in low density MLTC was not due to an impairment of cytotoxic precursors since cytotoxicity was rescued by adding exogenous interleukin-2 in experimental conditions in which no lymphokine-activated killer cells could develop relevant anti-CA-2 lysis. When low density MLTC were supplemented with either 800 R-irradiated cells or nonirradiated, negatively selected Lyt 1+ cells from the same immune mice, induction of a cytotoxic response against CA-2 occurred and interleukin-2 production became detectable. Additional studies indicated that spleen cells of CA-2-immune mice were also impaired in their ability to provide help to syngeneic thymocytes for the generation of cytotoxic T lymphocytes against C57BL/6J alloantigens. Dilution effect of helper cells due to immunization procedures was excluded since spleen cells of mice immunized against another BALB/c tumor, the YC8 lymphoma, or against DBA/2 minor histocompatibility antigens provided good help to thymocytes against the same alloantigens. These results indicate that tumor-immune animals may also have selective T helper defects in an important lymphoid organ like spleen.
Highly malignant cell lines and low-malignant cell lines isolated from three different methylcholanthrene-induced murine fibrosarcomas were examined for their ability to attach to plastic dishes and collagen-coated dishes under serum-free conditions and in the presence of serum. Most of the cells from the three highly malignant lines attached and spread under all conditions. By 72 h, there was a significant increase in the number of cells indicating that at least some of the cells had undergone division (even in the absence of serum). In contrast, fewer of the cells from the three low-malignant lines attached and spread on the plastic or collagen substrates in the absence of serum or in the presence of 0.1 per cent serum. However, when 15 micrograms laminin per dish was added along with the low-malignant cells, they then attached and spread on the plastic and collagen-coated dishes. Previous studies have indicated that the highly malignant lines express cell surface antigens that cross-react with laminin while the low-malignant cell lines do not. We speculate that the differences between the high- and low-malignant cells in the expression of cell surface laminin-like antigens contribute to the dissimilarities in attachment and spreading capacity. These differences may also contribute to the dissimilarity between these cells in malignant potential.
Aurintricarboxylic acid (ATA) is a polyanionic, polyaromatic compound which has been shown to inhibit apoptotic cell death in various cell types induced by a variety of factors. Since ATA is known to be a general inhibitor of nuclease activities in vitro (ID50S ranging from 2 to 50 microM), the in vivo effects are usually attributed to inhibition of endogenous endonuclease activities. We show herein that ATA is a potent inhibitor of the nuclear enzyme DNA topoisomerase II. ATA inhibits the catalytic activity of purified yeast topoisomerase II with an ID50 of approx. 75nM as measured by relaxation assays. ATA does not stabilize the covalent DNA-topoisomerase II reaction intermediate ("cleavable complex") as do other inhibitors of this enzyme such as 4'-(9-acridinylamino)-methane sulfon-m-anisidide (amsacrime), 4'-demethyl-epipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-gluco pyr anoside) (etoposide) and ellipticines. In contrast, cleavable complex formation induced by amsacrine and etoposide is trongly inhibited in the presence of ATA. ATA also prevents the binding of topoisomerase II to DNA and inhibits topoisomerase II-catalysed ATP hydrolysis. The ability of ATA to interfere with more than one step in t he catalytic cycle of DNA topoisomerase II may explain its unusual potency as an inhibitor of this enzyme. ATA reduces the number of amsacrine-induced DNA-protein complexes in intact DC-3F Chinese hamster fibrosarcoma cells and protects these cells from the cytotoxic action of amsacrine. The effects of ATA on DNA-protein complex formation in living cells appear to be due to the direct interaction of the drug with topoisomerase II, since similar results are found when nuclei from untreated DC-3F cells are exposed to amsacrine after a short preincubation with ATA. Cells resistant to 9-hydroxyellipticine, which have been shown to possess altered topoisomerase II activity, are approx. 5-fold more resistant to ATA than the sensitive parental cells as shown by colony formation essays. We conclude that ATA is a potent inhibitor of topoisomerase II and that the drug interacts with topoisomerase II in living cells. Our findings raise the possibility that the protective effects of ATA towards apoptotic cell death might, at least in part, involve DNA topoisomerase II.
Immunity to a local (wing web) challenge with transplantable, chemically induced tumors, such as CHCT-NYU-4, can be transferred to histocompatible SC chickens with intravenously injected splenic T cells from tumor-immune chickens. Simultaneous iv injection of splenic T cells from chickens bearing progressively growing CHCT-NYU-4 prevents the expression of this adoptive systemic tumor immunity. The splenic suppressor T cells are B-L(Ia) positive and adhere to dishes coated with cimetidine-protein conjugate, suggesting that they bear type II histamine receptors (H2R). Intravenous injection of gamma-irradiated CHCT-NYU-4 cells 7 days prior to a local challenge with the same tumor promotes growth of a normally suboptimal tumor cell dose such that the incidence of progressive tumor growth is significantly increased. Concomitant treatment with the H2R antagonist, ranitidine, inhibits tumor growth of an optimal tumor dose challenge and promotes induction of tumor immunity. However, this drug cannot reverse the effect of iv injected tumor cells. Another drug with reported antisuppressor cell activity, cyclophosphamide (50 mg/kg), injected 1 day prior to challenge causes a transient inhibition of tumor growth. Injection of this drug on Day 7 does not have a significant effect by itself but, in combination with the Day-1 pretreatment, a significant inhibition of tumor growth by size and tumor incidence measurements is obtained. These results indicate that manipulation of immunity to transplantable fibrosarcomas in the chicken is possible with drugs acting on suppressor cells.
cDNA libraries from the murine UV-2237-IP3 fibrosarcoma cell line were prepared in the expression vector lambda gt11. Using specific antibodies, cDNA clones coding for the 14.5-kDa and the 34.0-kDa endogenous galactoside-specific lectins were isolated. In vitro translation and immunoprecipitation of mRNAs hybrid-selected by the cloned sequences from whole cell RNA provided confirmation for the clones. RNA and DNA blot analyses revealed that the two lectin proteins represent products of two different genes. We found differential levels of the specific mRNAs when low- and high-metastatic counterparts of the UV-2237 tumor system were compared, and these genes were not expressed in detectable amounts in normal mouse liver.
Two cases of malignant transformation of ameloblastic fibro-odontomas are presented, along with a review of the literature on ameloblastic fibrosarcomas. The occurrence of this malignant transformation of ameloblastic fibromas, ameloblastic odontomas, and ameloblastic fibro-odontomas appears to be more frequent than previously thought. This potential transformation alone does not justify radical treatment of all these benign lesions. If there is recurrence accompanied by a histologic pattern change toward a more unorganized fibrous stroma with displacement of the epithelial component, however, then more extensive treatment procedures appear to be indicated.
We report a case of radiation-induced neurogenic fibrosarcoma that developed in a patient who received radiation therapy for seminoma. The sarcoma developed within the irradiated field after a latency period of nineteen years. Although the occurrence of a secondary neoplasm is unusual, this possibility should be included in the differential diagnosis of patients who present with tumor growth after a long interval following radiation therapy.
A case of an ameloblastic fibrosarcoma in the mandible is described. The primary tumor was seen in a 5-year-old child. In spite of repeated surgical interventions, the tumor recurred three times within a one and a half year period, but not metastases have been observed. The difficulties in arriving at a correct diagnosis for this rare tumor involving the mandible are discussed. The treatment of choice seems to be radical surgery.
A biphasic odontogenic tumor with aggressive clinical behaviour is reported. The tumor arose posterior to the right mandibular third molar involving the angle of the mandible and the ascending ramus. Within a 5 years period the patient suffered from two episodes of local progression and final disease generalization occurred 6 years after initial surgical therapy. On histopathologic evaluation, both recurrences and the distant metastasis preserved the biphasic pattern seen in the primary tumor with both epithelial and mesenchymal components exhibiting clear cytological features of malignancy. There was no evidence of sarcomatous overgrowth within the progression of the tumor. By contrast, the proportion of the epithelial component was even enlarged in the second recurrence. Thus, both pathologic features and clinical behaviour clearly distinguishes this tumor from ameloblastic fibrosarcoma and demonstrates the clear morphological as well as clinical characteristics of a true malignant mixed type tumor with a definite sarcomatous and carcinomatous component. Thus, even though a very rare lesion, our case supports the consideration of the odontogenic carcinosarcoma as an individual entity.
Balb/c mice bearing a methylcholanthrene-induced fibrosarcoma were used to compare the activation levels of tumor-associated and peritoneal macrophages. Two stages of tumor growth were examined, namely "small" and "large" tumors, with average diameters of 10 and 30 mm, respectively. The activation state, determined by measurement of both phagocytic index and beta-glucuronidase content, was found to be markedly higher in tumor-associated macrophages than in their peritoneal counterparts and it was, in addition, independent of tumor progression. The percentage of tumor-associated macrophages, which were detected on the basis of Fc receptor expression, remained constant in the growing neoplasm, at approximately 23% of total cell population. None of these parameters were affected by inoculation with an immunopotentiating dose of heat-killed Candida albicans which, on the other hand, seemed not to alter the course of the tumor. These data suggest that within the tumor microenvironment macrophages would somehow be maintained at a constant proportion and at a highly activated state, while outside the tumor they would be at a lower activation level. Our results also suggest that TAM would not possess antitumor activity in vivo, although we have found this activity in vitro.
A case of recurrent ameloblastic fibrosarcoma (AFS) in the mandibular molar region of a 22-year-old male is reported. The tumor was first diagnosed as a sarcoma of undetermined origin, because the benign epithelial component of AFS had disappeared after repeated surgical procedures. The lesion grew rapidly in the time from hospital admission until operation, suggesting progression from low to high malignancy. The correlation between the benign epithelial component and malignancy is discussed.
Soluble kappa-elastin peptides were shown to stimulate the expression of MMP-2 (but not MMP-9) by human fibrosarcoma HT-1080 cells, both at the protein and mRNA levels; maximal effect being observed at a concentration of 25 microg/ml of kappa-elastin. The stimulatory effect could be reproduced using Val-Gly-Val-Ala-Pro-Gly (VGVAPG) peptide, an elastin-derived hydrophobic hexapeptide which represented the elastin receptor binding sequence of tropoelastin. Furthermore, treatment of cells with lactose (30 mM), which dissociated 67-kDa elastin binding protein (EBP) from cell surfaces, completely abolished this effect, suggesting that the elastin receptor could mediate such a response. Using a specific monoclonal antibody, 67-kDa EBP was detected in HT-1080 membrane preparations by Western immunoblotting. Following treatment with 25 microg/ml kappa-elastin or 200 microg/ml VGVAPG, increased levels of the active 62-kDa form of MMP-2 were found in HT-1080 cell extracts. Stimulation of MT1-MMP mRNA expression by treatment with elastin-derived peptides (EDPs) was shown by competitive polymerase chain reaction (PCR). A reverse zymography analysis revealed that EDPs also stimulated TIMP-2 (but not TIMP-1) production by HT-1080 cells. Competitive PCR confirmed increased TIMP-2 mRNA expression by such treatment. These results suggest that occupancy of the 67-kDa elastin receptor by elastin-derived peptides enhanced both expression and activation of proMMP-2 and consequently, could promote the invasive/metastatic ability of tumor cells expressing this receptor.