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PubMed1997

Suppression of polarity, locomotion and F-actin levels of Walker carcinosarcoma cells by the inhibitor CI-959.

Locomotor activity of tumor cells is an important factor for the capacity for invasion and metastasis. Therefore, inhibitors interfering with cellular mechanisms regulating spontaneous cell locomotion are of particular interest for cancer therapy. CI-959, a new benzothiophene cell activation inhibitor, has the capacity to suppress spontaneous polarity and locomotion of Walker carcinosarcoma cells. Suppression of polarity and locomotion was closely associated with a reduction in the relative amount of F-actin. The mechanisms involved in suppression of motility are Ca2(+)-independent and not related to cell-substratum adhesion. Walker carcinosarcoma cells appear to be able to locomote at very low (nM) levels of free [Ca2+]i.

Actins↗

PubMed2002

Phenotype modulation in non-adherent and adherent sublines of Walker carcinosarcoma cells: the role of cell-substratum contacts and microtubules in controlling cell shape, locomotion and cytoskeletal structure.

We characterised two sublines of Walker carcinosarcoma cells generated by epigenetic changes. Subline 1 cells were mostly polarised and made no or only non-adhesive cell-substratum contacts. Subline 2 cells were spread, adhesive and mainly non-polar. Subline 1 cells migrate in a non-adhesive mode which is very efficient but operates only in a 3D environment, whereas subline 2 cells migrate in an adhesive mode, which is less efficient but works on 2D and 3D substrata. Nocodazole had little or no effect on shape, polarity and locomotion of subline 1 cells. In glass-adherent subline 2 cells, 10(-6)M nocodazole increased the proportion of polarised cells migrating in an adhesive mode and decreased adhesion to the substratum, whereas 10(-5)M nocodazole further reduced the contacts and the cells reverted to a non-adhesive mode of locomotion. When non-polar subline 2 cells were detached mechanically or by nocodazole, they became polarised and morphologically indistinguishable from non-adherent subline 1 cells. On more adhesive plastic substrata, subline 2 cells produced heterogeneous responses to nocodazole including loss of polarity. The phenotypes of Walker carcinosarcoma sublines have similarities with a broad range of cell types ranging from leucocytes to fibroblast-like cells, suggesting that these phenotypic differences can be controlled by the adhesive and contractile state rather than the cell type. Adhesion modulates contractility (isometric or isotonic contraction) and vice versa and this determines morphology (shape, F-actin, myosin and alpha-actinin), locomotion and responses to microtubule-disassembly. The model may be applied to analyse the mechanisms controlling the phenotype of cells in general.

Actinin↗

PubMed1976

Circadian variations in 32P uptake of DMBA-induced mammary tumour and Walker carcinosarcoma in rats.

The 32P uptake in a mammary tumour induced by DMBA and in the Walker 256 carcinosarcoma was measured by external GM -tubes. The uptake was significantly higher than in the skin. During exposure to a synchronized light regime a circadian variation was present in the 32P uptake of the hormone-dependent DMBA-induced tumour. The maximal 32P uptake was in the dark period, in which the highest temperature in the tumour has also been found (Møoller and Bojsen, 1975). In the hormone-independent Walker 256 carcinosarcoma there was no periodicity in 32P uptake. No variation in 32P uptake was registered in the skin of normal controls or in tumour-bearing rats.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1980

Prostaglandin E production and hypercalcaemia in rats bearing the Walker carcinosarcoma.

The hypothesis that there is prostaglandin-mediated hypercalcaemia associated with the Walker carcinosarcoma in the rat was tested by measuring PGE production during the development of the hypercalcaemia, and determining the effects of inhibition of prostaglandin synthesis on serum calcium concentration. Parathyroid hormone (PTH) activity was estimated by the determination of the serum concentration of immunoreactive PTH. There was a 3-fold increase in the urinary excretion of 7α-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid (PGE-M), a major urinary metabolite of the E prostaglandins from basal levels. Treatment with indomethacin, a potent inhibitor of prostaglandin synthesis, did not lower serum calcium concentrations with two different doses (1·6 mg/kg/day orally and 5 mg/kg/day i.m.); effective inhibition of prostaglandin synthesis was demonstrated by the suppression of PGE-M excretion rates below basal levels. Serum concentrations of immunoreactive PTH were not significantly altered by either tumour growth or indomethacin. Dexamethasone (0·5 mg/kg/day i.m.) attenuated both the increased urinary excretion of PGE-M and the rise in serum calcium concentration, suggesting that one or several lipoxygenase products might be the actual mediators of the hypercalcaemia. We conclude that the hypercalcaemia in the rat with Walker carcinosarcoma is probably not mediated by E-prostaglandins and probably not by any other product of the cyclo-oxygenase pathway. The increased PGE turnover may be considered as a biochemical marker of tumour load, but not as an indicator of a prostaglandin-mediated hypercalcaemia.

Animals↗

PubMed1985

Failure of systemic ketosis to control cachexia and the growth rate of the Walker 256 carcinosarcoma in rats.

The Walker 256 carcinosarcoma was shown to lack the enzyme 3-ketoacid CoA transferase. This suggests that ketone bodies cannot be used as a major substrate for the energy metabolism of this tumour. Systemic ketosis (1-2 mM acetoacetate plus 3-hydroxybutyrate) was induced both in tumour-bearing and in non-tumour-bearing rats with a diet containing 70% medium chain triglyceride. However, in rats bearing the Walker 256 tumour, this dietary ketosis did not reduce the tumour growth rate nor did it prevent the subsequent decrease in host body weight. Host body nitrogen losses were similarly unaffected. The ketosis induced in tumour bearing rats was shown to be abnormal since the blood glucose concentration of ketotic, tumour-bearing rats was significantly higher compared with that of ketotic non-tumour bearing rats (5.2 +/- 0.4 mM cf 3.4 +/- 0.6 mM, P less than 0.01). These results may partly explain why systemic ketosis failed to alter the growth and cachexia induced by the Walker 256 carcinosarcoma.

Acetyl-CoA C-Acetyltransferase↗

PubMed1992

Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells.

The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (ID50 of about 6.0 x 10(-8) M) as well as spontaneous and colchicine-stimulated locomotion at 10(-7) M. K 252a suppresses cell polarity (ID50 of about 4.5 x 10(-6) M) and inhibits spontaneous and colchicine-stimulated locomotion at 10(-5) M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotide-dependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.

Alkaloids↗

PubMed1994

Carcinosarcoma of the ovary treated over a 10-year period at the Christie Hospital.

Carcinosarcomas (previously termed malignant mixed Müllerian tumors) are highly malignant but rare tumors of the ovary. Most patients have been treated according to a wide variety of protocols for soft tissue sarcoma or for epithelial ovarian carcinoma and as a result the optimal treatment for this neoplasm is unknown. We describe here 20 patients with this ovarian tumor (15 with heterologous sarcomatous elements and five with homologous sarcomatous elements) referred to our institute. Five patients were treated with surgery alone, two patients with chemotherapy alone and 13 patients with a combination of surgery and chemotherapy. A variety of chemotherapeutic regimens were used reflecting the 10-year time span it took to accrue these patients. Forty-five per cent of all patients died within 1 year of initial surgery and there was a median survival of 14 months. Two patients achieved a complete remission following treatment with 10 cycles of intravenous cyclophosphamide and are still alive at 103 and 106 months follow-up. We suggest that a chemotherapy regimen combining cyclophosphamide and a platinum analog may be useful for the management of patients with carcinosarcoma of the ovary requiring further therapy following surgery.

Journal Article↗

PubMed2005

Primary bone carcinosarcoma: chondrosarcoma and squamous cell carcinoma with keratin pearl formation.

Malignant bone tumors with epithelial differentiation are extremely rare. Only one case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma has ever been reported. Reported herein is a case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma, so-called carcinosarcoma of bone, arising in the femur of a 53-year-old man. The tumor was located within the femur and was diagnosed by curettage as a well-differentiated chondrosarcoma. No primary tumor was detected in any other organ. Within a few months the tumor had rapidly grown toward the soft tissue, and hemipelvectomy was performed. Examination of the surgical specimen revealed that the tumor was mainly composed of undifferentiated spindle sarcoma cells with scattered foci of chondrosarcoma and of squamous cell carcinoma with keratin pearl formation. The patient died approximately 6 months postoperatively. At autopsy multiple metastases were detected in the heart, both lungs, muscles, and lymph nodes. Interestingly, the chondrosarcoma and squamous cell carcinoma components were observed in several metastatic foci. The tumors in both the previously reported case and the present case contained components of chondrosarcoma and squamous cell carcinoma with keratin pearl formation, and this combination of histological features may be a unique characteristic of carcinosarcoma of bone.

Bone Neoplasms↗

PubMed2006

[Effect of vasopressin gene expression on the growth of Walker 256 carcinosarcoma in rats].

The growth pattern of the Walker 256 solid tumor has been studied in rats with different doses of the mutant vasopressin gene. In contrast to the vasopressin gene of normal WA rats, that of mutant Brattleboro rats has a deletion in the coding region that blocks expression at the translation level. The mutation is inherited as a recessive character and is expressed in homozygous Brattleboro rats as diabetes insipidus with an increased water consumption because of the absence of vasopressin in the blood. (WAG x Brattleboro) F1 hybrids have the same normal phenotype as WAG rats, including a low water consumption. Walker 256 carcinosarcoma, which is not strain-specific, intensely grows only in WAG and (WAG x Brattleboro) F1 rats. In these groups, the growth of the tumor leads to the animal death within approximately 30 days after the inoculation of tumor cells. In Brattleboro rats, the carcinosarcoma grows less intensely: the tumor node somewhat increases only within the first two weeks, after which the tumor began to decrease and eventually disappears altogether. Both characters exhibit a 100% concordance at the individual level.

Animals↗

PubMed1989

Effect of diets with different protein levels on the growth of Walker 256 carcinosarcoma in rats.

1. The effect of different nutritional situations on the growth of experimental Walker 256 carcinosarcoma was investigated in rats. Fifty adult male Wistar rats were randomly assigned to three groups: group NN received standard chow throughout the experiment; group DD initially received an isocaloric protein-free diet, and some of the animals in this group (DN) were fed normal chow from the 37th to the 53rd day of the study. 2. On the 42nd day of the experiments all animals were inoculated subcutaneously in the flank with 2.5 to 3.0 x 10(5) viable Walker 256 carcinosarcoma cells and tumor growth and rat body weight were monitored daily thereafter. 3. Significantly greater tumor growth was detected in well-nourished (group NNT) as compared with malnourished animals (group DDT), but not in protein-depleted-refed (group DNT) animals, whose tumor growth was not significantly different from that of constantly malnourished (group DDT) rats. 4. Comparison of tumor weight and of the tumor weight/carcass weight (TW/CW) ratio showed no significant difference between malnourished and malnourished/refed animals, whereas well-nourished animals showed higher tumor weight and TW/CW ratios. 5. TW/CW curves for malnourished rats were parallel to those for malnourished/refed rats. TW/CW curves for constantly malnourished rats differed from those for well-nourished rats during the first observation period but there was no difference during the second week of tumor growth. 6. Although the protein-free diet inhibited tumor growth and refeeding enhanced it, carcass weight increased at the same rate, and therefore no change was observed in the TW/CW ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Shape changes and chemokinesis of Walker carcinosarcoma cells: effects of protein kinase inhibitors (HA-1004, polymyxin B, sangivamycin and tamoxifen) and an inhibitor of diacylglycerol kinase (R 59022).

Previous work has shown that PMA and diacylglycerols, activators of protein kinase C (PKC) can suppress cell polarity and locomotor activity of Walker carcinosarcoma cells in vitro, suggesting that PKC activation may result in a stop signal for tumor cell locomotion. This hypothesis was further analysed. The present results show that the DAG kinase inhibitor, R 59022, suppressed tumor cell polarity and strongly inhibited cell locomotion at a concentration of 10(-4), thus supporting the earlier finding that an increased availability of DAGs can suppress the locomotor activity of Walker carcinosarcoma cells. The results support the stop-signal hypothesis of PKC activation insofar as DAG kinase inhibition mimics the effects of DAGs and PMA. In order to clarify further the effects of protein kinase modulation on locomotion, we now extended our studies on structurally different inhibitors of protein kinases. In contrast to H-7, HA-1004 had no effect on cell polarity and did not reduce cell locomotion in the presence of colchicine, but reduced the proportion of spontaneously locomoting cells by 70% at 3 x 10(-4) M. Polymyxin B suppressed cell polarity and locomotion only at concentrations that proved to be toxic. Tamoxifen had no significant effect on cell polarity and locomotor activity. Sangivamycin did not suppress cell polarity and spontaneous locomotion at a concentration range of 10(-9) M to 10(-4) M. However, at 10(-4) M it decreased the proportion of migrating, colchicine-stimulated cells by 50%. The diverse responses to structurally different PKC inhibitors may be explained by their limited and variable specificity for PKC and different mechanisms of action on PKC.

Animals↗

PubMed1999

Characterization of type I collagen synthesis and maturation in uterine carcinosarcomas.

BACKGROUND: Epithelial malignancies often induce an enhanced expression of interstitial collagens in the fibroblasts within the tumor tissue and the surrounding non-neoplastic stroma. In uterine carcinosarcomas (malignant mixed müllerian tumors [MMMTs]) both the stroma and the epithelium are malignant. METHODS: In this investigation, both in situ hybridization and immunohistochemical staining were applied with two different antibodies that were capable of distinguishing between newly synthesized and mature, trivalently cross-linked Type I collagen to define Type I procollagen mRNA expression and the synthesis and maturation of the corresponding protein in MMMTs. RESULTS: In the better differentiated parts of these tumors, in which anticytokeratins stained only clearly carcinomatous cells, Type I procollagen mRNA expression was limited to stromal fibroblasts; mature Type I collagen bundles were abundant and regular. In poorly differentiated areas, in which anticytokeratins stained only a few individual cells, Type I procollagen mRNA was expressed peculiarly by three morphologically different cell types. In addition to benign mesenchymal cells, Type I procollagen mRNA was present in atypical epithelial and mesenchymal cells. In these tumors, the collagen bundles close to the malignant cells were comprised of newly synthesized Type I collagen, with only little evidence of the presence of mature, fully cross-linked collagen. CONCLUSIONS: These results strongly suggest that the undifferentiated cells of MMMTs are capable of producing their own stroma with irregularly arranged collagen bundles.

Aged↗

PubMed1998

Actin accumulation in pseudopods or in the tail of polarized walker carcinosarcoma cells quantitatively correlates with local folding of the cell surface membrane.

We determined the actin distribution and the relationship between actin and the cell surface membrane in polarized Walker carcinosarcoma cells showing lamellipodia or blebs at the front in order to get a better insight into actin's role in shape changes and cell locomotion. Using two different techniques, we found that actin is mainly present as a submembraneous layer. The actin concentration detectable in the cytoplasm was about 16X lower. F-actin staining was increased mainly at the contracted tail and to a lesser extent in lamellipodia. However, there is also accumulation of the cell surface membrane at these sites. The quantitative analysis of electron micrographs showed that the apparent accumulation of F-actin at the tail and in the leading lamellipodia was, on the average, fully explained by increased membrane folding. The cell membrane as well as the cortical actin may fold and unfold during shape changes and polarized cells have reserves of plasma membrane as well as of cortical actin at the tail. In addition, the cells may show spots where the surface membrane was dissociated from the cortical actin layer. Polarized cells showed no increase in actin within the blebs or at the basis of lamellipodia. In this respect, the distribution of polymerized actin was different from other currently studied locomoting metazoan cells. So far, the data are difficult to reconcile with models, postulating that polymerized actin within the protrusions is the direct force driving the membrane forward.

Actins↗

PubMed1997

Suppression of W256 carcinosarcoma cell apoptosis by arachidonic acid and other polyunsaturated fatty acids.

Serum-cultured rat W256 carcinosarcoma cells of the monocytoid origin undergo rapid apoptosis in response to the lipoxygenase inhibitor NDGA (nordihydroguaiaretic acid). Exogenous arachidonic acid (AA), in a time- and dose-dependent fashion, suppressed NDGA-induced W256 cell apoptosis as well as DNA fragmentation, with the maximal effect observed at approximately 25 microM. Mobilization of endogenous AA by calcium ionophore A23187 provided an even stronger and longer-lasting protection against NDGA-caused cell death. The A23187 effect on AA release as well as W256 cell death can be blocked by bromophenacyl bromide, thus suggesting involvement of phospholipase A2 activation. Serum withdrawal similarly caused W256 cells to undergo typical apoptosis, which was not rescued by several growth factors commonly found in serum. However, exogenous AA suppressed serum starvation-induced W256 cell apoptosis and significantly extended cell survival in a dose-dependent manner. Lipoxygenase products, 12(S)- and 15(S)-, but not 5(S)-hydroxyeicosatetraenoic acid (HETE), in a dose-dependent fashion, also prevented both NDGA- and serum-starvation-induced W256 cell apoptosis. AA appears to suppress W256 cell apoptosis via distinct signaling pathway(s) since it does not prevent cell death triggered by several other inducers. Examination of a panel of polyunsaturated fatty acids revealed that alpha-linolenic and linoleic acid can also suppress NDGA-induced W256 cell apoptosis. Our data suggest that AA and other polyunsaturated fatty acids and/or their metabolites may enhance tumor growth not only by promoting cell proliferation but also by suppressing apoptosis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1997

Apoptosis of W256 carcinosarcoma cells of the monocytoid origin induced by NDGA involves lipid peroxidation and depletion of GSH: role of 12-lipoxygenase in regulating tumor cell survival.

Arachidonate lipoxygenases (LOX) and their products play an important role in mediating growth factor-supported tumor cell proliferation and growth. The LOX pathway may also be critical in regulating tumor cell survival and apoptosis. Blocking the 12-LOX gene expression with sequence-specific antisense oligos or its activity with general or isoform-specific LOX inhibitors induces a strong apoptotic response in rat W256 carcinosarcoma cells of the monocytoid origin (Tang et al., 1996, Proc. Natl. Acad. Sci. U.S.A., 93:5241-5246). In the present study, several molecular approaches confirmed the predominant expression of platelet-type 12-LOX in W256 cells, with no or little expression of 5- and 15-LOX. NDGA, a general LOX inhibitor and BHPP, a 12-LOX-selective inhibitor, induced rapid and dose-dependent apoptosis of serum-cultured W256 cells as well as several other tumor (in particular leukemia) cell lines, thus suggesting a potential role for LOX in mediating serum-supported tumor cell survival. The molecular mechanism of NDGA-induced W256 cell death was subsequently investigated. NDGA-induced apoptosis could be significantly postponed by overexpression of 12-LOX, thus suggesting that the NDGA effect is, at least partly, dependent on its inhibition of LOX (i.e., 12-LOX). W256 cell apoptosis induced by NDGA could also be effectively inhibited by GSH-elevating or thiol agents as well as by lipid peroxidation inhibitors and an inhibitor of mitochondria respiratory chain rotenone. Further experiments demonstrated that NDGA treatment triggered rapid lipid peroxidation leading to the depletion of cytosolic and mitochondrial GSH pools. Interestingly, the lipid peroxidation induced by NDGA could not be inhibited by conventional free radical scavengers nor by cyclooxygenase or cytochrome P-450 monooxygenase inhibitors. In summary, the present work suggests a role of 12-LOX in regulating serum (growth factor)-supported survival of certain tumor cells.

Animals↗

PubMed1976

Carcinosarcoma and mixed müllerian tumors of the fallopian tube: report of four cases.

We report a 74-year-old woman with malignant mixed müllerian tumor and three women, aged 47, 58, and 76 years, with carcinosarcomas, all primary in the fallopian tube. The tumors grew predominantly intraluminally and were associated with hydrosalpinx. All four patients underwent salpingectomy. Two of them received radiation therapy; one died within 9 months because of the tumor and the second is well 2 years after diagnosis. Of the two women without additional therapy, one is alive with tumor 53 months postoperatively and the other is well 1 year after surgery. Available data suggest that these neoplasms are relatively radioresistant and that their prognosis correlates best with local invasiveness.

Aged↗

PubMed1981

Carcinosarcoma of the uterine cervix: a light and electron microscopic study.

A case of carcinosarcoma of the uterine cervix is presented. Light microscopic and ultrastructural features of the tumor are described. While the epithelial component had the appearance of a carcinoma arising from endocervical epithelium, the stromal component was composed of malignant smooth muscle cells together with some cells having the charactristics of malignant fibroblasts. The tumor is considered to arise from the müllerian tract mesoderm and to be part of the spectrum of tumors which range from the totally benign adenofibroma to the malignant heterologous mixed mesodermal tumor.

Carcinosarcoma↗

PubMed1982

Carcinosarcoma and separate carcinoid tumor of the stomach. A case report with light and electron microscopic studies.

A carcinosarcoma of the cardia of stomach is reported. This is a rare entity which is of further interest because of an associated but distinctly separate carcinoid tumor. The main tumor showed distinct adenocarcinomatous and spindle cell components which collided in many areas. The sarcomatous nature of the spindle cell component was confirmed by ultrastructural studies. We have reviewed the literature and have not found a similar case.

Aged↗