Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined the effect of triflavin, an Arg-Gly-Asp (RGD)-containing snake venom peptide, on human cervical carcinoma (HeLa) cell- and B16-F10 mouse melanoma cell-induced platelet aggregation (TCIPA) in heparinized platelet-rich plasma. TCIPA appears to play an important role in the development of certain experimental tumor metastases. Two ADP-scavenging agents, apyrase (10 U/ml) and creatine phosphate (CP) (5 mM)/creatine phosphokinase (CPK) (5 U/ml) completely inhibited B16-F10 TCIPA, but hirudin (5 U/ml) had no effect. In contrast, apyrase and CP/CPK did not inhibit HeLa TCIPA while hirudin completely inhibited it. Furthermore, HeLa cells initially induced platelet aggregation and then blood coagulation at a later stage. In addition, HeLa cells shortened, in a concentration-dependent manner, the recalcification time of normal as well as factor VIII- and IX-deficient human plasma, but did not affect the recalcification time of factor VII-deficient plasma. This suggests that HeLa TCIPA occurs via activation of the extrinsic pathway, probably owing to tumor cell expression of tissue factor-like activity. HeLa cell-induced thrombin generation was confirmed by detection of amidolytic activity towards a chromogenic substrate, S-2238 (H-D-Phe-Pip-Arg-p-NA). Triflavin and GRGDS inhibited, in a dose-dependent manner, TCIPA caused by either cell line. On a molar basis, triflavin was 10,000-30,000 times more potent than GRGDS in this regard. Moreover, monoclonal antibodies raised against glycoprotein (GP) IIb/IIIa complex (i.e., 7E3 and AP2) and against GP Ib (i.e., AP1) completely inhibited HeLa TCIPA. 7E3 and AP2 inhibited B16-F10 TCIPA by up to 80% whereas AP1 showed only 30% inhibition of B16-F10 TCIPA. In conclusion, the inhibitory effect of triflavin on HeLa and B16-F10 TCIPA may be mediated principally by the binding of triflavin to the fibrinogen receptor associated with GP IIb/IIIa complex on the platelet surface. However, GP Ib is also involved in HeLa TCIPA as thrombin formation is the key factor in triggering platelet aggregation caused by HeLa cells.
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PMID:Triflavin, an Arg-Gly-Asp-containing peptide, inhibits tumor cell-induced platelet aggregation. 822 81

We investigated the antitumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic B16 melanoma clone F10.9. These tumor cells were found to have very low levels of IL-6 receptors and in vitro IL-6 had no effect on cell proliferation or on the expression of MHC class I antigens. However, in vivo IL-6 was active against the metastatic growth of this tumor in mice, presumably through indirect immune effects. Low-dose IL-6 (1-10 micrograms/day), in three daily injections, 4 days a week, for 3 weeks, strongly inhibited the formation of experimental lung metastases following intravenous tumor cell inoculation. IL-6 therapy could be started even 10 days after tumor injection, when metastases are already established. Moreover, IL-6 treatment of mice bearing F10.9 tumors in the footpads resulted in complete protection against pulmonary spontaneous metastasis and in long-term survival. Histology confirmed the absence of micrometastases in most of the IL-6-treated animals. Analysis of the cytolytic activity of splenocytes at different times during therapy of tumor-bearing mice revealed significant lysis (up to 42%) of the melanoma F10.9 cells in the mice receiving IL-6 but not in the control mice.
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PMID:Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy. 831 1

Recent suggestions that tumor-cell targeting of elastin-rich tissues (e.g., lung) correlates with the presence of surface elastin receptors have been investigated. Receptors for insoluble (fibrous) elastin and for soluble elastin peptides have been implemented in these correlations. A rapid assay for binding of insoluble elastin has been devised. Two of the cell lines tested (M27 and MAT-LyLu), which metastasize to the lung, strongly bound fibrous elastin whereas a third (B16-F10) did not. None of 4 metastatic cell lines that do not target the lung (A549, 3LL, TA3, TA3-iso2) bound fibrous elastin. The ability of cell lines to interact with soluble elastin was tested by cell attachment to high-molecular-weight soluble elastin peptides adsorbed on a plastic surface. Three of 7 tested cell lines, B16-F10, M27 and TA3, attached to a soluble elastin coating. In contrast to the rapid binding of insoluble elastin particles, the cell interaction with immobilized soluble elastin peptides was delayed, suggesting that induction of receptors for soluble elastin and/or modification of the elastin coat was occurring. Thus, all 3 tested cell lines where metastases target the lung, namely, MAT-LyLu, B16-F10 and M-27, show soluble- or insoluble-elastin interactions, whereas, of 4 cell lines not targeting lungs, only one, TA3, reacts with soluble elastin.
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PMID:Binding of some metastatic tumor cell lines to fibrous elastin and elastin peptides. 838 30

A malignant tumor that arose spontaneously in the subcutaneous tissue of the back of a C57BL/6 female mouse was found to metastasize spontaneously to the liver. The primary and metastatic tumors, SML (spontaneous metastasis to the liver) 1 and SML 2, were established in vitro in long-term cell suspension culture and were passaged 10 times in vivo for 18 months. When 100,000 cells were injected subcutaneously in the orthotopic position, tumor growth appeared in 60% of the SML 1 mice and 100% of the SML 2 mice. SML 1 did not grow when injected in the footpad, while SML 2 did. The median survival was 47 days for SML 1 and 48.5 days for SML 2 (P = 0.013). The pattern of metastasis was similar for both tumor cell lines, irrespective of intravenous or subcutaneous injection routes. Spontaneous metastasis of the SML 2 line occurred from both the orthotopic and heterotopic sites, while the SML 1 metastasized spontaneously from the orthotopic site only. Liver metastasis appeared in > 90% of the mice for both SML 1 and SML 2. Metastasis to the spleen occurred in about half the mice. Other sites of metastasis were the ovaries (36% and 52%, respectively, for SML 1 and SML 2), the kidneys (approximately 15%) and the small bowel (very rarely). Metastasis to the lungs did not occur except very rarely in the later passages of the SML 2 line. Histologic, immunohistochemical and electron microscopic studies showed a histiocytic tumor with macrophage characteristics. The cells exhibited chemotaxis toward liver extracellular matrix and reduced motility toward collagen IV, laminin and fibronectin compared to the B16-F10 melanoma line. This spontaneously occurring tumor should prove useful for the study of organ-specific metastasis to the liver.
Clin Exp Metastasis 1993 Jan
PMID:A spontaneous subcutaneous tumor in C57BL/6 mice that metastasizes to the liver. 842 5

Lu-ECAM-1 is a 90-kDa lectin-like, melanoma-cell-binding endothelial-cell adhesion molecule that mediates colonization of the lungs by B16-F10 melanoma cells. The well-known formation of pleural and sub-pleural B16-F10 melanoma colonies is correlated quantitatively with prominent histochemical staining of endothelia of pleural capillaries and sub-pleural venules with anti-Lu-ECAM-1 MAb 6D3. The less frequent endothelial staining of perivenous and peribronchial venules is associated with fewer B16-F10 colonies in these locations, and the occasional segmental staining of pulmonary veins coincides with rare tumor nodules which usually expand in an asymmetric fashion around these veins. Lu-ECAM-1 is also expressed on endothelia of some tumor vessels, indicating that these vessels are recruited from the same host blood vessels that originally caused the arrest of blood-borne B16-F10 melanoma cells. The close association between the lung distribution patterns of Lu-ECAM-1-positive blood vessels and experimental melanoma metastases is further evidence of the importance of endothelial-cell adhesion molecules in the formation of metastases.
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PMID:Correlation between the lung distribution patterns of Lu-ECAM-1 and melanoma experimental metastases. 843 36

B16-F10 and B16-BL6 are B16 mouse melanoma sublines that preferentially metastasize to the lung following i.v. and s.c. injections, respectively. To study molecular mechanisms underlying the different metastatic behaviors exhibited by the B16 melanoma sublines, we performed differential hybridization of the genes transcribed in these cells and compared their expression levels. We isolated four genes that were highly expressed in B16-F10 cells but not in B16-BL6 cells: TI-225 (polyubiquitin), TI-229 (pyruvate kinase), TI-241 (LRF-1 homologue), and TI-227 (novel gene). Triosephosphate isomerase, 10-formyltetrahydrofolate dehydrogenase, tyrosinase-related protein 2, cytochrome c oxidase, ATP synthetase alpha subunit, RNA helicase, and ribosomal protein (L37, J1, acidic phosphoprotein), however, showed higher expression in B16-BL6 cells than in B16-F10 cells. Among these clones, transfection of TI-241 into the low metastatic clone F1 converted the parental cells from low- into high-metastatic cells. TI-241 may regulate the expression of various genes as a transcription factor in the complex process of metastasis.
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PMID:Identification of genes differentially expressed in B16 murine melanoma sublines with different metastatic potentials. 863 Oct 27

Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.
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PMID:Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. 876 Aug 11

The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials.
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PMID:Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models. 882 57

Thalidomide was recently suggested to be angiogenesis-inhibitor following the demonstration of its activity in a rabbit cornea micropocket model. The purpose of the present study was to test its efficacy in solid tumors in mice. B16-F10 melanoma and CT-26 colon carcinoma cells were injected subcutaneously, intravenously and intraperitoneally, and mice received daily gavage of 0.3-1.0 mg thalidomide starting either two or 10 days following tumor cell injection. The tumors were measured and compared with controls. There was no growth retardation in CT-26 bearing mice nor in mice with pulmonary or peritoneal metastases of B16-F10 melanoma. In 3/7 groups of mice with SC B16-F10 tumors, growth retardation was demonstrated, however the difference was not statistically significant. All tumors eventually reached maximal size, similar to controls. Morphological evaluation of the blood vessels oriented towards the tumor revealed that in both thalidomide and control groups, all mice had developed an intact network of new blood vessels. In our model for the oral administration of thalidomide inhibition of tumor growth and angiogenesis did not occur. We hypothesize that the lack of sustained antiangiogenic response was either due to immune modulation or to tumor heterogeneity and adaptation.
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PMID:Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo. 904 40

In order to explore the influence of activated macrophages on tumor cells, we cultured a series of weakly metastatic clones isolated from the murine T3 fibrosarcoma line (T3 clones) and the B16-F10 melanoma cells on feeder layers of C. parvum- or thioglycollate-elicited macrophages, or 'resident' (unstimulated) macrophages. Co-cultivation with C. parvum-elicited macrophages, but not with resident macrophages, induced an increase of the lung-colonizing potential of T3 clones and B16-F10 cells. An enhancement of lung-colonizing potential was also found in tumor cells grown in media conditioned by C. parvum-elicited macrophages. Thioglycollate-elicited macrophages also generated a pro-clonogenic activity which was however effective only on T3 clones but not on B16-F10 cells. The increase in the lung-colonizing potential of tumor cells stimulated by activated macrophages was retained to some degree after subcultivation in tissue culture medium or transplantation into syngeneic animals. In conclusion, our data support the notion that macrophages at different states of activation may enhance lung colonization of tumor cells by inducing a partially stable change of phenotype.
Clin Exp Metastasis 1997 Mar
PMID:Enhancement of lung-colonizing potential of murine tumor cell lines co-cultivated with activated macrophages. 906 85


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