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)

Prostaglandins and other eicosanoids have been studied extensively in their physical, biochemical, biophysical and pharmacological aspects. However, studies on their role in tumor progression, especially metastases are relatively recent. Following a brief overview of the history of discovery and metabolism of eicosanoids and other fatty acids, we discuss the functions of these fatty acids (with emphasis on prostacyclin, thromboxane A2, 12-hydroxyeicosatetraenoic acid and 13-hydroxyoctadecadienoic acid) in cell transformation, tumor promotion and particularly in tumor cell metastasis. The relation between these monohydroxy fatty acids and tumor cell metastasis is discussed from three different perspectives, i.e., their effects on tumor cells, on platelets and on endothelial cells. The mechanism of these effects are then addressed at cell adhesion molecule, motility, protease, cell cytoskeleton, protein kinase and eicosanoid receptor levels. Finally, regulation of three key enzymes which generate eicosanoids (phospholipase, prostaglandin endoperoxide synthase and lipoxygenase) is explored.
Cancer Metastasis Rev 1992 Nov
PMID:Fatty acid modulation of tumor cell-platelet-vessel wall interaction. 142 24

Unsaturated fatty acids of the n-6 and n-3 class have been shown to affect tumor growth and metastasis. The very long chain polyunsaturated fatty acids of the n-3 family, e.g. eicosapentaenoic acids (C20:5n-3) and docosahexaenoic acids (C22:5n-3), have an inhibiting effect on tumor growth. Metastasis is promoted by n-6 polyunsaturated fatty acids, e.g. linoleic acid (C18:2n-6) and gamma-linolenic acid (C18:3n-6). The mechanisms of promotion and inhibition are described in the present review. The mechanisms of lipid peroxidation, which appears to be an important factor in the inhibition of tumor growth, are discussed. Lipid peroxidation is induced by polyunsaturated fatty acids involving autoperoxidation a.o. and the enzymes cytochrome P450, cyclooxygenase and lipoxygenase. In tumor cells these enzymes are decreased in activity but at present the reason for this reduction is not known. Lipid peroxidation products such as hydroxyeicosatetraenoic acids (HETES), hydroperoxy eicosatetraenoic acids (HPETES) and malondialdehyde may have a regulating effect on DNA duplication enzymes (e.g. polymerases). Prostaglandin synthesis in tumor cells and macrophages is also affected by polyunsaturated fatty acids. The fish oil fatty acids are known to reduce prostaglandin synthesis by competing with arachidonic acid for the enzyme cyclooxygenase. However, fish oil fatty acids have an antagonistic effect on cyclooxygenase. Polyunsaturated fatty acids also have an effect on the immune system and particularly on macrophages. Macrophages, but also T-cells and B-cells, are inhibited by prostaglandins such as PGE2, while immunosuppressor cells are stimulated by PGE2.
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PMID:Effects of dietary fatty acid composition on tumor growth and metastasis. 144 14

Adhesion of tumor cells to vascular endothelial surfaces is one of the key steps in metastatic dissemination. Several factors are believed to be implicated in the regulation of the adhesive properties of tumor cells. We show that the adhesion of five different tumor cell lines, all of them of human origin, to human umbilical vascular endothelial cells (ECs) significantly increases following pretreatment of ECs with the cytokines interleukin-1 and tumor necrosis factor, whereas tumor cell/EC interactions remained unchanged after incubation with interferon-gamma. Significant augmentation in tumor cell adhesion was also observed when ECs were treated with the lipoxygenase inhibitors salicylate and the compound BW755C. In all cases, increased tumor cell adhesion was concomitant with significant decreases in the EC levels of linoleic acid, lipoxygenase-derived metabolite 13-hydroxy-octadecadienoic acid (13-HODE). On the contrary, pretreatment of the EC monolayers with aspirin did not result in any changes towards tumor cell adhesion. These results suggest that tumor cell/EC interaction is modulated, at least in part, by intracellular levels of 13-HODE and is independent of prostacyclin (PGI2) production by the ECs.
Invasion Metastasis 1991
PMID:Effects of endothelial cell treatment on 13-HODE and prostacyclin synthesis and its correlation with tumor cell-vascular endothelial cell adhesion. 180 Apr 51

There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase), verapamil (calcium antagonist), forskolin (stimulator of platelet adenylate cyclase), and indomethacin (inhibitor of cyclooxygenase) were examined, alone and in combination, to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically, and the animals were divided into control, single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore, when these agents were combined, similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008), while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also, the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.
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PMID:Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse. 189 Aug 39

Recent studies have shown that the cyclooxygenase and the 5-lipoxygenase pathways of arachidonic acid, are required for the invasive and metastatic activity of certain tumor cells. We show here that malignant murine melanoma and human fibrosarcoma cells cultured in media supplemented with eicosapentaenoic acid show a dose and time dependent decrease in invasiveness, in collagenase IV production and in the case of the murine cells, a reduced ability to metastasize to the lung after intravenous injection. It was also shown that a metabolite of eicosapentaenoic acid was less potent than the comparable arachidonic acid metabolite in restoring collagenase IV production and invasiveness after inhibition of the lipoxygenase pathway. These studies indicate that such supplements have the potential to reduce the metastasis of certain tumor cells, converting them to benign status.
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PMID:Eicosapentaenoic acid reduces the invasive and metastatic activities of malignant tumor cells. 254 5

Phorbol ester binding was examined in two lines of murine fibrosarcoma cells. The two cell lines were isolated from the same parent tumor but respond differentially to stimulation with phorbol esters. In one of the lines, these agents stimulate a rapid attachment and spreading response and induce directional migration. The other cell line does not migrate in response to stimulation with phorbol esters and the attachment and spreading response is slow. The cell line which responds actively to phorbol ester stimulation is highly malignant when injected into syngeneic animals while the other line is of low tumorigenicity and is virtually non-metastatic. In spite of these differences, both lines were found in the present study to bind [3H]4 beta-phorbol-12 beta, 13 alpha-dibutyrate in a receptor-mediated fashion. The characteristics of binding were virtually identical between the two cell lines. In additional studies, arachidonic acid metabolism was examined in the same two lines. In the highly responsive line, PMA stimulated a rapid release of [3H]arachidonic acid and its conversion into cyclooxygenase and lipoxygenase products. In the less-responsive line, PMA stimulated a slower release of [3H]arachidonic acid from prelabeled cells. The quantity of arachidonic acid metabolites produced was also much less. These studies suggest that the disparity between the two cell lines in their response to phorbol ester stimulation is not the result of differences in the initial interaction between the cells and ligand but may result from alterations in their signal transductance mechanism. This may be the result of inherent differences in capacity for arachidonic acid metabolism.
Clin Exp Metastasis
PMID:Phorbol ester binding and phorbol ester-induced arachidonic acid metabolism in a highly responsive murine fibrosarcoma cell line and in a less-responsive variant. 308 51

Arachidonic acid metabolites can act as tumor promoters and can affect growth and metastases of tumors in three ways: (a) Prostacyclin inhibits and thromboxane facilitates platelet-tumor cell interactions and, thereby, tumor cell invasiveness; (b) the cytoprotective action of prostaglandins contributes to epithelial cell integrity and influences tissue response to tumor-promoting agents; and (c) lipoxygenase products may act as tumor promoters.
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PMID:Arachidonic acid metabolism. 311 36

In recent studies, we have demonstrated that recombinant human tumor necrosis factor (rH TNF), as a single agent, has only minimal therapeutic activity for the treatment of metastatic disease, but when combined with recombinant murine gamma-interferon (rM gamma-IFN), we observed significantly more therapeutic activity than when either agent was administered alone. However, this combination also resulted in increased toxicity. Thus, we undertook a systematic toxicologic study of rH TNF alone or in combination with rM gamma-IFN. Briefly, the toxicity was similar to the generalized Shwartzman's reaction seen during endotoxin shock, with multifocal microthrombi and ischemic necrosis as sequelae. Lesions were observed in the lungs, liver, gastrointestinal tract (preferentially in the duodenum and cecum), testes or uterus, and bone marrow. Our results suggest that TNF (either directly administered or induced in situ) and its induction of arachidonic acid metabolites form one element of toxicity in this model. This conclusion is supported by studies revealing that the toxicity of rH TNF in combination with rM gamma-IFN can be reduced by inhibitors of the cyclooxygenase/lipoxygenase pathway.
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PMID:Toxicity of tumor necrosis factor is synergistic with gamma-interferon and can be reduced with cyclooxygenase inhibitors. 311 9

Monocytes are thought to play a role in host resistance to tumor cell growth in animals and humans. In addition, platelets are known to be involved in tumor metastases. To investigate the interaction of these two cell types and their effect on tumor cells, human monocytes and platelets were examined using an in vitro monocyte-tumor cell cytotoxicity assay. Monocytes alone resulted in 32% +/- 1.5 (mean +/- SEM) tumor cell kill. When platelets were added to monocytes in a 1:1 ratio, an increase in cytotoxicity to 61% +/- 3.2 was observed. The cytotoxicity noted when platelets were added to a fixed number of monocytes and tumor cells was dependent on the number of platelets added. A decrease in cytotoxicity from 32% +/- 1.5 to 12% +/- 2.3 was observed when contaminating platelets were removed from monocyte preparations. Platelets added to tumor cells in the absence of any monocytes were also toxic, resulting in a maximum kill of 95% at a 4:1 platelet/tumor cell ratio. Secreted products of freshly isolated platelets may be responsible for much of the observed cytotoxicity, since supernatants from the platelets were toxic for tumor cells. Platelets pretreated with a cyclooxygenase inhibitor (ASA) or a lipoxygenase inhibitor had decreased cytotoxicity compared with untreated platelets. Our results indicate that products of platelet arachidonate metabolism are toxic for tumor cell lines. They also suggest that the role of the platelet must be considered when studying monocyte-tumor cell cytotoxicity.
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PMID:Human platelets exert cytotoxic effects on tumor cells. 392 50

A number of factors have been identified which are chemotactic for tumor cells. Recent studies have shown that, in addition to inducing directional motility in the Boyden chamber assay, these factors also induce a number of other responses. Included among these responses are cell swelling and foreign surface adhesiveness. The adherence response has been studied in detail using the Walker 256 carcinosarcoma cells and several other cell types. In the Walker cells, treatment with the C5a-derived tumor cell chemotactic peptide, the synthetic tripeptide, N-formyl-methionyl-leucyl-phenylalanine or with 12-O-tetradecanoyl phorbol ester induces a rapid, transient adherence response. The response is completely inhibited by several agents known to block the activity of phospholipase A2 or the metabolism of arachidonic acid through the lipoxygenase pathway but is not inhibited by inhibition of the cyclooxygenase pathway. This suggests that lipoxygenase metabolites of arachidonic acid may actually mediate the adherence response. It has been shown that chemotactic factor treatment of animals that are bearing circulating tumor cells induces a localization of these cells at the site of chemotactic factor injection. On the basis of these observations it has been hypothesized that tumor cells respond to chemotactic factors in much the same way that leukocytes do and that tumor cell localization at metastatic sites in vivo may be influenced by chemotactic factors in much the same way that leukocyte localization at inflammatory sites is.
Cancer Metastasis Rev 1982
PMID:Chemotaxis of metastatic tumor cells. 718 18


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