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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Prostaglandin E2 (PGE2) is known to downregulate the generation of lymphokine-activated killer (LAK) cell activity. Indomethacin, an inhibitor of cyclooxygenase catalyzing the biosynthesis of PGE2, has been shown to augment LAK cell activities generated from peripheral blood mononuclear cells of normal healthy individuals. This study was undertaken to examine whether or not this augmentation is also a common phenomenon in cancer patients. LAK cell activities generated in the presence and the absence of indomethacin were examined in 15 normal healthy individuals and in 83 cancer patients. Paired data analysis revealed that indomethacin exhibited a significant augmentation of LAK activity generated from healthy individuals. Indomethacin enhanced LAK activity in patients with no distant metastases (TxNxM0); but depressed LAK activity in patients with distant metastases (TxNxM1). In patients without distant metastases, indomethacin showed an upregulating effect on LAK activity in those with an early T stage (T1-2NxM0), and no such effect was detected in those with a late T stage (T3-4NxM0). Indomethacin also significantly enhanced LAK cell generation in cancer patients with an ECOG performance status of 1, but significantly inhibited LAK cell generation in patients with a performance status of 4. These results indicated that indomethacin inhibited generation of LAK cell activity in cancer patients with a poor performance status or with distant metastatic disease, who normally would be the subjects of adoptive immunotherapy. Further, PGE2 production in cultured LAK cell medium was suppressed by indomethacin in all 20 cancer patients that were examined, suggesting that other yet to be identified factors or mechanisms may be responsible for the paradoxical effects of indomethacin on LAK cell activity.
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PMID:Effects of indomethacin on lymphokine-activated killer cell activities in cancer patients. 760 4

It has been assumed that the rate-limiting step in the ligand-induced synthesis of prostaglandins is the release of arachidonic acid from membrane phospholipid stores as a result of the activation of phospholipase. The assumption has been that the arachidonic acid is converted to PGH2 by the constitutive prostaglandin synthase/cyclooxygenase EC1.14.99.1 (PGS-1) enzyme present in cells. In this model, PGS-1 is proposed to be present in excess, and the production of arachidonic acid is thought to be rate limiting. However, a second prostaglandin synthase gene, PGS-2 has recently been described. The PGS-2 gene is induced by a variety of ligands, in cells as diverse as fibroblasts, monocytes, macrophages, smooth muscle cells, ovarian granulosa cells, epithelial cells, endothelial cells, and neurons. Moreover, PGS-2 induction is inhibited in nearly all contexts by glucocorticoids. It seems likely, therefore, that the regulation of PGS-2 expression plays a critical role in the production of prostanoids, both in normal physiological processes and in pathophysiological processes involving these paracrine mediators. In this review, we consider the regulation of the two genes, PGS-1 and PGS-2, that encode the isoforms of prostaglandin synthase.
Cancer Metastasis Rev 1994 Dec
PMID:Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. 771 87

Arachidonic acid metabolites have been implicated in multiple steps of carcinogenesis. Their role in tumor cell metastasis, the ultimate challenge for the treatment of cancer patients, are however not well-documented. Arachidonic acid is primarily metabolized through three pathways, i.e., cyclooxygenase, lipoxygenase, and P450-dependent monooxygenase. In this review we focus our attention on one specific lipoxygenase, i.e., 12-lipoxygenase, and its potential role in modulating the metastatic process. In mammalian cells there exist three types of 12-lipoxygenases which differ in tissue distribution, preferential substrates, and profile of their metabolites. Most of these 12-lipoxygenases have been cloned and sequenced, and the molecular and biochemical determinants responsible for catalysis of specific substrates characterized. Solid tumor cells express 12-lipoxygenase mRNA, possess 12-lipoxygenase protein, and biosynthesize 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid], as revealed by numerous experimental approaches. The ability of tumor cells to generate 12(S)-HETE is positively correlated to their metastatic potential. A large collection of experimental data suggest that 12(S)-HETE is a crucial intracellular signaling molecule that activates protein kinase C and mediates the biological functions of many growth factors and cytokines such as bFGF, PDGF, EGF, and AMF. 12(S)-HETE plays a pivotal role in multiple steps of the metastatic 'cascade' encompassing tumor cell-vasculature interactions, tumor cell motility, proteolysis, invasion, and angiogenesis. The fact that 12-lipoxygenase is expressed in a wide diversity of tumor cell lines and 12(S)-HETE is a key modulatory molecule in metastasis provides the rationale for targeting these molecules in anti-cancer and anti-metastasis therapeutic protocols.
Cancer Metastasis Rev 1994 Dec
PMID:12-lipoxygenases and 12(S)-HETE: role in cancer metastasis. 771 97

Comparative investigation of prostaglandin E (PGE) levels in primary malignant and benign epithelial tumors, metastases, and normal tissue of the ovaries has revealed more significant variations in PGE levels in malignant tumors than in benign ones. PGE content was reliably higher in adenocarcinomas as against benign tumors and normal ovarian tissue. No noticeable differences in PGE levels of benign tumors and normal tissue were revealed. The possibility of using arachidonic acid cyclooxygenase metabolism blockers in therapy of ovarian carcinoma, besides the common methods of treatment, is discussed.
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PMID:[The characteristics of prostaglandin E synthesis in epithelial ovarian tumors]. 804 88

Like many clinical non-small-cell lung cancers, the Lewis lung carcinoma produces prostaglandins. The Lewis lung carcinoma was used as a model of both primary and metastatic disease to assess the ability of cyclooxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indomethacin), the collagenase inhibitor minocycline, and the lipoxygenase inhibitor phenidone to act as modulators of cytotoxic cancer therapies. Although none of the single modulators given i.p. daily on days 4-18 altered tumor growth or the number of metastases found on day 20, modulator combinations consisting of minocycline/a cyclooxygenase inhibitor and, especially, of phenidone/a cyclooxygenase inhibitor resulted in modest tumor growth delay and a decreased number of lung metastases on day 20. The most effective modulators of cisplatin (CDDP) were phenidone/sulindac and phenidone/indomethacin, which led to 2.4- to 2.5-fold increases in the tumor growth delay produced by CDDP. The most effective modulations of cyclophosphamide resulted from administration of minocycline, minocycline/sulindac, or phenidone/sulindac and led to 2.0- to 2.1-fold increases in tumor growth delay by cyclophosphamide. The most effective modulators of melphalan produced 4.5- to 4.7-fold increases in tumor growth delay by the drug and were minocycline/sulindac, minocycline/mefenamic acid, and phenidone/sulindac. The most effective modulation of carmustine (BCNU) was obtained with minocycline/sulindac and minocycline/diflunisal leading to 2.8- to 3.1-fold increases in tumor growth delay by BCNU. Finally, the most effective modulation of radiation was obtained with minocycline/sulindac and phenidone/sulindac and resulted in 2.8- to 3.3-fold increases in tumor growth delay by radiation. The modulator combination that along with the cytotoxic therapies was most effective against metastatic disease was phenidone/mefenamic acid. There was no clear relationship between effective modulation of the cancer therapies and the degree of reduction in serum levels of prostaglandin E2 and leukotriene B4 by the agents in Lewis lung tumor bearing mice.
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PMID:Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies. 813 63

Diets rich in linoleic acid (LA) stimulate the metastasis of MDA-MB-435 human breast cancer cells from the mammary fat pads of nude mice. This omega-6 fatty acid is metabolized to various cyclo-oxygenase and lipoxygenase products, several of which have been previously associated with tumor cell invasion and metastasis. We now report that MDA-MB-435 cells secreted increased levels of prostaglandin E2 (PGE2), and 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE when cultured in the presence of 2.7 microM (0.75 micrograms/ml) LA; 5-HETE secretion was unchanged. The 12-lipoxygenase inhibitor esculetin (20 microM) completely blocked the LA-stimulated 12-HETE secretion. Linoleic acid also increased MDA-MB-435 cell invasion in an in vitro assay; this stimulation was abolished by 20 microM esculetin, but was unaffected by piroxicam, a selective cyclooxygenase inhibitor. The effect of LA on invasion was replicated by 0.1 microM 12-HETE, but not by 5-HETE or PGE2; 15-HETE was stimulatory only at a concentration of 1.0 microM. Zymographic and Northern blot analyses showed that these events are accompanied by the induction of 92 kDa isoform type IV collagenase (metalloproteinase-9) enzymic activity and mRNA expression by exogenous LA and 12-HETE, and their suppression by the 12-lipoxygenase inhibitor. These results suggest that the effects of dietary LA on breast cancer cell metastasis in the nude mouse model are due, at least in part, to enhanced 12-HETE biosynthesis, with an associated increase in proteolytic enzyme activity and tumor cell invasiveness.
Clin Exp Metastasis 1996 Mar
PMID:Eicosanoids as mediators of linoleic acid-stimulated invasion and type IV collagenase production by a metastatic human breast cancer cell line. 860 28

Growth and metastasis to the lung of the human breast cancer cell line MDA-MB-435 in nude mice fed a high-fat (20% wt/wt) high-linoleic acid (LA; 12% wt/wt) diet were significantly reduced by the addition of the cyclooxygenase inhibitor indomethacin to the drinking water at a dose of 10 micrograms/ml (approximately 1 mg/kg body wt). No toxicity was observed in these mice; at 20 micrograms/ml indomethacin, gastric ulcerations occurred. After necropsy, tumor eicosanoids were measured by radioimmunoassay in the control and 10 micrograms/ml indomethacin treatment groups. Levels of the cyclooxygenase products prostaglandin (PG) E (PGE), 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) were significantly reduced in indomethacin-treated mice compared with controls; however, the 6-keto-PGF1 alpha-to-TxB2 ratio was significantly increased. Two lipoxygenase products, 5-hydroxyeicosatetraenoic acid (5-HETE) and 15-HETE, were unaffected, but the 12-HETE levels were increased compared with the untreated high-LA-fed group. Metastases to the lungs in mice fed a high-fat low-LA (2% wt/wt) diet were also reduced compared with those in the high-LA-fed control mice, but whereas tumor cyclooxygenase and lipoxygenase product levels were reduced, no change in the 6-keto-PGF1 alpha-to-TxB2 ratio was observed. The use of selective cyclooxygenase inhibitors may prevent LA-mediated progression of breast cancer at several levels of the metastatic cascade, among which may be interference with tumor cell-vascular endothelial cell interaction and with angiogenesis.
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PMID:Dietary linoleic acid-stimulated human breast cancer cell growth and metastasis in nude mice and their suppression by indomethacin, a cyclooxygenase inhibitor. 877 66

Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.
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PMID:Identification of arachidonic acid pathways required for the invasive and metastatic activity of malignant tumor cells. 890 Apr 40


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