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)

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50 values of 15, 20 and 3 microM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 microM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells.
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PMID:Bisphosphonates induce apoptosis in human breast cancer cell lines. 1078 May 27

A correlation exists between the ability of tumor cells to aggregate platelets and their tendency to metastasize. Tumor cell-induced platelet aggregation (TCIPA) facilitates the embolization of the vasculature with tumor cells and the formation of metastatic foci. It is well documented that matrix metalloproteinases (MMPs) play an integral part in tumor spread and the metastatic cascade. Therefore, we have examined the role of MMPs during TCIPA and its regulation by nitric oxide (NO) in vitro. Human HT-1080 fibrosarcoma and A549 lung epithelial cancer cells induced TCIPA in a concentration-dependent manner that was monitored by aggregometry. This aggregation resulted in the release of MMIP-2 from platelets and cancer cells, as measured by zymography. HT-1080 cells released significantly more MMP-2 than A549 cells and were more efficacious in inducing TCIPA. Inhibition of MMP-2 with phenanthroline (1-1000 microM), a synthetic inhibitor of MMPs, and by neutralizing anti-MMIP-2 antibody (10 microg/ml) reduced TCIPA induced by HT-1080 cells. TCIPA was abolished by simultaneous inhibition of platelet function with acetylsalicylic acid (100 microM; thromboxane pathway inhibitor), apyrase (250 microg/ml; ADP pathway inhibitor), and phenanthroline. NO donors such as S-nitroso-n-acetylpenicillamine and S-nitrosoglutathione (both at 0.01-100 microM) inhibited TCIPA and MMP-2 release from platelets and tumor cells. The inhibitory actions of S-nitroso-n-acetylpenicillamine and S-nitrosoglutathione were reversed by 1H-[1,2,4]oxadiazole[4,3]quinoxalin-1-one (0.01-30 microM), a selective inhibitor of the soluble guanylyl cyclase. We conclude that (a) human fibrosarcoma cells aggregate platelets via mechanism(s) that are mediated, in part, by MMP-2; (b) NO inhibits TCIPA, in part, by attenuating the release of MMP-2; and (c) these effects of NO are cGMP-dependent.
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PMID:Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide. 1119 90

Viper venom disintegrins have been used frequently to study the cellular receptors which characterize various types of cells, including platelets, endothelial cells and cancer cells. While the majority of such analyses have pointed to involvement of integrin receptors alphavbeta3, alpha5beta1 or alphaIIbbeta3, this may not always be so. Eristostatin, from Eristocophis macmahoni, is a potent inhibitor of ADP-induced platelet aggregation as well as of human and murine melanoma metastases in mouse model systems. This disintegrin requires an RGDW motif, as well as an intact C-terminus, in order to interact with both platelets and four different types of melanoma cells. Eristostatin causes nonmetastatic SBc12 melanoma cells to show higher susceptibility to specific killing by NK-like TALL-104 cells. While it is known that eristostatin binds to alphaIIbbeta3 on platelets, the receptor with which eristostatin binds to the melanoma cells has not yet been identified.
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PMID:New insights on disintegrin-receptor interactions: eristostatin and melanoma cells. 1191 Jan 83

The WH2 (WASP homology domain-2) is a small actin monomer-binding motif and is found in many proteins that regulate the actin cytoskeleton, including the beta-thymosins, ciboulot, WASP, and verprolin/WIP (WASP-interacting protein). In sequence database searches we identified a novel mouse protein containing a WH2 domain in its C-terminal region. This mouse gene also shows strong sequence homology to human MIM (Missing in Metastasis), a cDNA fragment that is present in non-metastatic but absent in metastatic bladder cancer cell lines. Northern blot and in situ hybridizations show that MIM is strongly expressed in the developing neurons and skeletal and cardiac muscles in mouse embryos. In adult mice, the strongest expression of MIM mRNA is in liver, outer layers of the kidney, and in the Purkinje cells of the brain. Recombinant MIM protein interacts with actin monomers and inhibits actin filament nucleation in vitro. However, the MIM/ATP-G-actin complex can participate in actin filament assembly at the barbed end. MIM binds ATP-G-actin with a higher affinity (K(D) = 0.06 microm) than ADP-G-actin (K(D) = 0.3 microm) and inhibits the nucleotide exchange on actin monomers. Site-directed mutagenesis demonstrates that the actin monomer-binding site resides in the C-terminal WH2 domain of MIM. Overexpression of mouse MIM in NIH 3T3 cells results in the disappearance of actin stress fibers and appearance of abnormal actin filament structures. These data show that MIM is an ATP-G-actin binding protein that regulates cytoskeletal dynamics in specialized mammalian cell-types.
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PMID:Mouse MIM, a tissue-specific regulator of cytoskeletal dynamics, interacts with ATP-actin monomers through its C-terminal WH2 domain. 1248 61

Matrix metalloproteinases, like MMP-2 and MMP-9 gelatinases, show multiple functions as extracellular/cell-surface enzymes, and are broadly recognised for their matrix-degrading ability and involvement in cell motility. Given that adherent cells have reduced attachment during migration and also detach from their substratum during apoptosis, we now investigated whether extracellular matrix-bound gelatinases and intracellular MMP-2 and MMP-9 are modified with progression of death-inducing stimuli. This report shows that melanoma cells undergoing death in response to 2-acetyl furanonaphtoquinone (FNQ) as evidenced by greater Annexin V binding, increased cytosolic expression of pro-MMP-2 and intracellular activation of particulate MMP-9. These changes were associated with early activation of a substrate-attached 40 kDa gelatinase reciprocal with changes in extracellular matrix-bound activated MMP-2. A subsequent activation of secreted MMP-9 and induction of apoptosis-associated fragmentation of poly ADP-Ribose polymerase (PARP) correlated with cell detachment. Our data suggests that intracellularly activated gelatinases may cleave survival-associated substrates other than gelatin that share the Gly-Leu/Iso-Pro like collagen-binding acetylcholinesterase, thereby linking them to apoptosis associated with cell detachment.
Clin Exp Metastasis 2005
PMID:Invasion-associated MMP-2 and MMP-9 are up-regulated intracellularly in concert with apoptosis linked to melanoma cell detachment. 1617 Jun 65

Formation of tumor cell-platelet aggregates facilitates hematogenous metastases. However, molecular mechanisms implicated in tumor cell-induced platelet aggregation (TCIPA) in colon cancer are unclear. To investigate mechanisms of TCIPA induced by colon adenocarcinoma cells in vitro, human Caco-2 cells were used to study their interactions with platelets using aggregometry, zymography, phase-contrast microscopy, and flow cytometry. Caco-2-induced platelet aggregation in a concentration-dependent manner. This aggregation resulted in the release of matrix metalloproteinase (MMP)-2, as measured by zymography. In addition, flow cytometry showed a significant up-regulation of activated GpIIb/IIIa, total GpIIb/IIIa, GpIb, and P-selectin receptors on platelets. Inhibition of MMP-2 by phenantroline and degradation of ADP by APT102, respectively, resulted in inhibition of TCIPA. Furthermore, both phenantroline and APT102 significantly down-regulated the surface abundance of platelet receptors. Caco-2 cells aggregate platelets, at least in part, via releasing MMP-2 and ADP. Modulation of MMP-2 and ADP actions could have therapeutic value in colonic cancer.
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PMID:Platelet aggregation-induced by caco-2 cells: regulation by matrix metalloproteinase-2 and adenosine diphosphate. 1642 48

In this study, geldanamycin (GA) was found to have an antiproliferative effect on both embryonal and alveolar rhabdomyosarcoma (RMS) cell lines. The maximum level of inhibition reached 80% for both embryonal and alveolar RMS. After GA treatment, cells also became apoptotic as judged by Annexin V-positive staining, activation of caspase-3 pathway and poly(ADP ribose) polymerase cleavage. GA was responsible for the arrest of RMS cells in both G1 and G2/M phases of the cell cycle. G1 blockade, however, was transient and was seen only in the first 24 h of GA treatment. RMS often gives distant metastases to various organs including bone marrow. RMS cells express high levels of MET receptor and respond to hepatocyte growth factor with increased motility. In our study, we found that GA decreased the level of MET expression and inhibited the chemotaxis of RMS cells toward the hepatocyte growth factor gradient. GA also blocked the homing of RMS cells into bone marrow of severe combined immune deficient mice. In all our experiments embryonal RMS cell lines were significantly more sensitive, and lower concentrations of GA were sufficient to block embryonal RMS cell proliferation, induce apoptosis and inhibit motility. Our data show that the HSP90 inhibitor GA has the potential to become a new drug in RMS treatment. It blocks RMS proliferation, decreases cell survival and inhibits motility of RMS cells.
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PMID:HSP90 antagonist, geldanamycin, inhibits proliferation, induces apoptosis and blocks migration of rhabdomyosarcoma cells in vitro and seeding into bone marrow in vivo. 1789 18

In the last years, a sharp rise in the morbidity due to lung cancer is observed, especially in the male population. Despite the intensive, multidirectional development of oncology, early detection and effective treatment of lung cancer is still limited. Its detection is delayed because of the lack of characteristic early signs. Especially poor in prognosis are patients with small cell lung cancer (SCLC), who usually die in consequence of distant metastases. This may result due to coating of the surface of circulating neoplastic cells with thrombocytes and clots. Platelets aggregates on the surface of neoplastic cells may have a protective action in relation to cytostatic drugs. This is why neoplastic cells that persist through this phase, implant themselves into various organs giving rise to metastases. The aim of the 1st part of the paper was to evaluate the influence of antiplatelet drugs (AD) on the haemostatic system of patients with SCLC. There is data in literature indicating a ameliorating influence of AD on time of survival of patients with certain neoplasms. The study was performed in 87 male patients aged 35-73 years with SCLC, limited to half of the chest (limited disease). After 2 i.v. chemotherapy series in 3 week intervals (VAC scheme according Greco): --Adriamycin (ADR) 40 mg on 1sq.m of body surface; --Vincristin (VCR) 1 mg; on 1sq.m of body surface; --Cyclophosfamid (CTX) 1000 mg on 1sq.m of body surface; radiation was also applied--40 Gy during 20 days on the tumor and mediastinum. The described treatment was performed in 22 patients from controls (Group I). Patients from Group II (n = 22) received additionally Defibrotide, Group III (n = 22) Ticlide and Group IV (n = 21) Aspirin. To evaluate of the influence of AD on the haemostatic system--every 3 months during the consecutive 27 weeks, the following tests were performed: bleeding time, clotting time, platelet aggregation, platelets aggregation ratio, euglobulin clot lysis time (ECLT), fibrinogen and fibrinogen degradation products (FDP). It was shown that AD prolonged bleeding and clotting time, increased the threshold ADP and collagen concentration causing platelets aggregation as well as increased platelet aggregation ratio. The used AD (Defibrotide, Ticlide) resulted in activation of the plasma fibrynolytic system as expressed by a shortening of the ECLT, lowering of fibrinogen level and increasing FDP. The influence of observed changes in the haemostatic system, as a result of AD on the remission and survival time of patients with SCLC will be presented in the 2nd part of this paper.
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PMID:[Influence of antiplatelet drugs (AD) on the efectiveness of combined therapy in patients with small cell lung cancer. Part I. Influence of AD on the haemostatic system]. 1885 60

Human breast cancer cells (MDA-MB-435s) secrete a nucleoside diphosphate kinase (NDPK-B) as a phosphoprotein capable of converting diphosphate nucleosides to triphosphate nucleotides for one round in the absence of a phosphoryl donor. Incubation of the partially purified NDPK-B (Nm23-H2 by Western blot) from [gamma32P]Pi-labeled cells with non-radioactive ADP results in the formation of [gamma32P]ATP (Proc. West. Pharmacol. Soc. 44: 61-63, 2001). The presence of a secreted protein that can maintain ATP levels in the vicinity of capillary and lymph vessels may support cancer metastasis in several ways based on the known actions of ATP at P2Y receptors: facilitate intravasation of breast cancer cells that migrate from a solid tumor, support their extravasation at a distal site, and stimulate angiogenesis. The putative role of angiostatin (AS) as an ATP-synthase inhibitor led us to test the notion that AS blocks NDPK-B activity. Addition of commercial AS (kringles 1-4) did not alter enzyme activity. However, AS produced by us and never lyophilized, blocked NDPK activity in a dose-dependent fashion consistent with the notion that extracellular ATP generation by tumor cells may be important to the development of metastases. The ability of 0.5 mg/ml angiostatin to block NDPK-B activity to approximately 75% of control activity compared poorly with the polyphenol inhibitors of. The catechin gallates, theaflavins and ellagic acid inhibited NDPK-B completely with the rank order of potency: EA > theaflavins > EGCG > ECG > PAPS. Our results suggest that the biological activity of angiostatin as a putative metastasis inhibitor may be in part the result of nm23 inhibition and that the production, lyophilization, packaging or storage of commercial angiostatin leads to the alteration of its biological activity against NDPK-B. Ellagic acid is a potent (IC50 = 10.5 microM) NDPK-B inhibitor that may prove useful in elucidating the role of cancer-cell secreted NDPK-B in tumor development.
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PMID:Inhibition of Nm23H2 gene product (NDPK-B) by angiostatin, polyphenols and nucleoside analogs. 1954 70

Several advances have recently expanded models of tumor growth and promoted the concept of tumor homeostasis, the hypothesis that primary tumors exert an anti-proliferative effect on both themselves and subclinical secondary metastases. Recent trials indicate that the characterization of tumor growth as uncontrolled is inconsistent with animal models, clinical models, and epidemiological models. There is a growing body of evidence which lends support to an updated concept of tumor growth: tumor homeostasis. In the case of breast cancer, if not all metastasizing tumors, these advances suggest an inconvenient truth. That is, if breast tumor cells metastasize to distant sites early in the tumorigenesis process, then removal of a breast tumor may hasten the development of its metastases. We explore the heretofore unappreciated notion that nucleotides generated by tumor cells following the secretion of an ADP-kinase can promote metastasis and support angiogenesis. Evidence is presented that blockade of the actions of nucleotides in the setting of newly diagnosed breast cancer may provide a useful adjunct to current anti-angiogenesis treatment.
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PMID:Purinergic mechanisms in breast cancer support intravasation, extravasation and angiogenesis. 1992 95


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