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)

The raf genes encode for a family of cytoplasmic proteins (A-raf, B-raf and c-raf-1) with associated serine/threonine kinase activities. Raf-1 is an important mediator of signals involving cell growth, transformation and differentiation. It is activated in response to a wide variety of extracellular stimuli such as insulin, nerve growth factor (NGF), platelet derived-growth factor (PDGF), and in response to expression of oncogenes, v-src and v-ras, in a cell-specific manner. Recently, the first physiological substrate for Raf-1 protein kinase was identified. Raf-1 was found to phosphorylate and activate Mitogen-Activated Protein Kinase Kinase (MEK), an activator of MAP kinase, thus linking the Raf-1 signaling pathway with that of MAP kinase. Cell specific differences in signalling pathways involving Raf-1 and MAP kinase have also been discovered. Accumulating evidence indicates that membrane tyrosine kinases, ras, Raf-1, MEK and MAP kinase are interconnected via a complex network rather than via a linear pathway involving multiple substrates and feedback loops.
Cancer Metastasis Rev 1994 Mar
PMID:Signal transduction pathways involving the Raf proto-oncogene. 814 42

Expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) by metastatic Lewis lung carcinoma cells (LLC-LN7) was previously shown to contribute to the maintenance of phenotypic characteristics associated with an increased capacity to metastasize. In the present study, pre-incubation of LLC-LN7 cells with neutralizing anti-GM-CSF antibodies diminished the capacity of the tumor cells to form experimental metastases after i.v. inoculation, while pre-incubation with recombinant GM-CSF (rGM-CSF) increased formation of metastases. In the presence of rGM-CSF, the LLC-LN7 cells exhibited an increased capacity to migrate, invade through a reconstituted basement membrane, and adhere to lung tissue. Studies to identify the signal transduction pathway through which GM-CSF enhanced the in vitro metastatic properties of the LLC-LN7 tumor cells implicated protein kinase A (PKA). Signaling through PKA was suggested by the demonstration that the stimulation of tumor-cell motility by GM-CSF was blocked in the presence of the adenylate cyclase inhibitor nicotinic acid, or the PKA inhibitors A3 or KT5720. In addition, the role of PKA as a signaling mechanism for GM-CSF was assessed by using REV-LN7 cells, which are LLC-LN7 cells that have been stably transfected with an expression vector encoding a mutant PKA RI alpha subunit and which, in turn, express a cAMP-resistant PKA. Adherence and invasion by the PKA-defective REV-LN7 cells were not stimulated by rGM-CSF, contrasting with the stimulation observed for wild-type LLC-LN7 cells. These data suggest that rGM-CSF can further enhance the in vitro metastatic characteristics of LLC-LN7 tumor cells and that this is dependent on signal transduction through PKA.
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PMID:Granulocyte-macrophage colony-stimulating factor stimulates the metastatic properties of Lewis lung carcinoma cells through a protein kinase A signal-transduction pathway. 843 41

A human myeloid leukemia cell line, KBM-7, was developed from a patient in the blastic phase of chronic myeloid leukemia (CML). We characterized its morphology, immunophenotype, cytogenetics, and proliferative capacity. Developed in the absence of exogenous lymphokines, KBM-7 in vitro cloning capacity actually decreased when colony-stimulating factors were added. The cells had an aberrant immature myeloid phenotype, a doubling time of 22 h in suspension cultures and a high cloning efficiency in semisolid system (24 +/- 3)%. Early passages contained one near-haploid (predominant) and one hyperdiploid stem line. Gradually the hyperdiploid stem line became predominant, reaching an average of 49 chromosomes per cell. Cells from passage 89 had two Philadelphia chromosomes [t(9;22)(q34;q11)] and lacked normal copies of chromosomes 9 and 22. Detailed molecular characterization of the breakpoint in the t(9;22)(q34;q11) revealed that KBM-7 had the BCR 2/ABL II splice junction. The cells had high protein kinase (p210BCR-ABL) activity and carried two identified variants of an ABL-BCR message. There was no evidence that normal BCR or c-ABL messages were expressed, assessed with the reverse-transcriptase polymerase chain reaction. When KBM-7 cells were heterotransplanted into nude mice without immunosuppressive pretreatment, one of three mice injected with 1 x 10(7) cells and all mice injected with 1 x 10(8) cells developed slowly growing granulocytic sarcomas within 6-8 weeks. These tumors were locally invasive but did not metastasize. We conclude that the KBM-7 cell line will be of value for investigating molecular events underlying neoplastic transformation in CML, in particular for studying the effects of BCR-ABL and ABL-BCR on the proliferation of CML cells in the absence of normal BCR and c-ABL messages.
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PMID:KBM-7, a human myeloid leukemia cell line with double Philadelphia chromosomes lacking normal c-ABL and BCR transcripts. 860 23

To elucidate the degree of malignancy or the host-killing ability of rat ascites hepatoma AH66F, AH66 and AH130, the chick embryo-polymerase chain reaction system was used to measure the metastasis of these hepatoma cells. When inoculated into the chorioallantoic membrane vein of 10-day fertilized chicken eggs, AH66F cells metastasized in the lung and liver in an inoculum size-dependent manner up to 10(6) cells, but AH66 and AH130 cells only a little even at 10(6) cells. The adhesion of AH66F cells, but not other hepatoma cells, to rat mesentery-derived mesothelial cells was inhibited by protein kinase C inhibitors NA-382 and H-7, but not by other protein kinase inhibitors, and the life-span of rats inoculated with AH66F cells was also prolonged by treatment with Na-382. AH66F cells, pretreated with protein kinase inhibitors were inoculated into the fertile eggs and micrometastasis was assayed. Metastasis of AH66F cells in the chick embryo was clearly decreased by treatment with NA-382. The chick embryo-polymerase chain reaction system is a sensitive method to measure the metastatic ability of mammalian tumor cells, and the high metastatic ability of AH66F cells is probably related to their adhesion to target cells mediated by the protein kinase C pathway.
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PMID:Assessment of the metastatic ability of rat hepatoma cells in chick embryos by the polymerase-chain reaction. 861 46

Tumor cell adhesion to and migration through the extracellular matrix (ECM) can influence their capacity to disseminate. Since prior studies with Lewis lung carcinoma (LLC) tumors had shown metastatic clones to have more protein kinase A (PKA) activity than nonmetastatic clones, the present study assessed if PKA regulates the interaction between tumor and the ECM, and how this may be associated with the metastatic capacity of the tumor cells. This was accomplished with the use of metastatic (LLC-LN7) and nonmetastatic (LLC-C8) variants that had been stably transfected to overexpress the PKA Calpha subunit or to have blocked PKA activity. Cells with increased PKA activity were less adherent to vitronectin, laminin, and collagen I, and could more readily migrate through these ECM components than could transfectants with reduced PKA activity. PKA did not regulate adhesion to or migration through fibronectin, and did not appear to be associated with changes in expression of surface integrins. In addition to modulating tumor adhesion and migration in vitro, PKA activation caused an increased formation of metastases from s.c. tumors, but did not regulate formation of experimental metastases by i.v. injected tumor cells. These results suggest that PKA signaling is important for modulating the tumor-ECM interaction and can facilitate tumor transit from the primary tumor site.
Clin Exp Metastasis 1996 May
PMID:Protein kinase A regulates Lewis lung carcinoma adherence to extracellular matrix components and spontaneous metastasis. 867 86

Regulation of two genes involved in tumor invasion, the matrix metalloproteinase (MMP)-1 and the tissue inhibitor of MMP (TIMP)-1, by activators of protein kinase C (PKC) or protein kinase A (PKA) was studied in MCF-7 mammary adenocarcinoma cells. The basal mRNA expression was undetectable for MMP-1 and low for TIMP-1. Treatment of MCF-7 cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 nM) was associated with a high expression of MMP-1 mRNA, as well as an induction of the level of TIMP-1 mRNA (5- to 10-fold). In the presence of actinomycin D (AMD, 4.0 microM), an inhibitor of transcription, these stimulatory effects of TPA were abolished. Similar responses were observed when protein synthesis was inhibited by cycloheximide (CHX, 50 microM). In the presence of the cyclic AMP (cAMP) analogue N6-benzoyl (N6-Bzl)-cAMP (500 microM), the MMP-1 mRNA was unaffected and still below the level of detection, whereas a non-significant increase (< 2-fold) in TIMP-1 mRNA was observed. The level of pS2 mRNA, of which the induction by TPA in MCF-7 cells is a primary transcriptional event, was up-regulated (10- to 15-fold) by TPA (100 nM), whereas a much weaker increase (2- to 3-fold) was observed by treatment with N6-Bzl-cAMP (500 microM). Again, these stimulatory effects were counteracted by AMD (4.0 microM) and CHX (50 microM). These data suggest that activation of PKC but not of PKA may induce transcription of MMP-1 and TIMP-1, possibly by the synthesis of transcription factor(s), in transformed cells of epithelial origin.
Clin Exp Metastasis 1996 Sep
PMID:Regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in MCF-7 cells: comparison with regulatory mechanisms of pS2 expression. 887 12

Invasive and metastatic cells require protease expression for migration through the extracellular matrix. Metastatic NIH 3T3 fibroblasts transformed by different activated ras genes showed two different protease phenotypes, rasuPA+/CL- and rasCL+/uPA- (Zhang, J-Y., and Schultz, R. M. (1992) Cancer Research 52, 6682-6689). Phenotype rasuPA+/CL- is dependent on expression of the serine-type protease urokinase plasminogen activator (uPA) and the phenotype rasCL+/uPA- on the cystine-type protease cathepsin L (CL) for lung colonization in experimental metastasis. The existence of multiple invasive phenotypes on ras-isoform transformation implied the activation of alternative pathways downstream from Ras. We now show that c-Raf-1, extracellular signal-regulated protein kinase (ERK)-1, and ERK-2 are hyperphosphorylated, and the ERK activity is high in both the uPA- and CL-dependent ras-transformed invasive phenotypes. Levels of c-Jun and c-Jun NH2-terminal kinase (JNK) activity are also high in the uPA-dependent phenotype, but they are almost undetectable in the CL-dependent phenotype. The uPA Ras-response element is a PEA3/URTF element, and mobility shift assays show a strong PEA3/URTF protein band in the uPA-dependent phenotype. This band is competed by a consensus AP-1 DNA sequence and by antibodies to PEA3 and c-Jun. Thus, the uPA-invasive phenotype appears to require the activation of Ets/PEA3 and c-Jun transcription factors activated by the ERK and JNK pathways, while the CL-invasive phenotype appears to require ERK activity with suppression of JNK and c-Jun activities. These postulates are supported by the introduction of a dominant negative c-Jun, TAM67, into cells of phenotype rasuPA+/CL-, which down-regulated the high uPA mRNA levels characteristic of this phenotype to basal levels and up-regulated basal levels of CL mRNA to levels similar to those observed in cells of phenotype rasCL+/uPA-. We conclude that the JNK pathway acts as a switch between two distinct protease phenotypes that are redundant in their abilities to grow tumors and metastasize.
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PMID:Characterization of downstream Ras signals that induce alternative protease-dependent invasive phenotypes. 903 12

The capacity of cloned metastatic Lewis lung carcinoma cells (LLC-LN7) to invade through reconstituted basement membrane-coated filters was reduced after incubation with 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. This was observed at doses as low as 10(-10) M 1,25(OH)2D3. The 1,25(OH)2D3-treated cells also had reduced levels of protein kinase A (PKA) activity and an increase in the level of polymerized actin, properties that have previously been demonstrated for less metastatic LLC variants. In addition, levels of the intermediate filament protein vimentin increased in 1,25(OH)2D3-treated LLC-LN7 tumor cells. In contrast, the levels and distribution of tubulin were not affected by 1,25(OH)2D3. The possibility that the decline in PKA activity was involved in the 1,25(OH)2D3 modulation of the cytoskeletal components was evaluated. To accomplish this, LLC-7 transfectants whose PKA levels were blocked due to expression of a mutated PKA R(1alpha) subunit (LN7-REV) were incubated with 1,25(OH)2D3 and their levels of F-actin were measured. In the absence of 1,25(OH)2D3 treatment, the PKA-defective LN7-REV cells had an increased level of polymerized actin as compared to the wild-type LLC-LN7 cells. This level of F-actin was minimally affected by 1,25(OH)2D3, suggesting that PKA activity is required for 1,25(OH)2D3 modulation of actin polymerization. These studies show that 1,25(OH)2D3 can reduce PKA activity in tumor cells, and that this reduction in PKA may be an intermediate signal through which 1,25(OH)2D3 affects the cytoskeleton and diminishes tumor invasiveness.
Clin Exp Metastasis 1997 Mar
PMID:Inhibition of tumor invasiveness by 1alpha,25-dihydroxyvitamin D3 coupled to a decline in protein kinase A activity and an increase in cytoskeletal organization. 906 86

Increasing phosphorylation reactions by protein kinase A (PKA) or reducing dephosphorylation reactions of protein phosphatase-2A (PP-2A) increases the invasiveness of Lewis lung carcinoma (LLC) cells, as measured by their capacity to traverse extracellular matrix (ECM)-coated filters. Metastatic LLC-LN7 variants have reduced PP-2A activity when compared to nonmetastatic LLC-C8 variants. Immunoblotting showed that this reduced level of PP-2A activity was not due to reduced levels of the PP-2A catalytic (C) subunit. The cellular PP-2A activity could be stimulated by addition of C2-ceramide to LLC-LN7 lysates, or by incubating cells with either C2-ceramide or with a noncalcemic analog of vitamin D3, which has previously been shown to stimulate the release of ceramide. These treatments to elevate PP-2A activity in metastatic LLC-LN7 cells resulted in a decline in their capacity to invade through select (ECM) components, particularly through vitronectin and laminin. Underscoring the importance of PP-2A in limiting the invasiveness of tumor cells was the demonstration that LLC-LN7 cell transfectants overexpressing the PP-2A C alpha subunit were less invasive through ECM components than the wild-type cells. Invasion by these cells was further reduced by additionally increasing PP-2A activity by incubation with C2-ceramide or the vitamin D3 analog. These results suggest a role of a vitamin D3/ceramide/PP-2A pathway in limiting the invasiveness of tumor cells through select ECM components.
Invasion Metastasis 1996
PMID:Vitamin D3 and ceramide reduce the invasion of tumor cells through extracellular matrix components by elevating protein phosphatase-2A. 937 Dec 27

Recently, we reported that low (PC-1)- and high-invasive cell lines (PC-1.0) were established on the basis of hamster pancreatic ductal adenocarcinomas, and PC-1.0 cells were secreting the dissociation factor in the supernatant (DF-CM) which induced cell dissociation and enhancement of cell motility. The cell motility of PC-1.0 is about 6 times as high as that of PC-1, which was continuously maintained in an autocrine fashion by DF-CM. In contrast, cell motility of PC-1 was rapidly induced by DF-CM with a high level of induction of endogenous c-fos mRNA and returned to a basal level within 6 h. The inhibition experiment using antisense oligonucleotides to c-fos indicated that the high level of induction of c-fos mRNA observed in the DF-CM-treated PC-1 cells was closely associated with their induction of cell motility. To elucidate these differences of responses against DF-CM between PC-1 and PC-1.0, signal transduction pathways of induction of the cell motilities were analyzed, using protein kinase C (PKC) inhibitor, 12-O-tetradecanoylphorbol-13-acetate, cyclic AMP antagonist, and cyclic AMP agonist. The transiently enhanced cell motility of DF-CM-treated PC-1 cells was completely inhibited by the cyclic AMP antagonist, and the cyclic AMP agonist was able to induce a similar pattern of induction of cell motility in PC-1 cells to DF-CM. On the other hand, the highly enhanced cell motility of PC-1.0 was completely inhibited by protein kinase C inhibitor, but not by cyclic AMP antagonist. These results suggest that cell motility of low-invasive PC-1 cells is under control through cyclic AMP-dependent protein kinase A, while the protein kinase C pathway seems favorable for high-invasive PC-1.0 cells to maintain the continuously enhanced cell motility responsible for their high invasiveness.
Invasion Metastasis 1997
PMID:Signal transduction pathway of the induction of cell motility in hamster pancreatic ductal adenocarcinoma cell. 942 21


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