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)

Cellular growth and differentiation are controlled by multiple extracellular signals, many of which activate extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinases. Components of the MAP kinase pathways also cause oncogenic transformation in their constitutively active forms. Moreover, expression of activated ras can confer metastatic potential upon some cells. Activation of MAP kinases requires phosphorylation of both Thr and Tyr in the catalytic domain by a family of dual-specificity kinases, called MEKs (MAP kinase/ERK kinase). MEK1 is activated by phosphorylation at Ser218 and Ser222 by Raf. Mutation of these two sites to acidic residues, specifically [Asp218], [Asp218, Asp222], and [Glu218, Glu222], results in constitutively active MEK1. Using these mutant variants of MEK1, we showed previously that transfection of NIH/3T3 or Swiss 3T3 cells causes morphological transformation and increases growth on soft agar, independent of ERK activity. The transformed cell lines show increased expression of matrix metalloproteinases 2 and 9 and cathepsin L, proteinases that have been implicated in the metastatic process. We tested NIH3T3 cells transfected with the [Asp218] or [Asp218, Asp222] for metastatic potential after i.v. injection into athymic mice. Parental 3T3 cells formed no tumors grossly or histologically. However, all MEK1 mutant transformants formed macroscopic metastases. Thus, like activated Ras, MEK1 can confer both tumorigenic and metastatic potential upon NIH3T3 cells. These results refine the mechanism through which ras could confer tumorigenic and metastatic potential (ie., the critical determinants of tumorigenic and metastatic potential are downstream of MEK1).
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PMID:Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. 1074 22

Increased urokinase plasminogen activator (u-PA) production is associated with tumor invasion and metastasis in several malignancies, including breast cancer. The mechanisms underlying constitutive u-PA expression are not well understood. We examined the relationship between the signal strength of the ERK pathway and the level of u-PA expression in the metastatic human breast cancer cell line MDA-MB-231. Treatment with the MEK1 inhibitor PD98059 resulted in decreased ERK1/2 phosphorylation and decreased u-PA mRNA and protein expression. Inhibition of ERK1/2 activity also led to decreased cell proliferation and to decreased cyclin D1 expression. Less than 5% of total ERK1/2 was phosphorylated in exponentially growing MDA-MB-231 cells, and ERK1/2 activity could be stimulated by okadaic acid. Okadaic acid did not stimulate u-PA expression, but induced strong expression of the cdk-inhibitor p21Cip1. These findings suggest that ERK1/2 signaling is tuned to a level which results in high u-PA expression and rapid cell proliferation.
Clin Exp Metastasis 1999
PMID:ERK signalling in metastatic human MDA-MB-231 breast carcinoma cells is adapted to obtain high urokinase expression and rapid cell proliferation. 1091 9

Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, P1-3 kinase inhibitors, Wortmannin and LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor and the P13-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activation of dual signaling pathways, MEKI-MAPK and P13K-Akt, is required for the FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic target for cancer.
Clin Exp Metastasis 2000
PMID:Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. 1146 75

Once cancer cells have spread and formed secondary masses, breast cancers are largely incurable even with state-of-the-art medicine. To improve diagnosis and therapy, better markers are needed to distinguish cells which have a high probability for causing clinically relevant, macroscopic metastases. In this review, we summarize the several genes that regulate breast cancer metastasis. Two categories of genes are presented--metastasis activator (ras, MEK1, mta1, proteinases, adhesion molecules, chemoattractants/receptors, autotaxin, PKC, S100A4, RhoC, osteopontin) and metastasis suppressor (Nm23, E-cadherin, TIMPs, KiSS1, Kai1, Maspin, MKK4, BRMS1). While the mechanisms of action for most of these genes are not fully elucidated, some clues are emerging and are presented.
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PMID:Genetic basis of human breast cancer metastasis. 1201 33

Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGbeta1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGbeta1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGbeta1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGbeta1 action indicated that the addition of HRGbeta1 to LM3 cells resulted in activation of phosphatidylinositol 3- kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGbeta1 also caused the rapid activation of ERK1/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGbeta1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEK1/ERKs activity with PD98059, resulted in suppression of the ability of HRGbeta1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGbeta1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGbeta1-induced proliferation appear to be distinct from those involved in HRGbeta1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.
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PMID:Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. 1220 1

Increased expression of the hepatocyte growth factor (HGF) receptor (c-met) and urokinase type plasminogen (uPA) correlated with the development and metastasis of cancers. To investigate the role of HGF/c-met signaling on metastasis in cancer cells stimulated with HGF, we examined the effects of a specific MEK1 inhibitor (PD98059) and a p38 MAP kinase inhibitor (SB203580) on HGF-induced uPA expression in pancreatic cancer cell lines, L3.6PL and IMIM-PC2. Pretreatment of PD98059 decreased HGF-mediated phosphorylation of extracellular receptor kinase (ERK), uPA secretion and expression of matrix metalloproteinases (MMP-2 and MMP-9) in a dose-dependent manner. In contrast, SB203580 pretreatment increased HGF-stimulated ERK phosphorylation, uPA secretion and expression of MMPs. SB203580 also reversed the inhibition of HGF-mediated ERK activation and uPA secretion in the PD98059-pretreated cells. These results suggest that ERK activation by HGF might play important roles in the metastasis of pancreatic cancer and the p38 MAPK pathway also involved in the HGF-mediated uPA secretion and metastasis by regulation of ERK pathway.
Clin Exp Metastasis 2003
PMID:Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis. 1459 83

Gastric cancers with liver metastasis are fatal diseases with rapid progression and poor patient outcome. To date, however, the molecular basis of their growth and metastasis remains essentially unknown, largely because of the presence of few available gastric cancer cell lines established from liver metastasis. In the present study, we developed two novel cultured cell lines (designated GLM-1 and GLM-2) and one transplantable line in nude mice (designated GLM-3) derived from liver metastasis of gastric cancer patients. These GLM cell lines share unique biological features such as differentiation, growth and metastasis. They form moderately differentiated tumors with CD10 positive and MUC2 negative intestinal absorptive phenotype when injected into nude mice. Their growth is stimulated by EGF and TGF-alpha in vitro like other gastric cancer cell lines. However, GLM cells differ from conventional gastric cancer cell lines in their high apoptotic rate, even in the absence of apoptosis inducing stimuli as revealed by Caspase3/7 assay and the TUNEL method. This apoptosis is further enhanced by phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not by MEK1/2 inhibitor (U0126), indicating the strong dependency of their survival on PI3K/Akt pathway rather than MAPK pathway, the major downstream signaling pathways of EGFR. GLM-1 cells can metastasize to the liver after intrasplenic injection, and GLM-3 cells have spontaneous lung metastatic potential after subcutaneous transplantation, respectively. These results indicate that the GLM series are the first cell lines reflecting the intestinal-type differentiated adenocarcinoma, a major subtype of gastric cancer with liver metastasis. Therefore, they would be excellent models for understanding the mechanism of metastatic growth and the development of a new molecular targeting therapy for gastric cancer with liver metastasis.
Clin Exp Metastasis 2005
PMID:Establishment and characterization of three novel human gastric cancer cell lines with differentiated intestinal phenotype derived from liver metastasis. 1608 34

We investigated the influence of TNF-alpha on the metastasis of cancer cells. Treatment of cultured colon 26 cells with TNF-alpha enhanced metastatic properties including production of MMP-9, adhesion, migration and invasion. Cells treated with TNF-alpha in vitro showed marked potential to metastasize to the lung and liver in vivo. U0126, an inhibitor of MEK1/2, inhibited the TNF-alpha-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the metastatic properties in vitro without affecting cell proliferation. In addition, pretreatment with U0126 in vitro completely abrogated the increased lung metastasis of TNF-alpha-treated cells. These results indicate that TNF-alpha-induced activation of cancer cells through the ERK pathway is sufficient for the enhanced metastatic potential of colon 26 cells.
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PMID:Stimulation of cultured colon 26 cells with TNF-alpha promotes lung metastasis through the extracellular signal-regulated kinase pathway. 1625 60

Up-regulation of extracellular-regulated kinases 1/2 (ERK1/2) has been implicated in tumor progression and metastasis in many types of cancer. We have previously shown that ERK1/2 is necessary for invasiveness of Dunning rat prostatic adenocarcinoma cell lines in which levels of activated ERK1/2 correlate with the metastatic potential. Here, we further examined the biological effects of elevated ERK1/2 in the highly metastatic Dunning cell line, MLL, in which the abilities to invade and metastasize are enhanced relative to its progenitor strain. Inhibition of ERK1/2 activation by the MEK1 inhibitor, PD98059, dose-dependently reduced MLL cell invasiveness and motility with similar IC50 values. On the other hand, the abilities of MLL cells to adhere to the extracellular matrix, phosphorylate myosin regulatory light chain and secrete matrix-degrading enzymes, matrix metalloproteinase (MMP)-2 and urokinase plasminogen activator (uPA) were marginally, if at all, affected by PD98059 treatment. These data indicated that the inhibitory effect of PD98059 on the invasiveness of MLL cells was primarily due to the suppression of cell motility, and the up-regulation of ERK1/2 is, at least in part, responsible for the enhanced cellular motility and invasiveness of the MLL cells.
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PMID:PD98059-inhibited invasion of Dunning rat prostate cancer cells involves suppression of motility but not MMP-2 or uPA secretion. 1668 2

Protein kinase C (PKC) has been shown to be a signal transducer during tumorigenesis, tumor cell invasion, and metastasis. Recent studies have reported that the PKC inhibitor, 7-hydroxystaurosporine, inhibits tumor cell invasion. However, the molecular mechanisms of this inhibition of invasion and metastasis are not well understood. In the present study, we attempt to clarify the mechanism by which H7, a PKC inhibitor, inhibits tumor cell invasion and metastasis in the melanoma cell line B16BL6. It was found that H7 inhibits B16BL6 cell invasion and metastasis. We also observed that H7 inhibits the mRNA expression and protein activities of matrix metalloproteinase (MMP)-1, -2, -9 and MT1-MMP. Furthermore, H7 suppresses phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). However, other signal transduction factors, such as p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase 1/2 (JNK1/2), were unaffected. Moreover, U0126, a MEK1/2 inhibitor, also inhibited B16BL6 cell invasion and metastasis, as well as the mRNA expression and protein activities of MMP-1, -2, -9 and MT1-MMP. This indicates that H7 inhibits signal transduction through the PKC/MEK/ERK pathway, thereby inhibiting B16BL6 cell invasion and metastasis. These results suggest that PKC inhibitors have potential clinical applications in the treatment of tumor cell metastasis.
Clin Exp Metastasis 2007
PMID:The protein kinase C inhibitor, H7, inhibits tumor cell invasion and metastasis in mouse melanoma via suppression of ERK1/2. 1763 10


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