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)

We have shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) inhibits the development of intrahepatic metastases of hepatocellular carcinoma CBO140C12, and EGFR transactivation by tumor necrosis factor-alpha is a possible target of gefitinib. In the present study, we focused on the fibronectin (FN)-dependent signaling pathway to further elucidate the antimetastatic activity of gefitinib in CBO140C12 cells. We initially observed that FN induced activation of extracellular signal-regulated kinase (ERK), p38 and Akt, as well as cell proliferation and CBO140C12 cell invasion. These responses were mediated by EGFR tyrosine kinase, because gefitinib inhibited these effects of FN. FN-induced ERK, p38 and Akt activation was partly blocked by the Arg-Gly-Asp (RGD)-pseudo-peptide FC-336, anti-alphav integrin antibody RMV-7, the broad-spectrum matrix metalloprotease inhibitor GM6001 and the broad spectrum a disintegrin and metalloprotease (ADAM) inhibitor TAPI-1. But these inhibitors had no effect on EGF-induced signaling pathways, suggesting that integrins and ADAM may be upstream components of EGFR in these responses. These results suggest that FN-induced activation of ERK, p38, Akt, cell proliferation and invasion was mediated, at least in part, via integrins, ADAM and EGFR, and that this FN-induced signaling pathway might be involved in the antimetastatic activity of gefitinib.
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PMID:Activation of MEK/ERK and PI3K/Akt pathways by fibronectin requires integrin alphav-mediated ADAM activity in hepatocellular carcinoma: a novel functional target for gefitinib. 1644 27

Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P < 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.
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PMID:Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. 1648 19

The adhesion molecule L1 is expressed in primary melanomas and cutaneous metastases in contrast to melanocytic nevi and melanocytes, and is significantly associated with metastatic spread. Recent studies have demonstrated that in carcinomas L1 expression is associated with sustained activation of the extracellular signal-regulated kinase (ERK) pathway and upregulation of ERK-dependent, motility- and invasion-associated gene products including alphavbeta3 integrin. The objective of this study was to further investigate the role of the adhesion molecule L1 in melanoma progression, and to evaluate whether targeting the L1 adhesion molecule would have therapeutic effects against invasive melanoma growth. Using human melanoma cells from different stages of progression in monolayer and organotypic human skin culture mimicking the pathophysiological environment of cutaneous melanoma, we found that (1) L1 expression mostly correlates with melanoma progression and alphavbeta3 integrin expression, (2) overexpression of L1 in early radial growth phase melanoma cells promotes conversion from radial to vertical growth phase melanoma without upregulation of alphavbeta3 integrin expression, and (3) suppression of L1 function significantly reduces migration and invasion of melanoma cells, but does not completely block invasive melanoma growth. Altogether, L1 plays a critical role in melanoma invasion and progression and offers therapeutic potential in combination with conventional anticancer agents.
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PMID:The adhesion molecule L1 (CD171) promotes melanoma progression. 1650 7

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 microM to 36.9 microM. In combination, gefitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.
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PMID:Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro. 1650 86

Chemokines are now known to play an important role in cancer growth and metastasis. Here we report that differentiating osteoclasts constitutively produce CCL22 (also called macrophage-derived chemokine) and potentially promote bone metastasis of lung cancer expressing its receptor CCR4. We first examined expression of chemokines by differentiating osteoclasts. CCL22 was selectively upregulated in osteoclast-like cells derived from RAW264.7 cells and mouse bone marrow cells upon stimulation with RANKL (receptor activator of nuclear factor-kappaB ligand). In addition, a human lung cancer cell line SBC-5 that efficiently metastasized to bone when intravenously injected into NK cell-depleted SCID mice was found to express CCR4. Stimulation of SBC-5 cells with CCL22 induced cell migration and also enhanced phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase (ERK). Furthermore, immunohistochemical analysis of bone metastasis lesions demonstrated close co-localization of tartrate-resistant alkaline phosphatase (TRAP)-positive osteoclasts expressing CCL22 and SBC-5 cells expressing CCR4. Collectively, these results suggest that osteoclasts may promote bone metastasis of cancer cells expressing CCR4 in the bone marrow by producing its ligand CCL22.
Clin Exp Metastasis 2006
PMID:RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4. 1682 Nov 25

Malignant melanoma has a high propensity for metastatic spread, making it the most deadly form of skin cancer. B-RAF has been identified as the most mutated gene in these invasive cells and therefore an attractive therapeutic target. However, for uncertain reasons, chemotherapy inhibiting B-Raf has not been clinically effective. This has raised questions whether this pathway is important in melanoma metastasis or whether targeting a protein other than B-Raf in the signaling cascade could more effectively inhibit this pathway to reduce lung metastases. Here, we investigated the role played by (V600E)B-Raf in melanoma metastasis and showed that targeting this signaling cascade significantly reduces lung metastases. Small interfering RNA (siRNA)-mediated inhibition was used in mice to reduce expression (activity) of each member of the signaling cascade and effects on metastasis development were measured. Targeting any member of the signaling cascade reduced metastasis but inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (Mek) 1 and Mek 2 almost completely prevented lung tumor development. Mechanistically, metastatic inhibition was mediated through reduction of melanoma cell extravasation through the endothelium and decreased proliferative capacity. Targeting B-Raf with the pharmacologic inhibitor BAY 43-9006, which was found ineffective in clinical trials and seems to act primarily as an angiogenesis inhibitor, did not decrease metastasis, whereas inhibition of Mek using U0126 decreased cellular proliferative capacity, thereby effectively reducing number and size of lung metastases. In summary, this study provides a mechanistic basis for targeting Mek and not B-Raf in the mutant (V600E)B-Raf signaling cascade to inhibit melanoma metastases.
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PMID:Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. 1691 99

Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P=0.017) and shorter disease-free survival (P=0.003) as well as with markers of cell proliferation (cyclin A (P=0.017) and p21 (P=0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P=0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK(1/2) (P=0.005) and p-p38 (P=0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (P<0.0005) and p-Akt (P=0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P=0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.
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PMID:Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma. 1695 73

N-cadherin is up-regulated in aggressive breast carcinomas, but its mechanism of action in vivo remains unknown. Transgenic mice coexpressing N-cadherin and polyomavirus middle T antigen (PyVmT) in the mammary epithelium displayed increased pulmonary metastasis, with no differences in tumor onset or growth relative to control PyVmT mice. PyVmT-N-cadherin tumors contained higher levels of phosphorylated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) than PyVmT controls, and phosphorylated ERK staining was further increased in pulmonary metastases. Tumor cell isolates from PyVmT-N-cadherin mice exhibited enhanced ERK activation, motility, invasion, and matrix metalloproteinase-9 (MMP-9) expression relative to PyVmT controls. MAPK/ERK kinase 1 inhibition in PyVmT-N-cadherin cells reduced MMP-9 production and invasion but not motility. Furthermore, inactivation of fibroblast growth factor receptor in PyVmT-N-cadherin cells reduced motility, invasion, and ERK activation but had no effect on PyVmT cells. Thus, de novo expression of N-cadherin in mammary ducts enhances metastasis of breast tumors via enhanced ERK signaling.
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PMID:N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. 1740 17

ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor receptor kinase insert domain receptor/flk-1 tyrosine kinase activity with additional activity against the epidermal growth factor receptor-1 tyrosine kinase. The aim of this study was to evaluate ZD6474, alone and in combination with gemcitabine, in an orthotopic model of metastatic pancreatic cancer. Nude mice (nine to 10/group) were injected orthotopically with 1x10(6) L3.6pl human pancreatic cancer cells. Eight days later, treatment was initiated with vehicle only, gemcitabine (100 mg/kg intraperitoneal twice weekly), ZD6474 (50 mg/kg oral once daily) or a combination of the two treatments. Animals were killed on day 24 posttreatment initiation. The phosphorylation status level of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor as well as the phosphorylation level of AKT and extracellular signal-regulated kinase-1/2 in different human pancreatic carcinoma cells and in human umbilical vein endothelial cells was analyzed by Western blotting. Compared with controls (1231 mg), the mean weight of treated tumors was reduced to 836, 541 and 308 mg in the gemcitabine, ZD6474 and combination groups, respectively. Lymph node metastasis was significantly reduced in both the ZD6474 alone and combined treatment groups, with 3/10 and 1/5 animals developing metastases, compared with 10/10 and 9/9 in the control and gemcitabine groups (P<0.003 and <0.0003, respectively). Microvessel density and cell proliferation were significantly reduced in the ZD6474 and combined treatment groups (P<0.02). Immunohistochemistry of tumor samples following treatment with ZD6474 resulted in a reduction of the activated and phosphorylated epidermal growth factor receptor, whereas total epidermal growth factor receptor levels were comparable with control tumors. On the basis of Western blot analysis, ZD6474 provides inhibition of tumor angiogenesis through an anti-vascular endothelial growth factor receptor-2 mechanism and inhibition of cancer cell growth through an anti-epidermal growth factor receptor mechanism. ZD6474 decreased primary pancreatic tumor growth and reduced lymph node and liver metastases compared with controls or gemcitabine alone. Tumor growth was inhibited further in animals receiving ZD6474 and gemcitabine in combination.
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PMID:Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model. 1741 26

Activation (phosphorylation) of mitogen-activated protein kinase (MAPK) signal transduction through BRAF and RAS causes a variety of functional effects including cell survival and cell death. In this study, we observed high extracellular signal-regulated kinase (ERK)1/2 phosphorylation levels in clinical melanoma metastases and various melanoma cell lines. Treatment of melanoma cell lines with cisplatin, a potent antitumor agent, increased the level of phosphorylated-ERK (P-ERK)1/2 and enhanced chemoresistance through activation of the cell survival protein 90-kDa ribosomal S6 kinase (RSK)1. The mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) was able to block this effect and reduced cell viability and sensitized cells to cisplatin-induced apoptosis, as shown by PARP cleavage, caspase 3 expression, and annexin-V staining. In conclusion, the MAP kinase-ERK pathway is activated in melanoma and reduces the sensitivity of melanoma to cisplatin. Thus, inhibition of ERK1/2 in combination with selected chemotherapeutic agents may hold promise for more effective therapy of melanoma.
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PMID:ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis. 1750 26


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