Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Focal adhesion kinase (FAK) is one of the central signaling molecules found at focal adhesion sites, which are specific areas on the cell membrane where cells attach to extracellular matrix proteins. Focal adhesion kinase interacts with multiple signaling and adaptor molecules and effects several signaling pathways. Overexpression of FAK and its substrate c-Src has been implicated in malignant transformation and acquisition of an invasive tumor phenotype of different tissues. Overexpression of the multidomain protein paxillin, which is also a FAK ligand and a c-Src substrate, has been associated with less malignant tumor behavior. The purpose of this study was to analyze the involvement of integrin signaling molecules FAK, c-Src, and paxillin in malignant transformation of the breast epithelium. Using phosphospecific antibodies FAK-pY(397) and Src-pY(416), we demonstrated that neither activation of FAK nor activation of c-Src correlates with development of invasive tumor properties. However, activation of both FAK and c-Src correlates with malignant transformation. We further demonstrated that overexpression of paxillin also correlates with malignant transformation and is a marker of a less invasive tumor phenotype. Using tissue microarray, we demonstrated that expression and activation of paxillin inversely correlated with lymph node metastases and lymphovascular invasion, respectively. No correlation between paxillin expression and activation and tumor grade, estrogen, progesterone, and Her2/Neu receptor expression was found. In summary, focal adhesion proteins FAK and c-Src can be used as markers of malignant transformation in epithelial cells but not invasive phenotype, whereas expression and activation of paxillin may represent a good prognosticator in breast carcinoma.
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PMID:Focal adhesion proteins as markers of malignant transformation and prognostic indicators in breast carcinoma. 1693 35

Hepatocyte growth factor (HGF) and its tyrosine kinase receptor Met play a pivotal role in the tumor metastatic phenotype and represent attractive therapeutic targets. We investigated the biochemical and biological effects of the tyrosine kinase inhibitor RPI-1 on the human lung cancer cell lines H460 and N592, which express constitutively active Met. RPI-1-treated cells showed down-regulation of Met activation and expression, inhibition of HGF/Met-dependent downstream signaling involving AKT, signal transducers and activators of transcription 3 and paxillin, as well as a reduced expression of the proangiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Cell growth in soft agar of H460 cells was strongly reduced in the presence of the drug. Furthermore, RPI-1 inhibited both spontaneous and HGF-induced motility/invasiveness of both H460 and human endothelial cells. Targeting of Met signaling by alternative methods (Met small interfering RNA and anti-phosphorylated Met antibody intracellular transfer) produced comparable biochemical and biological effects. Using the spontaneously metastasizing lung carcinoma xenograft H460, daily oral treatment with well-tolerated doses of RPI-1 produced a significant reduction of spontaneous lung metastases (-75%; P < 0.001, compared with control mice). In addition, a significant inhibition of angiogenesis in primary s.c. tumors of treated mice was observed, possibly contributing to limit the development of metastases. The results provide preclinical evidence in support of Met targeting pharmacologic approach as a new option for the control of tumor metastatic dissemination.
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PMID:Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1. 1698 73

Elevated levels of Src kinase expression have been found in a variety of human epithelial cancers. Most notably in colon cancer, elevated Src expression correlates with malignant potential and is also associated with metastatic disease. Dasatinib (BMS-354825) is a novel, orally active, multi-targeted kinase inhibitor that targets Src family kinases and is currently under clinical evaluation for the treatment of solid tumors. However, the effects of dasatinib on epithelial tumors are not fully understood. We show that concentrations of dasatinib that inhibit Src activity do not inhibit proliferation in 10 of 12 colon cancer cells lines. However, inhibition of integrin-dependent adhesion and migration by dasatinib correlated with inhibition of Src activity, suggesting that dasatinib may have anti-invasive or anti-metastatic activity and antiproliferative activity in epithelial tumors. Using phospho-specific antibodies, we show that inhibition of Src activity in colon cancer cell lines correlates with reduced phosphorylation of focal adhesion kinase and paxillin on specific Src-dependent phosphorylation sites. We have validated the use of phospho-specific antibodies against Src Tyr(419) and paxillin Tyr(118) as biomarkers of dasatinib activity in vivo. Colon carcinoma-bearing mice treated with dasatinib showed a decrease in both phospho-Src Tyr(419) and phospho-paxillin Tyr(118) in peripheral blood mononuclear cells, which correlated with inhibition of Src activity in the colon tumors. Thus, peripheral blood mononuclear cells may provide a useful surrogate tissue for biomarker studies with dasatinib using inhibition of Src Tyr(419) and paxillin Tyr(118) phosphorylation as read-outs of Src activity.
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PMID:Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. 1714 60

CNTO 95 is a fully human monoclonal antibody that recognizes alphav integrins. Previous studies have shown that CNTO 95 exhibits both anti-tumor and anti-angiogenic activities (Trikha M et al., Int J Cancer 110:326-335, 2004). In this study we investigated the biological activities of CNTO 95 on breast tumor cells both in vitro and in vivo. In vitro treatment with CNTO 95 decreased the viability of breast tumor cells adhering to vitronectin. CNTO 95 inhibited tumor cell adhesion, migration, and invasion in vitro. CNTO 95 treatment also induced tyrosine dephosphorylation of focal adhesion kinase (FAK), and the docking protein paxillin that recruits both structural and signaling molecules to focal adhesions (Turner CE, Int J Biochem Cell Biol 30:955-959, 1998; O'Neil GM et al., Trends Cell Biol 10:111-119, 2000). These results suggest that CNTO 95 inhibits breast tumor cell growth, migration and invasion by interruption of alphav integrin mediated focal adhesions and cell motility signals. In vivo studies of CNTO 95 were conducted in an orthotopic breast tumor xenograft model. Treatment with CNTO 95 resulted in significant inhibition of both tumor growth and spontaneous metastasis of MDA-MB-231 cells to the lungs. CNTO 95 also inhibited lung metastasis in a separate experimental (tail vein injection) model of metastasis. The results presented here demonstrate the anti-tumor and anti-metastatic activities of CNTO 95 in breast cancer models and provide insight into the cellular and molecular mechanisms mediating its inhibitory effects on metastasis.
Clin Exp Metastasis 2008
PMID:CNTO 95, a fully human anti alphav integrin antibody, inhibits cell signaling, migration, invasion, and spontaneous metastasis of human breast cancer cells. 1806 30

Signal transduction exerted by the microenvironment around the primary tumor locus may trigger tumor metastasis especially at the migration stage. Sustained mitogen activated protein kinase (MAPK) signaling involved in uncontrolled tumor cell migration rely on the cross talks between integrin, receptor tyrosine kinase (RTK) and protein kinase C (PKC). The molecular mechanisms for cross talking between these migration-related signal cascades leading to sustained cell migration are reviewed, focusing on the focal adhesion scaffold protein paxillin as the platform for signal integration. We proposed reactive oxygen species (ROS) as the critical signal messenger sustaining these signal cascades. For the cross talk of integrin with RTK, ROS may suppress paxillin-associated protein tyrosine phosphatase (PTP-PEST) relieving its negative regulatory effects. For the cross talk of integrin with PKC, PKC itself may phosphorylate integrin or paxillin-associated focal adhesion proteins to induce generation of ROS which may reactivate PKC. In the future, ROS will be validated as the promising therapeutic targets for prevention of tumor metastasis.
Cancer Metastasis Rev 2008 Jun
PMID:Signal cross talks for sustained MAPK activation and cell migration: the potential role of reactive oxygen species. 1829 6

Changes in cellular behavior that cause epithelial cells to lose adhesiveness, acquire a motile invasive phenotype and metastasize to secondary sites are complex and poorly understood. Molecules that normally function to integrate adhesive spatial information with cytoskeleton dynamics and membrane trafficking probably serve important functions in cellular transformation. One such complex is the Exocyst, which is essential for targeted delivery of membrane and secretory proteins to specific plasma membrane sites to maintain epithelial cell polarity. Upon loss of cadherin-mediated adhesion in Dunning R3327-5'A prostate tumor cells, Exocyst localization shifts from lateral membranes to tips of protrusive membrane extensions. Here, it colocalizes and co-purifies with focal complex proteins that regulate membrane trafficking and cytoskeleton dynamics. These sites are the preferred destination of post-Golgi transport vesicles ferrying biosynthetic cargo, such as alpha(5)-integrin, which mediates adhesion of cells to the substratum, a process essential to cell motility. Interference with Exocyst activity impairs integrin delivery to plasma membrane and inhibits tumor cell motility and matrix invasiveness. Localization of Exocyst and, by extension, targeting of Exocyst-dependent cargo, is dependent on Ral GTPases, which control association between Sec5 and paxillin. Overexpression of Ral-uncoupled Sec5 mutants inhibited Exocyst interaction with paxillin in 5'A cells, as did RNAi-mediated reduction of either RalA or RalB. Reduction of neither GTPase significantly altered steady-state levels of assembled Exocyst in these cells, but did change the observed localization of Exocyst proteins.
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PMID:Ral-regulated interaction between Sec5 and paxillin targets Exocyst to focal complexes during cell migration. 1869 30

The mechanisms of invasion and metastasis are poorly understood. Our previous studies demonstrated that cancer cell invasion may result from reorganization of membrane molecules, thereby initiating signaling pathways. To increase our understanding on how cancer cells govern metastases we studied the established LNCaP prostate cancer progression model. Herein we show that the bone metastatic derivative cell line, C4-2B, displays changes in adhesion to collagen type I and invasion into collagen type I. Moreover, we found that these changes were concomitant with activation of the FAK/src/paxillin/Rac/JNK signaling pathway and increased activity of matrix metalloproteinases (MMPs)-2 and -9. Inhibition of src and JNK resulted in inhibition of adhesion and invasion, and deactivation of the signaling molecules in the identified pathway as well as reduced activity of MMPs. Additionally, we found a pivotal role for the integrin alpha2 subunit since lateral redistribution and clustering were responsible for activation of the downstream signaling and function blocking of the integrin alpha2 subunit resulted in poor adhesion and inhibition of invasion. In conclusion, our results suggest that invasion of prostate cancer cells can be ascribed to reorganization and clustering of integrin alpha2 subunits, resulting in activation of associated FAK/src/paxillin/Rac/JNK, leading to increased activity of MMPs and thus invasion.
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PMID:Reorganization of the integrin alpha2 subunit controls cell adhesion and cancer cell invasion in prostate cancer. 1942 90

Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.
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PMID:Src kinases as therapeutic targets for cancer. 1978 2

The protein and mRNA expression of focal adhesion plaque associated cytoskeletons, including talin, vinculin, paxillin, and tensin, was studied using immunofluorescence in combination with confocal laser scanning microscopy and fluorescent quantitative polymerase chain reaction in 41 matched samples of human normal colorectal mucosae, primary colorectal adenocarcinomas, and 19 separate lymph node metastases. All specimens showed expression. The results showed talin, vinculin, tensin, and paxillin expression were correlated with carcinogenesis, invasion, and metastasis of colorectal carcinoma (CRC). Talin, vinculin, and tensin underwent downregulation while paxillin went up. So these cytoskeletons may play bidirectional regulating roles during the progression of CRC.
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PMID:Focal adhesion plaque associated cytoskeletons are involved in the invasion and metastasis of human colorectal carcinoma. 1991 45

The phosphatases of regenerating liver (PRLs) are a unique family of plasma membrane-associated protein tyrosine phosphatases that have been hypothesized to be involved in metastatic cancer. How PRLs control cancer cell migration, invasion, and proliferation remains largely unknown. In the current study, we demonstrate a role for PRL-1 in the regulation of filamentous actin dynamics, which could promote cell metastatic processes. Human A549 non-small-cell lung cancer cells stably expressing wild-type PRL-1 exhibited a 60% increase in migration and a 3-fold increase in invasion. Cells expressing catalytic mutants of PRL-1 (C104S and D72A) lacked increased cell migration and invasion, indicating that these phenotypic changes required PRL-1 phosphatase activity. In contrast, PRL-1 small interfering RNA decreased in vitro lung cancer cell migration and invasion. The cadherin-catenin complex and dynamic filamentous actin are believed to control cellular invasiveness. Expression of wild-type PRL-1, but not phosphatase-inactive PRL-1 (C104S or D72A), decreased E-cadherin, vinculin, and paxillin expression. Ectopic expression of wild-type PRL-1 increased RhoA levels, which have an important role in actin filament assembly and stabilization of focal adhesion, and decreased activated Cdc42 and Rac. The Rho-associated protein kinase inhibitor, (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride (Y-27632), decreased RhoA activity, actin filament levels, and cellular migration and invasion in PRL-1-expressing cells. These results suggest that PRL-1 could be a productive cancer therapeutic target and support further efforts to identify its substrates.
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PMID:Phosphatase of regenerating liver-1 promotes cell migration and invasion and regulates filamentous actin dynamics. 2048 58


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