Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER receptors are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). We performed a retrospective study on archival breast cancer samples from patients with long follow-up and compared the protein expression between individual HERs and between HERs and the PTK6. Univariate and multivariate analyses were used to study the prognostic value of parameters. Metastases-free survival of patients for longer than 240 months was inversely associated (P< or =0.05) with nodal status, tumour size, and oestrogen receptor status, but was also directly associated with high protein expression levels of HER4 and PTK6 in Kaplan-Meier analysis. In multivariate analysis for metastases-free survival of >240 months, the stepwise selected parameters were tumour size (relative risk 3.1), PTK6 expression (0.4), and number of positive lymph nodes (1.2). Furthermore, we demonstrated a timedependence of the prognostic value attributed to the parameters. The HER receptors (HER2,4), but not PTK6, were independent prognostic markers for metastases-free survival at 60 months, whereas at 240 months PTK6 is the strongest prognostic marker. We demonstrate that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumour size, and HER2 status.
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PMID:PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas. 1729 91

Melanoma is a highly metastatic cancer resistant to current chemotherapeutic and radiotherapeutic approaches. Several studies have shown that interactions between cancer cells and the extracellular matrix (ECM) are critical for the survival and invasion of metastatic cancer cells. In this study, we examine the effects of methylselenol generated from selenomethionine (SeMet) by methioninase (METase) on cell proliferation, adhesion, and expression of integrins in murine melanoma B16F10 cells, which are metastatic in the lungs of syngeneic C57BL/6J mice. Combined treatment with SeMet-METase decreased the expression of integrins alpha(4), beta(1), alpha(nu), and beta(3), and inhibited melanoma-ECM adhesion. Caspase-mediated apoptosis was induced following loss of cell adherence. Phosphorylation of focal adhesion kinase (FAK) and Akt, related to integrin-mediated survival, were decreased upon treatment with SeMet-METase while phosphorylation of p38, PKC-delta, and IkappaBalpha increased. In the presence of specific inhibitors of p38, PKC-delta, and NF-kappaB, expression of integrins and cell adhesion to ECM were maintained and cell apoptosis was prevented in SeMet-METase-treated melanoma cells. Treatment with caspase inhibitors restored cell viability and blocked poly (ADP-ribose) polymerase (PARP) cleavage, but did not restore integrin expression and cell adhesion to ECMs reduced by SeMet-METase. Based on these results, we propose that combined treatment with SeMet-METase induces caspase-mediated apoptosis in melanoma cells by altering integrin expression and adhesion. Furthermore, activation of p38, PKC-delta, and NF-kappaB is a prerequisite for the down-regulation of integrin expression, followed by detachment-mediated apoptosis.
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PMID:Methylselenol generated from selenomethionine by methioninase downregulates integrin expression and induces caspase-mediated apoptosis of B16F10 melanoma cells. 1734 6

Src kinase is intimately involved in the control of matrix adhesion and cell migration through its ability to modulate the activity of focal adhesion kinase (FAK). In light of our previous observations that acquisition of tamoxifen resistance in breast cancer cells is accompanied by elevated Src kinase activity, we wish to investigate whether FAK function is also altered in these cells and if this leads to an enhanced migratory phenotype. In in vitro adhesion assays, tamoxifen-resistant (TamR) MCF7 cells had a greater affinity for the matrix proteins fibronectin, laminin, vitronectin and collagen and subsequently demonstrated a much greater migratory capacity across these substrates compared to their weakly-migratory, endocrine-sensitive counterparts. Additionally, elevated levels of activated Src in TamR cells promoted an increase in FAK phosphorylation at Y861 and Y925 and uncoupled FAK activation from an adhesion-dependent process. Inhibition of Src activity using the Src/Abl inhibitor AZD0530 reduced FAK activity, suppressed cell spreading on matrix-coated surfaces and significantly inhibited cell migration. Our data thus suggest that Src kinase plays a central role in the enhanced migratory phenotype that accompanies endocrine resistance through its modulation of FAK signalling and demonstrates the potential use of Src inhibitors as potent suppressors of tumour cell migration.
Clin Exp Metastasis 2007
PMID:Src kinase promotes adhesion-independent activation of FAK and enhances cellular migration in tamoxifen-resistant breast cancer cells. 1739 86

Today's treatment and diagnosis of prostate cancer still exhibit major limitations. The search for new and additional prognostic markers is therefore still an actual field of interest. Potential markers involved in numerous biological processes in the tumor cell have been investigated intensively. For therapeutic interventions it is important to distinguish between harmless and aggressive disease in an early stage. Therefore the subject of this review is limited to markers associated with those functional processes, which discriminate early stage aggressive, metastatic cancer from harmless disease. Important processes in this respect are: altered cell adhesion and cellular migration. E-cadherin, N-cadherin, beta-catenin, integrins, focal adhesion kinase, connexins and matrix metalloproteinases all appear promising biological markers associated with the early stage metastatic process in prostate cancer. Here we discuss their potential to become valid biological markers based on literature data. Thus far, none of these markers proved to be a valid individual marker by itself due to prostate cancer heterogeneity and transient expression. Analyzing a combination of the potential markers discussed in this review is expected to be a better approach toward discriminating high- from low-risk tumors in an early stage of prostate cancer.
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PMID:New experimental markers for early detection of high-risk prostate cancer: role of cell-cell adhesion and cell migration. 1752 Feb 86

Drug resistance and metastasis are major impediments for the successful treatment of cancer. A common feature among drug resistant and metastatic tumor cells is that they exhibit profound resistance to apoptosis. This property enables cancer cells not only to grow and survive in stressful environments (metastasis) but also to display resistance against many anticancer agents. Therefore, perturbation of the intrinsic apoptotic pathways of cancer cells will affect their ability to respond to chemotherapy and to metastasize and survive in distant sites. Recent studies have demonstrated that cancer cells and cancer cell lines selected for resistance against chemotherapeutic drugs or isolated from metastatic sites, express elevated levels of the multifunctional protein, tissue transglutaminase (TG2). TG2 is the most diverse and ubiquitous member of the transglutaminase family of proteins that is implicated to play a role in apoptosis, wound healing, cell migration, cell attachment, cell growth, angiogenesis, and matrix assembly. TG2 can associate with certain beta members of the integrin family of proteins (beta1, beta3, beta4, and beta5) and promote stable interaction between cells and the extracellular matrix (ECM), resulting in increased cell survival, cell migration, and invasion. Additionally, TG2 forms a ternary complex with IkappaB/p65:p50 and results in constitutive activation of the nuclear transcription factor-kappaB (NF-kappaB). Moreover, TG2 expression in cancer cells leads to constitutive activation of the focal adhesion kinase (FAK) and its downstream PI3K/Akt survival pathway. Importantly, the inhibition of endogenous TG2 by small interfering RNA (siRNA) resulted in the reversal of drug resistance and the invasive phenotype. Conversely, ectopic expression of TG2 promoted cell survival, cell motility and invasive functions of cancer cells. This review discusses the current thinking and implications of increased TG2 expression in development of drug resistance and metastasis by cancer cells.
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PMID:Tissue transglutaminase-mediated chemoresistance in cancer cells. 1766 45

This work was conducted to find out new potential serum markers and study their role as predictive factors in patients with metastatic melanoma. Serum samples from 68 patients with stage IV malignant melanoma were collected just before current treatment and screened for 79 different cytokines by using a multi-cytokine array. Angiogenin, which is a protein capable of promoting angiogenesis, was found to be markedly elevated among a sub-group of patients with progressive disease (PD) and thus was subjected to further analysis. The mean serum angiogenin level was 270 ng/ml and the median 236 ng/ml (STD 163 ng/ml). Concentrations were significantly higher among men than in women (P = 0.031), whereas patient's age, site of the primary tumour, Clark's or Breslow's classifications were not associated with angiogenin levels. Patients with only lymph node metastases had markedly lower angiogenin levels than those with metastases at other sites (P = 0.05). High angiogenin levels were significantly (P = 0.015; Kruskal-Wallis) associated with poor treatment response with chemoimmunotherapy. Treatment-related survival (TRS) was shorter (10 months) in patients with above-median values than in those with below-median levels (19 months, P = NS). Cox multivariate regression model was used to control for the confounding by the classical prognostic factors of melanoma (age, sex, disease burden, performance score, site of metastases). Disease burden was the only variable that remained in the model as a significant independent predictor of TRS (P = 0.044). These data suggest that serum angiogenin levels might be of predictive value in the evaluation of treatment response for patients with stage IV melanoma.
Clin Exp Metastasis 2007
PMID:Serum angiogenin levels predict treatment response in patients with stage IV melanoma. 1776 72

CD39/ecto-nucleoside triphosphate diphosphohydrolase-type-1 (ENTPD1) is the dominant vascular ecto-nucleotidase that catalyzes the phosphohydrolysis of extracellular nucleotides in the blood and extracellular space. This ecto-enzymatic process modulates endothelial cell, leukocyte, and platelet purinergic receptor-mediated responses to extracellular nucleotides in the setting of thrombosis and vascular inflammation. We show here that deletion of Cd39/Entpd1 results in abrogation of angiogenesis, causing decreased growth of implanted tumors and inhibiting development of pulmonary metastases. Qualitative abnormalities of Cd39-null endothelial cell adhesion and integrin dysfunction were demonstrated in vitro. These changes were associated with decreased activation of focal adhesion kinase and extracellular signaling-regulated kinase-1 and -2 in endothelial cells. Our data indicate novel links between CD39/ENTPD1, extracellular nucleotide-mediated signaling, and vascular endothelial cell integrin function that impact on angiogenesis and tumor growth.
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PMID:Disordered purinergic signaling inhibits pathological angiogenesis in cd39/Entpd1-null mice. 1782 93

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors in the gastrointestinal tract, metastasize in up to 50 % of cases and are resistant to conventional radio- and chemotherapy. They are characterized by the expression of the type III receptor tyrosine kinase KIT which is the most important diagnostic immunohistochemical feature. Genomically, the majority of GISTs carry heterozygous mutations in the KIT or the PDGF receptor alpha gene leading to an autophosphorylation of the respective receptor protein. The evaluation of the mutational status allows the subdivision of GISTs into different prognostic sub-groups. For example, GISTs carrying an activating mutation in PDGF receptor alpha are most often located in the stomach and seem to have a better prognosis than GISTs with a KIT mutation. Specific mutational subtypes of KIT mutations in exon 11 (esp. proximal deletions of codons tryptophane-557 and lysine-558) have a significantly higher metastatic risk than GISTs with KIT mutations located in the distal part of exon 11 (esp. insertions/duplications). GISTs in the small bowel most often carry KIT exon 9 mutations and have a worse prognosis than GISTs with exon 11 mutations. Mutational subtype in KIT or PDGF receptor alpha not only influences the biological behavior of GISTs but also their response to treatment with imatinib, a tyrosine kinase inhibitor also inhibiting ARG, PDGF receptor beta and BCR-ABL. KIT exon 11 mutated tumors show response rates of up to 80 % of cases whereas KIT exon 9 mutated GISTs respond in less then 50 %. GISTs without detectable KIT mutation in these both exons often are resistant to imatinib. The development of secondary resistance to imatinib in GIST patients occurs in up to 40% of cases and is partly due to secondary KIT mutations occuring additionally to the primary mutation. Actually, several studies evaluate the efficacy of alternative small molecules such as SU 11248, RAD001 and AMG706 inhibiting signal transduction pathways downstream of KIT and PDGF receptor alpha. In summary, mutational status in KIT or PDGF receptor alpha of GISTs is relevant for prognosis, for response to treatment and for further insights into mechanisms of treatment failure.
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PMID:[Therapeutic targets in gastrointestinal stromal tumors]. 1786 82

The term EMT (epithelial-mesenchymal transition) is used in many settings. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors. In mice, most 'EMT' tumors have a spindle cell phenotype. The definition of EMT is controversial because spindle cell tumors are not common in humans, especially in human breast cancers. Spindle cell tumors of the mouse mammary gland have been observed for many years where they are usually classified as sarcomas or carcinosarcomas. Genetically engineered mice develop mammary spindle cell tumors that appear to arise in the epithelium and undergo EMT. To better understand the origin and evolution of these spindle cell tumors in progression and metastases, seven cohorts of spindle cell tumors from the archives of the University of California, Davis Mutant Mouse Pathology Laboratory were studied. This study provides experimental and immunohistochemical evidence of EMT showing that dual epithelial and mesenchymal staining of tumor spindle cells identifies some, but not all, EMT-type tumors in the mouse. This suggests that potential EMT tumors are best designated EMT-phenotype tumors.
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PMID:EMT tumorigenesis in the mouse mammary gland. 1792 20

EMT (epithelial-mesenchymal transition) is a morphogenetic process in which cells loose their epithelial characteristics and gain mesenchymal properties during embryogenesis. Similar processes regulated by similar pathways are recapitulated during tumour progression, endowing cells with invasive properties, thereby contributing to the formation of metastases. In this review, we outline key features of EMT and discuss the evidence for its involvement in the dissemination of tumours. Finally we review the recent literature concerning the mechanisms that regulate EMT in the tumour context, with a particular focus on breast cancer.
Clin Exp Metastasis 2007
PMID:Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. 1797 54


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