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: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few systematic trials have studied metastatic tumors to the heart and there are currently no guidelines for the treatment of heart metastases and its associated symptoms. This article presents the first known case of effective pharmacological treatment of heart failure due to metastases of renal cell carcinoma (RCC). Due to pressure caused by metastatic tissue on the left atrium and the decreased blood inflow to the left ventricle, the 61-year-old male patient suffered from dyspnea. Treatment with sunitinib, an oral multitargeted receptor tyrosine kinase inhibitor, was initiated and led to a decrease in the mass of the metastasis infiltrating the left atrium. Arterial hypertension caused by sunitinib therapy was effectively controlled by the use of an angiotensin-converting-enzyme inhibitor. Therapy with sunitinib reduced the symptoms of exercise intolerance; the patient felt much better and was able to return to his family and resume professional activity. Further studies are required to confirm the utility of sunitinib therapy in patients with symptoms of heart failure due to heart metastases from RCC.
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PMID:Sunitinib malate, a receptor tyrosine kinase inhibitor, is effective in the treatment of restrictive heart failure due to heart metastases from renal cell carcinoma. 1937 77

The Met receptor tyrosine kinase (RTK) is aberrantly expressed in human osteosarcoma and is an attractive molecular target for cancer therapy. We studied spontaneous canine osteosarcoma (OSA) as a potential pre-clinical model for evaluation of Met-targeted therapies. The canine MET oncogene exhibits 90% homology compared with human MET, indicating that cross-species functional studies are a viable strategy. Expression and activation of the canine Met receptor were studied utilizing immunohistochemical techniques in 39 samples of canine osteosarcoma, including 35 primary tumours and four metastases. Although the Met RTK is barely detectable in primary culture of canine osteoblasts, high expression of Met protein was observed in 80% of canine osteosarcoma samples acquired from various breeds. Met protein overexpression was also concordant with its activation as indicated by phosphorylation of critical tyrosine residues. In addition, Met was expressed and constitutively activated in canine osteosarcoma cell lines. OSA cells expressing high levels of Met demonstrated activation of downstream transducers, elevated spontaneous motility, and invasiveness which were impaired by both a small molecule inhibitor of Met catalytic activity (PHA-665752) and met-specific, stable RNA interference obtained by means of lentiviral vector. Similar to observations in human OSA, these data suggest that Met is commonly overexpressed and activated in canine OSA and that inhibition of Met impairs the invasive and motogenic properties of canine OSA cells. These data implicate Met as a potentially important factor for canine OSA progression and indicate that it represents a viable model to study Met-targeted therapies.
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PMID:met oncogene activation qualifies spontaneous canine osteosarcoma as a suitable pre-clinical model of human osteosarcoma. 1940 29

While many genetic alterations have been identified in melanoma, the relevant molecular events that contribute to disease progression are poorly understood. Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of the canonical mitogen-activated protein kinase signaling pathway. In this study, we used a Cdkn2a-deficient mouse melanocyte cell line to screen for secondary genetic events in melanoma tumor progression. Upon investigation, intrachromosomal gene amplification of Met, a receptor tyrosine kinase implicated in melanoma progression, was identified in Cdkn2a-deficient tumors. RNA interference targeting Met in these tumor cells resulted in a significant delay in tumor growth in vivo compared with the control cells. MET expression is rarely detected in primary human melanoma but is frequently observed in metastatic disease. This study validates a role for Met activation in melanoma tumor progression in the context of Cdkn2a deficiency.
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PMID:Met amplification and tumor progression in Cdkn2a-deficient melanocytes. 1942 7

c-Met is a receptor tyrosine kinase involved in tumor cell growth, invasion, metastases and angiogenesis. Overexpression of c-Met is frequently observed in several tumor types. Here, we report the in vitro cell-binding properties and biodistribution and SPECT/CT imaging in glioma (U87MG) xenograft-bearing mice of (125)I-labeled c-Met-binding peptides (cMBPs) including analogs conjugated to amino acid and aliphatic carbon linkers. In vitro assays showed that the peptide without any linker and those with GGG and 8-aminooctanoic acid linkers had low cellular internalization and that IC(50) values of peptides were 1.5 microM, 65 nM and 85.3 nM, respectively. Biodistribution studies showed the GGG-containing peptide had higher tumor uptake and a higher tumor-to-blood activity concentration ratio than other receptor-binding ligands. SPECT/CT studies with a dedicated small-animal imaging system were performed in U87MG-bearing athymic mice. Although U87MG tumor xenografts could be visualized by SPECT/micro-CT using the various (125)I labeled cMBPs, image contrast and overall quality were unremarkable.
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PMID:Characterization, biodistribution and small-animal SPECT of I-125-labeled c-Met binding peptide in mice bearing c-Met receptor tyrosine kinase-positive tumor xenografts. 1942 4

The HER2 gene encodes the receptor tyrosine kinase HER2 and is often over-expressed or amplified in breast cancer. Up-regulation of HER2 contributes to tumor progression. Many aspects of tumor growth are favorably affected through activation of HER2 signaling. Indeed, HER2 plays a role in increasing proliferation and survival of the primary tumor and distant lesions which upon completion of full transformation cause metastases. P185(HER2/neu) receptors and signaling from them and associated molecules increase motility of both intravasating and extravasating cells, decrease apoptosis, enhance signaling interactions with the microenvironment, regulate adhesion, as well as a multitude of other functions. Recent experimental and clinical evidence supports the view that the spread of incompletely transformed cells occurs at a very early stage in tumor progression. This review concerns the identification and characterization of HER2, the evolution of the metastasis model, and the more recent cancer stem cell model. In particular, we review the evidence for an emerging mechanism of HER2(+) breast cancer progression, whereby the untransformed HER2-expressing cell shows characteristics of stem/progenitor cell, metastasizes, and then completes its final transformation at the secondary site.
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PMID:The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies. 1945 May 79

Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase. In addition to its role as a major mediator of signal transduction by integrins, FAK also participates in signaling by a wide range of extracellular stimuli including growth factors, G-protein-coupled receptor agonists, cytokines, and other inflammatory mediators. The link between FAK and breast cancers is strongly suggested by a number of reports showing that FAK gene is amplified and overexpressed in a large fraction of breast cancer specimens. In addition, increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis. Since its discovery in early 1990s, numerous studies have shown a role for FAK in the regulation of cell spreading, adhesion, migration, survival, proliferation, differentiation, and angiogenesis. Many of these studies in cultured cells provided strong evidence to connect FAK expression/activation to the promotion of cancer. Recently, a prominent role of FAK in promoting mammary tumorigenesis, progression and metastasis has been unveiled by different animal models of human breast cancer, including xenograft models in immunodeficient rodents and spontaneous tumor models in transgenic mice that have specific deletion of FAK in the mammary epithelial cells during embryonic or postnatal development. These in vivo studies established FAK as a prominent determinant in mammary cancer initiation, progression and metastasis. Furthermore, a novel function of FAK in maintaining mammary cancer stem/progenitor cells in vivo has been recently reported, which may provide a novel cellular mechanism of FAK in promoting breast cancer initiation and progression. The wealth of knowledge accumulated over almost two decades of research on FAK should help to design potentially novel therapies for breast cancer.
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PMID:Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. 1964 31

Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma.
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PMID:NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. 1965 70

We recently identified the metastasis-associated in colon cancer 1 (MACC1) gene by a genome-wide search for differentially expressed genes in human colon cancer tissues, metastases, and normal tissues. Based on MACC1 expression in primary colon cancers, which did not present with metastases, our negative and positive prediction for metachronous metastasis was correct in 80% and 74% of cases, respectively. The 5-year-survival was 80% for MACC1 low expressors, but 15% for individuals who showed high MACC1 expression in their primary tumors. MACC1 induces migration, invasion and proliferation in cell culture, and liver and lung metastases in xenograft models. Here, we describe features of MACC1 beyond its utility as an indicator of metastasis. We elucidate its genomic localization and organization, its predicted splice variants, and single nucleotide polymorphisms. We discuss the MACC1 protein domain structure, posttranslational modifications, its conservation through evolution, and some family ties to SH3BP4. Furthermore, we summarize the predicted expressions of MACC1 in normal and malignant human tissues. We also evaluate the MACC1 levels in the context of one of its transcriptional targets, the receptor tyrosine kinase Met that activates the hepatocyte growth factor/Met signaling pathway, leading to enhanced cell motility, invasion, and metastasis.
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PMID:MACC1 - more than metastasis? Facts and predictions about a novel gene. 1978 27

Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94 (7.5%) primary human RMS tumors. The mutants K535 and E550 increased autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3 cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell lines expressing the empty vector or wild-type FGFR4. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe to be the first known mutations in a receptor tyrosine kinase in RMS. These findings support the potential therapeutic targeting of FGFR4 in RMS.
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PMID:Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. 1980 59

Overexpression of the receptor tyrosine kinase EphA2 occurs in non-small cell lung cancer (NSCLC) and a number of other human cancers. This overexpression correlates with a poor prognosis, smoking, and the presence of Kirsten rat sarcoma (K-Ras) mutations in NSCLC. In other cancers, EphA2 has been implicated in migration and metastasis. To determine if EphA2 can promote NSCLC progression, we examined the relationship of EphA2 with proliferation and migration in cell lines and with metastases in patient tumors. We also examined potential mechanisms involving AKT, Src, focal adhesion kinase, Rho guanosine triphosphatases (GTPase), and extracellular signal-regulated kinase (ERK)-1/2. Knockdown of EphA2 in NSCLC cell lines decreased proliferation (colony size) by 20% to 70% in four of five cell lines (P < 0. 04) and cell migration by 7% to 75% in five of six cell lines (P < 0. 03). ERK1/2 activation correlated with effects on proliferation, and inhibition of ERK1/2 activation also suppressed proliferation. In accordance with the in vitro data, high tumor expression of EphA2 was an independent prognostic factor in time to recurrence (P = 0.057) and time to metastases (P = 0.046) of NSCLC patients. We also examined EphA2 expression in the putative premalignant lung lesion, atypical adenomatous hyperplasia, and the noninvasive bronchioloalveolar component of adenocarcinoma because K-Ras mutations occur in atypical adenomatous hyperplasia and are common in lung adenocarcinomas. Both preinvasive lesion types expressed EphA2, showing its expression in the early pathogenesis of lung adenocarcinoma. Our data suggest that EphA2 may be a promising target for treating and preventing NSCLC.
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PMID:EphA2 in the early pathogenesis and progression of non-small cell lung cancer. 1993 38


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