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)

Medulloblastoma, the most common malignant brain tumor in children, is a highly metastatic disease, with up to 30% of children having evidence of disseminated disease at presentation. Recently, the hepatocyte growth factor (HGF) and its receptor, the tyrosine kinase Met, have emerged as key components of human medulloblastoma growth and metastasis, suggesting that inhibition of this pathway may represent an attractive target for the prevention and treatment of this disease. Using immunoblotting procedures, we observed that the dietary-derived flavonols quercetin, kaempferol, and myricetin inhibited HGF/Met signaling in a medulloblastoma cell line (DAOY), preventing the formation of actin-rich membrane ruffles and resulting in the inhibition of Met-induced cell migration in Boyden chambers. Furthermore, quercetin and kaempferol also strongly diminished HGF-mediated Akt activation. Interestingly, the inhibitory effects of quercetin on the tyrosine kinase receptor Met [half-maximal inhibitory effect (IC(50)) of 12 micromol/L] or on the Met-induced activation of Akt (IC(50) of 2.5 micromol/L) occurred at concentrations achievable through dietary approaches. These results highlight quercetin, kaempferol, and myricetin as dietary-derived inhibitors of Met activity and suggest that this inhibitory effect may contribute to the chemopreventive properties of these molecules.
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PMID:The flavonols quercetin, kaempferol, and myricetin inhibit hepatocyte growth factor-induced medulloblastoma cell migration. 1924 81

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

Colon cancer is still the second most frequent malignancy in the Western world. Despite major efforts in diagnosis and treatment it is one of the leading causes of cancer related deaths. The metastatic dissemination of primary tumors is directly linked to patient's survival and accounts for about 90% of all colon cancer deaths. Current clinical predictions on whether colon cancer will metastasize are mainly defined by histopathological staging, describing the tumor spread within a surgical specimen. This review focuses on the need for molecule-based staging as essential prerequisite for individualized diagnosis, prognosis and therapy. Molecular determinants for progression and metastasis of colon cancer are discussed. Moreover, a newly identified molecule playing a decisive role in colon cancer metastasis is highlighted: MACC1. MACC1 acts as a key regulator of the metastasis-inducing HGF/Met pathway, predicts the risk for metastasis in early cancer stages, and represents a novel target to attack metastasis.
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PMID:Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. 1966 36

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

Complete resection of early-stage non-small cell lung cancer (NSCLC) is potentially curative, yet approximately 50% of patients are at risk for developing metastatic recurrence. Met, the receptor for hepatocyte growth factor (HGF) is a receptor tyrosine kinase with demonstrated roles in regulating cellular proliferation, motility, morphogenesis, and apoptosis. Met receptor and its ligand, HGF, are commonly overexpressed in NSCLC, and their overexpression has been associated with poor prognosis, which could potentially involve a paracrine and/or autocrine activation loop. However, there is as yet no direct evidence that HGF-Met signaling directly promotes metastasis in NSCLC cells. Using retroviral transduction, we overexpressed the human c-met and hgf complementary DNA, alone or in combination in the NCI-H460 human large cell carcinoma cell line. The HGF/Met co-overexpressing (H460-HGF/Met) cells demonstrated enhanced tumorigenicity in xenograft SCID mice. When these cells are implanted orthotopically into the lungs of nude rats, only the H460-HGF/Met cells showed higher spontaneous metastases to distant organs including bone, brain, and kidney. These results provide evidence that autocrine overactivation of the Met- HGF loop enhances systemic metastases in NSCLC. Targeted interference of this loop may potentially be an effective adjuvant therapy to improve survival of early-stage NSCLC patients.
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PMID:Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells. 2001 37

Most non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitor (TKI) therapy. However, about 30% exhibit primary resistance to EGFR TKI therapy. Here we report that Met protein expression and phosphorylation were associated with primary resistance to EGFR TKI therapy in NSCLC patients harboring EGFR mutations, implicating Met as a de novo mechanism of resistance. In a separate patient cohort, Met expression and phosphorylation were also associated with development of NSCLC brain metastasis and were selectively enriched in brain metastases relative to paired primary lung tumors. A similar metastasis-specific activation of Met occurred in vitro in the isogenous cell lines H2073 and H1993, which are derived from the primary lung tumor and a metastasis, respectively, from the same patient. We conclude that Met activation is found in NSCLC before EGFR-targeted therapy and is associated with both primary resistance to EGFR inhibitor therapy and with the development of metastases. If confirmed in larger cohorts, our analysis suggests that patient tumors harboring both Met activation and EGFR mutation could potentially benefit from early intervention with a combination of EGFR and Met inhibitors.
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PMID:Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. 2048 50

The deregulation of Met/hepatocyte growth factor (HGF) receptor tyrosine kinase signaling constitutes a common event in colorectal cancers. However, the physiopathological functions of such a deregulation remain poorly understood. In the present study, we investigated the role of the deregulation of Met receptor in the neoplastic transformation of intestinal epithelial cells. To do so, the normal, well-established and characterized rat intestinal epithelial IEC-6 cells were transduced with a retrovirus carrying the oncogenic constitutive active form of Met receptor, Tpr-Met. Herein, we show that compared with control IEC-6 cells, Tpr-Met-IEC-6 cells exhibit enhanced proliferation, loss of growth-contact inhibition, cell morphological alterations, actin cytoskeletal reorganization, loss of E-cadherin expression and anchorage-independent growth. Moreover, Tpr-Met-IEC-6 cells are conferred the capacity to produce the proangiogenic factor VEGF and to reduce the potent antiangiogenic factor thrombospondin-1. Of significance, Tpr-Met-IEC-6 cells are endowed with the ability to elicit angiogenic responses and to form tumors and metastases in vivo. Hence, our study demonstrates for the first time that the sole oncogenic engagement of Met receptor in normal intestinal epithelial cells is sufficient to induce a wide array of cancerous biological processes that are fundamental to the initiation and malignant progression of colorectal cancers.
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PMID:Oncogenic engagement of the Met receptor is sufficient to evoke angiogenic, tumorigenic, and metastatic activities in rat intestinal epithelial cells. 2053 3

During tumor progression, malignant cells must repeatedly survive microenvironmental stress. Hypoxia-inducible factor-1 (HIF-1) signaling has emerged as one major pathway allowing cellular adaptation to stress. Recent findings led to the hypothesis that HIF-1alpha may enhance the metastatic potential of tumor cells by a survival-independent mechanism. So far it has not been shown that HIF-1alpha also directly regulates invasive processes during metastasis in addition to conferring a survival advantage to metastasizing tumor cells. In a hypoxia-tolerant tumor cell line (L-CI.5s), which did not rely on HIF-1 signaling for viability in vitro and in vivo, knockdown of Hif-1alpha reduced invasiveness of the tumor cells in vitro as well as extravasation and secondary infiltration in vivo. Liver metastases associated induction of proinvasive receptor tyrosine kinase Met phosphorylation as well as gelatinolytic activity were Hif-1alpha-dependent. Indeed, promoter activity of the matrix metalloproteinase-9 (mmp-9) was shown to be Hif-1alpha-dependent. This study uncovers a new survival-independent biological function of HIF-1alpha contributing to the efficacy of metastases formation.
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PMID:Identification of a survival-independent metastasis-enhancing role of hypoxia-inducible factor-1alpha with a hypoxia-tolerant tumor cell line. 2056 31

As a tumor-associated antigen and a surface marker of breast cancer stem cells (BCSCs), epithelial cell adhesion molecule (EpCAM) plays an important role in not only cell adhesion, morphogenesis, metastases but also carcinogenesis. A non-synonymous C/T polymorphism (rs1126497) in exon3 of EpCAM causes a transition of 115 amino acid from Met to Thr. Another polymorphism (A/G, rs1421) in the 3'UTR causes loss of has-miR-1183 binding. A multiple independent case-control analysis was performed to assess the association between EpCAM genotypes and breast cancer risk. We observed that the variant EpCAM genotype (rs1126497 CT, and TT) was associated with substantially increased risk of breast cancer. Genotyping a total of 1643 individuals with breast cancer and 1818 control subjects in Eastern and Southern Chinese populations showed that rs1126497 CT + TT genotype had an odd ratio of 1.40 (95% confidence interval, 1.16-1.57) for developing breast cancer compared with CC genotype. The allele T increases the risk of breast cancer in a dose-dependent response manner (P (trend) < 0.001). Moreover, compared to breast cancer patients carrying the CC genotype, the EpCAM SNP rs1126497 CT or TT carrier was significantly associated with early breast cancer onset (P = 0.0023). However, no significant difference was found in genotype frequencies at the rs1421 A/G site between cases and controls. These findings suggest that M115T polymorphism in EpCAM may be a genetic modifier for developing breast cancer.
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PMID:A non-synonymous polymorphism Thr115Met in the EpCAM gene is associated with an increased risk of breast cancer in Chinese population. 2068 52


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