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

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

Recent reports on the role of the membrane-cytoskeleton linker protein ezrin in sarcomas showed an effect on the formation of metastases, dependent on the level of ezrin expression. In this study, we explore the role of ezrin in Ewing's sarcoma, a frequently fatal mesenchymal neoplasm of children and young adults. Through both immunohistochemistry and Western immunoblot studies we find ubiquitous, high-level expression of ezrin in Ewing's sarcoma. In contrast to the observations in osteosarcoma and rhabdomyosarcoma, we demonstrate that inhibition of ezrin-mediated signal transduction, through the expression of a non-phosphorylatable T567A mutant, slows primary growth of Ewing's sarcoma cells in vitro. This reduction in growth is a result of increased apoptosis in the mutant expressing cells. We further show that expression of this mutant reduces the ability of Ewing's sarcoma cells to form experimental metastases in vivo. Molecular examination reveals that the action of ezrin in Ewing's sarcoma is dependent on the AKT/mTOR signal transduction cascade, but not MAP Kinase. These results, therefore, demonstrate that, in Ewing's sarcoma, the biology of ezrin is distinct from that described in other sarcomas. This study further validates ezrin as a potential therapeutic target.
Clin Exp Metastasis 2006
PMID:Ezrin mediates growth and survival in Ewing's sarcoma through the AKT/mTOR, but not the MAPK, signaling pathway. 1702 19

Tumor metastasis to sentinel lymph nodes represents the first step of tumor dissemination in most human cancers and serves as a major prognostic indicator for disease progression. Recent studies have revealed that tumors can actively induce the formation of lymphatic vessels, and that tumor lymphangiogenesis is correlated with lymph node metastasis in experimental cancer models and in several types of human cancers. Metastatic tumor cells may continue to promote lymphatic vessel growth even after their metastasis to sentinel lymph nodes, likely promoting further cancer spread. Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were the first specific lymphangiogenesis factors identified, acting predominantly via VEGF receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells, and a large number of clinical studies have shown a correlation between tumor expression of VEGF-C or VEGF-D and lymph node metastasis. VEGFR-3 activation promotes lymphatic endothelial cell proliferation, migration, and survival via the extracellular signal-regulated kinase 1/2, the phosphatidylinositol 3-kinase/AKT, and the c-Jun NH(2)-terminal kinase 1/2 pathways. Additional tumor lymphangiogenesis factors have been recently identified, including VEGF-A. Importantly, blockade of the VEGFR-3 pathway by specific antibodies, by soluble receptor constructs, and by small molecule kinase inhibitors efficiently inhibits experimental tumor lymphangiogenesis and metastasis and might also represent a novel therapeutic avenue for the treatment of human cancers.
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PMID:Pathways targeting tumor lymphangiogenesis. 1714 2

Most cancer patients die of metastatic or recurrent disease, hence the importance to identify target genes upregulated in these lesions. Although a variety of gene signatures associated with metastasis or poor prognosis have been identified in various cancer types, it remains a critical problem to identify key genes as candidate therapeutic targets in metastatic or recurrent cancer. The aim of our study was to identify genes consistently upregulated in both lymph node micrometastases and recurrent tumours compared to matched primary tumours in human cervical cancer. Taqman Low-Density Arrays were used to analyse matched tumour samples, obtained after laser-capture microdissection of tumour cell islands for the expression of 96 genes known to be involved in tumour progression. Immunohistochemistry was performed for a panel of up- and downregulated genes. In lymph node micrometastases, most genes were downregulated or showed expressions equal to the levels found in primary tumours. In more than 50% of lymph node micrometastases studied, eight genes (AKT, BCL2, CSFR1, EGFR1, FGF1, MMP3, MMP9 and TGF-beta) were upregulated at least two-fold. Some of these genes (AKT and MMP3) are key regulators of epithelial-mesenchymal transition in cancer. In recurrent tumours, almost all genes were upregulated when compared to the expression profiles of the matched primary tumours, possibly reflecting their aggressive biological behaviour. The two genes showing a consistent downregulated expression in almost all lymph node metastases and recurrent tumours were BAX and APC. As treatment strategies are very limited for metastatic and recurrent cervical cancer, the upregulated genes identified in this study are potential targets for new molecular treatment strategies in metastatic or recurrent cervical cancer.
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PMID:Molecular profiling of cervical cancer progression. 1724 1

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

The aim of this study is to investigate the expression of CXCR4 receptor in cervical adenocarcinoma and related mechanisms involved in pelvic lymph node metastasis. Immunohistochemistry was used to evaluate the expression of CXCR4 and the association of pelvic lymph node metastasis in archived tissue from clinical stage IB cervical adenocarcinomas (n = 37) and from benign specimens obtained at hysterectomy for other causes (n = 48). The HeLa cell (cervical adenocarcinoma-derived cell) line that expresses CXCR4 was used to study the interaction between the CXCR4 receptor and stromal cell-derived factor 1alpha (SDF-1alpha). Cell migration assays, cell numbers, flow cytometry, cell proliferation assay, and western blot were used to study the function of CXCR4 and its downstream signal transduction. The positive cases were semiquantitatively divided into three score classes according to their staining. Tumors with strong CXCR4 stainings were more likely to have pelvic lymph node metastasis than those with weak or negative stainings (87.5% vs 34.5%; P = 0.014). Only 25% of the benign specimens had weak or negative staining for CXCR4. Functioning CXCR4 receptor was expressed on HeLa cells. SDF-1alpha provoked significant signal transduction events, including chemotaxis and rescue from apoptosis. These actions were apparently mediated by the activation and phosphorylation of the extracellular signal-regulated kinase 1/2 and AKT pathways. We conclude CXCR4 expression is associated with cervical adenocarcinoma cell migration and proliferation, and primary cervical adenocarcinoma cells expressing CXCR4 are significantly more likely to metastasize to pelvic lymph nodes.
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PMID:CXCR4 expression is associated with pelvic lymph node metastasis in cervical adenocarcinoma. 1750 81

Syk, a non-receptor tyrosine kinase, is an important component of immunoreceptor signaling in hematopoietic cells. It has been implicated in key regulatory pathways including phosphoinositide 3-kinase and phospholipase Cgamma (PLCgamma) activation in B cells and integrin signaling in platelets and bronchial epithelial cells. Recently, potential roles in cancer have been reported. In breast cancers, reduced Syk expression was associated with invasion, and its overexpression in cell lines was shown to inhibit cell motility. In contrast, Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. Its role in squamous cell carcinomas of the head and neck (SCCHN) has not yet been investigated. Syk mRNA and protein expression was detected in 6 of 10 SCCHN cell lines. When Syk was transfected into Syk-negative cells (SIHN-011A), chemomigration was enhanced in vitro and this was associated with activation of PLCgamma1. Conversely, abrogation of Syk activity by pharmacologic inhibition or small interfering RNA in HN6 cells with high levels of endogenous expression inhibited migration, haptotaxis, and engagement with matrix proteins; this was accompanied by decreased levels of phosphorylated AKT. Similar effects were seen in Syk-positive CAL 27 cells but not in Syk-negative SIHN-011A cells. Immunoprecipitation suggested co-association of Syk with epidermal growth factor receptor and GRB-2. Syk expression in SCCHN patient tissues was examined by semiquantitative real-time PCR (n = 45) and immunohistochemistry (n = 38) in two independent cohorts. Higher levels of Syk expression were observed in tumors and lymph node metastases relative to normal tissues. High Syk expression significantly correlated with worse survival and may be of prognostic value in SCCHN due to its potential role in cell migration and invasion.
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PMID:Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. 1769 97

Ovarian cancer is the most lethal of all gynecological cancers. Most deaths from ovarian cancer are due to widespread intraperitoneal metastases and malignant ascites. However, mechanisms of invasion in ovarian cancer remain poorly understood. In this study, we examined the effects of gonadotropin-releasing hormone (GnRH)-I (the classical mammalian GnRH), GnRH-II (a second form of GnRH), and GnRH receptor on invasion using two human ovarian carcinoma cell lines, OVCAR-3 and SKOV-3. Here we demonstrated that in OVCAR-3, GnRH-I and GnRH-II promoted cell invasion, whereas in SKOV-3, GnRH-I and GnRH-II inhibited cell invasion. Transfection of small interfering RNA to abrogate the gene expression of GnRH receptor reversed GnRH-I and GnRH-II-mediated invasion activities, suggesting that the same receptor, type I GnRH receptor, is essential for the effects of GnRH-I and GnRH-II in both OVCAR-3 and SKOV-3. Treatment of SKOV-3 cells with GnRH-I or GnRH-II resulted in a decrease in matrix metalloproteinase 2 but an increase in tissue inhibitor of metalloproteinase 2 secretions. In addition, we found that GnRH-I and GnRH-II interfered with activation of the phosphatidylinositol-3-kinase/AKT pathway that is well documented to stimulate proteolysis and invasion of ovarian cancer cells. Taken together, these observations suggest that GnRH-I and GnRH-II play key regulatory roles in ovarian tumor cell invasion and extracellular matrix degradation.
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PMID:Differential role of gonadotropin-releasing hormone on human ovarian epithelial cancer cell invasion. 1790 81

Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
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PMID:The genome and epigenome of malignant melanoma. 1804 49

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.
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PMID:Targeted therapy for uveal melanoma. 1822 59


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