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)

Fluorescence in situ hybridization was applied on a collection of 609 squamous cell carcinomas of the head and neck (HNSCCs),including 511 primary carcinomas of different clinical stage and anatomical localization and 98 recurrent carcinomas, second primary carcinomas, and regional metastases on a tissue microarray. The overall prevalence of amplifications of five oncogenes analyzed was 34.5% for CCND1, 12.7% for EGFR, 8.8% for MYC, 6.2% for ZNF217, and 3.6% for ERBB2. CCND1 amplifications were associated with the pharyngeal site in primary carcinomas (P < 0.001), whereas amplifications of ZNF217 were less frequent in pharyngeal carcinomas as compared with primary oral and laryngeal carcinomas (P = 0.02). The amplification pattern of these oncogenes suggests that different molecular pathways are involved in HNSCCs of different localizations.
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PMID:Tissue microarray analysis reveals site-specific prevalence of oncogene amplifications in head and neck squamous cell carcinoma. 1264 72

Metastasis is usually responsible for mortality in patients suffering from muscle invasive bladder cancer. Whilst expression of a great number of genes and their protein products have been associated with metastasis and/or poor prognosis in bladder cancer, evidence that they actively drive the metastatic process, and hence make potentially good therapeutic targets, is often lacking. This is due to the limited number and application of effective animal models which reflect the pathogenesis of the human disease. In this review I will discuss the processes involved in metastasis, consider the established animal models of bladder cancer progression and metastasis, and review the evidence for a role of various gene products in this process. Consideration of clinical studies in conjunction with evidence from experimental animal models reveals that the tyrosine kinase receptor erbB1/EGFR, the calcium binding protein S100A4 and the the cell cycle arrest/apoptosis-inducing p53 protein are amongst the most promising targets for therapy against metastatic disease in patients with bladder cancer.
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PMID:Gene products involved in metastasis of bladder cancer. 1279 7

C-erbB-2 (HER2/neu) protein overexpression or amplification has been noted in some solid tumors a molecular target for tumor suppression. C-erbB-2 protein is localized on the membrane surface and is classified in the EGFR family. Trastuzumab is a humanized monoclonal antibody which binds to the extracellular domain of the c-erbB-2 protein in breast cancer cells. Good responders to trastuzumab may be ICH 2 + and FISH positive breast tumors, and ICH 3 + cancer. The response rate is approximately 15% with single administration of trastuzumab. Combination therapy with paclitaxel for the treatment of patients with metastatic cancer may bring more than 60% response and improve time to disease progression. Congestive heart failure associated with trastuzumab may be severe, and combination therapy which includes anthracyclines increases the incidence and severity of cardiac dysfunction. Other toxicities include infusion reaction.
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PMID:[Clinical implications of trastuzumab]. 1293 63

Tight junctions (TJs) are the most apical cell-cell junctions, and claudins, the recently identified TJ proteins, are critical for maintaining cell-cell adhesion in epithelial cell sheets. Based on their in vivo distribution and the results of overexpression studies, certain claudins, including claudin-1 and -4, are postulated to increase, whereas other claudins, especially claudin-2, are postulated to decrease the overall transcellular resistance. The overall ratio among claudins expressed in a cell/tissue has been hypothesized to define the complexity of TJs. Disruption of the TJs contributes to various human diseases, and a correlation between reduction of TJ function and tumor dedifferentiation has been postulated. The epidermal growth factor (EGF) receptor (EGFR) is overexpressed in a wide spectrum of epithelial cancers, and its expression correlates with a more metastatic cancer phenotype. However, normal functioning of EGFR is essential for normal epithelial cell proliferation and differentiation. The role of EGFR-dependent signaling in the development and maintenance of epithelial TJ integrity has not been studied in detail. This study demonstrates that, in polarized Madin-Darby canine kidney II cells, EGF-induced EGFR activation significantly inhibited claudin-2 expression while simultaneously inducing cellular redistribution and increased expression of claudin-1, -3, and -4. Accompanying these EGF-induced changes in claudin expression was a 3-fold increase in transepithelial resistance, a functional measure of TJs. In contrast, there were no alterations in protein expression and/or intracellular localization of other TJ-related proteins (ZO-1 and occludin) or adherens junction-associated proteins (E-cadherin and beta-catenin), suggesting that EGF regulates TJ function through selective and differential regulation of claudins.
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PMID:Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepithelial resistance in Madin-Darby canine kidney cells. 1459 19

In vivo models utilizing orthotopic injection of tumor cells into nude mice have proven valuable for the study of metastasis. However, breast cancers are among the more difficult of human tumors to grow in immunodeficient mice, with a relatively low tumor take. Fewer still develop spontaneous metastases. The injection of GI101A breast cancer cells into the mammary fatpad (mfp) produced lung metastases in 25% of tumor-bearing mice. Selecting cells from the lung metastases and recycling in vivo resulted in the isolation of a series of variant cell lines. These cell lines were tested for tumorigenicity and metastasis in nude mice following mfp injection compared with the original cell line, and in vitro expression of factors associated with the metastatic phenotype measured. The in vivo selected cell lines were more aggressive, with higher tumor take, faster local growth rate and increased incidence (> or = 85%) and extent of lung metastasis. However, the metastasis-selected variants showed no increases in expression of the growth factor receptors EGFR or HER-2, and the pro-angiogenic factors VEGF-A and IL-8. Immunohistochemistry of mfp tumors revealed no differences in microvessel density (counting CD-31 positive structures) and cell proliferation (PCNA-positive cells) comparing the GI101A line with selected variants. No TUNEL-positive cells were detected in the tumors of the metastasis-derived variant, with a small number of cells undergoing apoptosis detected in sections of GI101A tumors. In vitro, the metastasis-derived variants were found to have a more robust expression of phosphorylated PKB/Akt, with or without EGF or serum stimulation, suggesting an association between Akt activation and metastatic ability. This new series of isogenic cell lines may be valuable for identifying molecular mechanisms involved in the metastatic progression of breast cancer.
Clin Exp Metastasis 2003
PMID:Selection of more aggressive variants of the gI101A human breast cancer cell line: a model for analyzing the metastatic phenotype of breast cancer. 1459 85

Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.
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PMID:EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. 1463 3

The expression of the NH2 terminally truncated ErbB2 receptor (p95ErbB2) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185ErbB2. We now show that heregulin (HRG), but not EGF, stimulates p95ErbB2 phosphorylation in BT474 breast cancer cells. Furthermore, phospho-p95ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185ErbB2 heterodimerizes with both EGFR and ErbB3. The predilection of p95ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand. GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95ErbB2 phosphorylation in BT474 cells and tumor xenografts. Inhibition of p95ErbB2, p185ErbB2, and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels. Increased phosphorylation of p95ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016. In contrast, trastuzumab did not inhibit p95ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D. It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95ErbB2-expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95ErbB2-ErbB3 heterodimers. Thus, p95ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.
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PMID:Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. 1473

Oncogenes, the abnormal forms of proto-oncogenes, were shown to be involved in malignant transformation and in tumor progression. c-erbB2/HER2/neu is member of EGFR family and encodes the p185 protein, which functions as a tyrosine-kinase. Gene amplification and/or p185 overexpression were reported to be associated with poor prognostic in cancer. Our purpose was to investigate p185 immunohistochemical expression in breast carcinomas and in the corresponding axillary lymph nodes metastases and to identify possible correlation between p185 and other factors of poor prognostic, such as loss of hormonal receptors expression. In our study, 40.91% of cases were erbB-2 positive, p185 expression being maintained from the primary tumors to axillary metastases and associated with positive nodal status and with the absence of hormonal receptors expression (p < 0.05). These findings support the hypothesis the c-erbB2 is an advantageous acquisition for the aggressive behavior of the tumor cell and for its ability to invade and metastasize.
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PMID:[Overexpression of c-erbB-2 gene product is associated with poor prognosis factors in breast carcinoma]. 1475 39

Despite new therapies and several treatment options, metastatic breast cancer (MBC) remains incurable. One reason for the low median survival rate may be intense cross-talk between growth factor receptors such as the epidermal growth factor receptor (EGFR/HER1) and the HER2 growth factor receptor. This report describes the case history of a patient with MBC whose disease had progressed despite surgery, radiotherapy and four different chemotherapy regimens, including trastuzumab (a monoclonal antibody that specifically blocks HER2) combined with docetaxel. However, treatment with 500 mg/day gefitinib ('Iressa', ZD1839), an EGFR tyrosine kinase inhibitor, and trastuzumab (2 mg/kg/week) caused a rapid and sustained regression of breast cancer metastases in skin and lymph nodes. Thus, for patients with MBC whose tumors co-express EGFR and HER2, gefitinib in combination with trastuzumab may prevent receptor cross-talk, improving the outcome of MBC.
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PMID:Induction of remission in a patient with metastatic breast cancer refractory to trastuzumab and chemotherapy following treatment with gefitinib ('Iressa', ZD1839). 1501 56

The prognostication of head and neck squamous cell carcinoma (HNSCC) is largely based upon the tumor size and location and the presence of lymph node metastases. Here we show that gene expression patterns from 60 HNSCC samples assayed on cDNA microarrays allowed categorization of these tumors into four distinct subtypes. These subtypes showed statistically significant differences in recurrence-free survival and included a subtype with a possible EGFR-pathway signature, a mesenchymal-enriched subtype, a normal epithelium-like subtype, and a subtype with high levels of antioxidant enzymes. Supervised analyses to predict lymph node metastasis status were approximately 80% accurate when tumor subsite and pathological node status were considered simultaneously. This work represents an important step toward the identification of clinically significant biomarkers for HNSCC.
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PMID:Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. 1514 56


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