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)

The purpose of this study was to investigate whether Her-2/neu expression at diagnosis of osteosarcoma could provide biologic and prognostic information that predicts the risk of pulmonary metastases and outcome. Human epidermal growth factor (Her-2/neu) expression in 25 initial pretreatment osteosarcoma biopsies and 12 posttreatment pulmonary metastatic osteosarcoma resection specimens was assessed by standard immunohistochemical techniques on formalin-fixed paraffin-embedded tissue. As a screening analysis to determine if gene amplification may be a mechanism for increased Her-2/neu expression, FISH analysis was conducted on seven Her-2/neu immunostain-positive samples and five Her-2/neu immunostain-negative samples. Cytoplasmic Her-2/neu reactivity was identified in 11/25 (44%) of primary tumors and in 7/12 (58%) resection specimens from pulmonary metastases. Cytoplasmic Her-2/neu expression was associated with shorter overall metastasis-free survival. Her-2/neu gene amplification was identified by FISH analysis in six of the seven immunostain-positive samples but was also identified in two of the five immunostain-negative samples. Her-2/neu expression in patients with osteosarcoma is associated with an increased risk of metastasis and may define a subset of patients with a more aggressive tumor phenotype. Her-2/neu gene amplification may provide a mechanism for Her-2/neu overexpression in certain cases of osteosarcoma. Whether Her-2/neu expression influences outcome needs to be examined further in a prospective fashion. The hope is that Her-2/neu expression will identify patients who may benefit from the addition of directed biologic therapy.
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PMID:Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. 1254 70

Systemic gene delivery systems are needed for therapeutic applications; in some situations, target cells might be spread throughout the organism, as in the case of cancer metastases, which can be reached only via the systemic route. Within the class of nonviral vectors, polymer-based transfection particles named DNA polyplexes and lipid-based systems named DNA lipoplexes are being developed for this purpose. For systemic circulation, masking the surface charge of DNA complexes has to be accomplished to avoid interactions with plasma components, erythrocytes, and the reticuloendothelial system. Among other vector formulations, polyplexes based on polyethylenimine (PEI), shielded with polyethylene glycol (PEG), and linked to the receptor binding ligands transferrin (Tf) or epidermal growth factor (EGF) have been developed. Complexes were found to mediate efficient gene transfer into tumor cell lines in a receptor-dependent and cell-cycle-dependent manner. Systemic administration of surface-shielded Tf-PEI polyplexes into the tail vein of mice resulted in preferential gene delivery into distantly growing subcutaneous tumors. In contrast, application of positively charged PEI polyplexes directed gene transfer primarily to the lung.
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PMID:Tumor-targeted gene transfer with DNA polyplexes. 1277 43

Renal cell carcinoma (RCC) frequently produces metastases to the musculoskeletal system that are a major source of morbidity in the form of pain, immobilization, fractures, neurological compromise, and a decreased ability to perform activities of daily living. Patients with metastatic RCC therefore have a dismal prognosis because there is no effective adjuvant treatment for this disease. Because the epidermal growth factor receptor (EGF-R) signaling cascade is important in the growth and metastasis of RCC, its blockade has been hypothesized to inhibit tumor growth and hence prevent resultant bone destruction. We determined whether blockade of EGF-R by the tyrosine kinase inhibitor PKI 166 inhibited the growth of RCC in bone. We use a novel cell line, RBM1-IT4, established from a human RCC bone metastasis. Protein and mRNA expression of the ligands and receptors was assessed by Western and Northern blots. The stimulation of RBM1-IT4 cells with epidermal growth factor or transforming growth factor alpha resulted in increased cellular proliferation and tyrosine kinase autophosphorylation. PKI 166 prevented these effects. First, RBM1-IT4 cells were implanted into the tibia of nude mice, where they established lytic, progressively growing lesions, after which the mice were treated with PKI 166 alone or in combination with paclitaxel (Taxol). Immunohistochemical analysis revealed that tumor cells and tumor-associated endothelial cells in control mice expressed activated EGF-R. Treatment of mice with PKI 166 alone or in combination with Taxol produced a significant decrease in the incidence and size of bone lesions as compared with the results in control or Taxol-treated mice (P < 0.001). Treatment with PKI 166 also decreased the expression of phosphorylated EGF-R by tumor cells and tumor-associated endothelial cells, and this was even more pronounced with PKI 166 plus Taxol treatment. The PKI 166 plus Taxol combination produced apoptosis of tumor cells and tumor-associated endothelial cells. Tumor cell proliferation, shown by proliferating cell nuclear antigen positivity, was decreased in all treatment groups. In addition, the integrity of the bone was maintained in mice treated with PKI 166 or PKI 166 plus Taxol, whereas massive bone destruction was seen in control and Taxol-treated mice. These results suggest that blockade of EGF-R signaling inhibits growth of RCC in the bone by its effect on tumor cells and tumor-associated endothelial cells.
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PMID:Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice. 1278 1

The HER-2/neu oncogene codes a protein of the family of epidermal growth factor receptors. The extracellular domain has a MW from 95-105 kDa and is shed into the blood. In some patients with malignant tumors there is a high expression of HER-2/neu connected with high levels of HER-2/neu protein in the serum. High concentrations signal aggressive growth, bad prognosis and shorter survival. The reference range lies between 4.0 and 14.0 ng/ml with a mean of 9.0 ng/ml. There is a significant difference of values between patients with and without metastases, but not between healthy people and patients without metastases. The advantage of this parameter lies in the early diagnosis of recurrence in the therapy of metastasizing breast carcinomas especially on treatment with Herceptin.
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PMID:HER-2/neu gene product in serum--an oncoprotein in the diagnosis and therapy of breast carcinoma. 1282 Mar 39

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

Growth-stimulating pathways activated independently of their normal tissue environment are critical to the carcinogenesis and progression of lung cancer. These pathways are comprised of extracellular growth factors; their specific receptors on the cellular membrane; signal transduction cascades in the cytosol; and target molecules, including cytoskeletal proteins, metabolic regulators, and transcription factors in the nucleus. Growth factors can be divided into two groups based on their receptors: G-protein-coupled receptors and receptor tyrosine kinases. Growth factors induce clonal expansion of lung cancer cells by autocrine and/or paracrine mechanisms. Signal transduction cascades form an extremely large and complicated network with cross-talk connections. Ras, phosphatidylinositol-3-OH kinase, and phospholipase C are three key regulators involved in the network. Recent progress in our understanding of the oncoproteins functioning in the pathways has led to the development of novel therapeutic agents. Some of the most exciting results have been obtained with inhibitors of receptor tyrosine kinases. Phase I studies of epidermal growth factor-receptor inhibitors demonstrate objective responses without severe toxicity as single agents in patients with non-small-cell lung cancer refractory to conventional chemotherapy. This new strategy might lead to breakthroughs in the treatment of lung cancer with distant metastases not curable by conventional chemotherapy alone.
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PMID:Growth-stimulating pathways in lung cancer: implications for targets of therapy. 1472 Mar 64

The MUC1 tumor antigen is overexpressed on most breast tumors and metastases. It interacts with signaling proteins such as the ErbB kinases and beta-catenin, and is involved in mammary gland oncogenesis and tumor progression. Herein, we report a novel interaction between MUC1 and adenomatous polyposis coli (APC), a tumor suppressor involved in downregulating beta-catenin signaling. Initially identified in colorectal cancer, APC is also downregulated in breast tumors and presumably involved in mammary carcinogenesis. MUC1 and APC co-immunoprecipitate from the ZR-75-1 human breast carcinoma cell line and co-localize in mouse mammary glands and tumors. These studies also indicate that the association of MUC1 and APC may be increased by epidermal growth factor stimulation. Intriguingly, the co-immunoprecipitation of MUC1 and APC increases in human breast tumors and metastases as compared to adjacent normal tissues, indicating that this association may play a role in the formation and progression of breast tumors.
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PMID:MUC1 can interact with adenomatous polyposis coli in breast cancer. 1502 Feb 26

Metastatic disease is present at diagnosis in 30% of the patients with colorectal cancer (CRC), and approximately half of early-stage patients with CRC will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic colorectal carcinoma (MCRC). Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient to use. Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new era of drug development. Anti-angiogenesis drugs, tyrosine kinase inhibitors, and epidermal growth factor blockers are among the new generation of agents.
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PMID:Meta-analysis of new treatment strategies for metastatic colorectal cancer. 1914 83

This article reviews the available data regarding the acticity of postoperative adjuvant systemic therapy for colorectal cancer as first and second-line treatment in metastatic disease. The efficacy of adjuvant treatment of patients with stage III colorectal cancer is well established. 5-fluorouracil (5-FU) and folic acid over 6 months (still) represent todays standard and should serve as comparison in randomized studies. The risk of relapse is low in stage II colon carcinoma and consequently the efficacy is relatively small compared to stage III. New investigation indicate, Capecitabene has the potential to replace 5-FU/FS as standard treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. In metastatic disease combination of 5-FU/folic acid plus CPT-11 or OXA are treatment of choice for the first-line therapy of metastatic colorectal carcinoma. FOLFOX is high-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second- line therapy for metastatic colorectal cancer. It resulted in prolongation of the median progress free survival from 6,8 to 8,8 months and increased the survival for 4,5 months. New perspectives are novel chemotherapeutic and targeted agents in metastatic colorectal cancer: For the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail.
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PMID:[Adjuvant and palliative anticancer treatment of colon carcinoma in 2004]. 1549 53

More than half the patients with malignat tumours have at the time of diagnosis already remote metastases or they develop remote dissemination after different intervals following termination of local treatment. Organ complications in case of metastatic dissemination are for the majority of patients the most life threatening condition. In therapeutic decisions the approach to some solid tumours is the same as in systemic diseases. The possibility to achieve a long-term therapeutic effect during conventional systemic therapy are limited in metastatizing solid tumours of adult age. Assessment of the extent of the disease incl. detection of metastatic dissemination is of decisive importance for the selection of therapeutic strategy. Imaging methods such as computed tomography, ultrasonography and nuclear magnetic resonance provide basic structural anatomic information. The limitating factor is obtaining functional information on tumor tissues and the possibility to differentiate the residual disease from non-viable or necrotic tumor masses. These data can be provided by radiopharmacological imaging methods such as positron emission tomography. Introduction of new imaging methods is becoming increasingly important when new therapeutic methods are used where the effect of the therapeutic result does not mean necessarily reduction of the tumour volume. Research of the metastatic process involved revolutionary changese lucidating individual stages linked in a cascade pattern. The metastatic potential of human tumours correlates with the expression of a number of genes regulating tumour growth (EGF - epidermal growth factor, IGF - insulin like growth factor) motility of tumour cells (AMF - autocrine motility factor) the process of angiogenesis (VEGF vascular endothelial growth factor, bFGF - basal fibroblastic growth factor, interleukin-8) and the invasiveness (genes for the matrix of metalloproteinase MMP-2/MMP-9). Expression of the surface glycoporotein E-cadherin which influences the cohesiveness of cells is in an inverse relationship with the invasiveness and metastatic potential. Identification of the appropriate genes in a heterogeneous tumour population calls for multiparametric, multivariation analysis of gene expression. Understanding of this complex problem opened new possibilities of therapeutic action and improved curability of neoplastic diseases in all stages of the disease. Gradual more detailed understanding of individual stages of a multigrade process of metastatizing helped to reveal new potential target structures for treatment. In the process of angiogenesis these are metalloproteinases, angiogenic growth factors, endothelial cells and vascular structures of tumours. Practical use for therapeutic purposes will develop on the basis of results of clinical studies which are underway.
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PMID:[Diagnosis and treatment of tumor metastases]. 1563 97


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