Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of the liver cancer (LC) patient is often problematic as the tumour is identified at an advanced stage: the frequent coexistence of cirrhosis limits the use of surgical resection, there is no efficacious chemotherapy, and in patients treatable with liver transplant, indication is rendered uncertain from the point of view of cost-effectiveness and the high risk of recurrence of the tumour and hepatitis infection. Surgical resection appears to be the treatment of choice in patients with a liver tumour in a ''healthy'' liver. Instead, orthotopic liver transplant is the most valid indication for patients with cirrhosis and tumours of dimensions smaller than 2-3 cm. Nevertheless, due to the lack of organs palliative treatments, like surgical resection, PEI and TACE are the most indicated in patients with advanced neoplastic disease, in practice patients with TNM III and IV; radiotherapy with protons and the coagulation of the tumour by microwaves or laser fibres are also used in the attempt to slow down the progress of the neoplastic process. These methods may increase the possibility of cure in well chosen patients. In some patients the most effective approach may be the combined use of various therapies, such as TACE, PEI and surgery.
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PMID:Hepatocellular carcinoma: screening and therapy. 1649 75

Despite considerable efforts no ideal treatment exists for HCC. The disease is usually detected late and few patients are candidates for potentially curative treatment options such as surgical resection or liver transplantation. Surgical resection is limited mostly by the impaired liver function in cirrhotic livers, whereas liver transplantation is limited by tumor size, multi-localized disease and, most important, by shortage of donor organs. TACE as a local ablative treatment is able to induce local disease control and to prolong survival and might even achieve survival similar to surgical resection. The high rates of recurrence of HCC after successful control of local tumor spread is the reason to consider that procedure as a non-curative treatment option. PEI and RFA are able to control local tumor growth, but cannot influence tumor recurrence or de novo tumor growth. Systemic therapies need to be investigated in large randomized trials, especially to evaluate the use of somatostain analogues, HMGCoA reductase inhibitors, or other drugs such as rapamycin or inhibitors of vascular endothelial growth factor (VEGF).
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PMID:Hepatocellular carcinoma--rising incidence, changing therapeutic strategies. 1693 43

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-alpha, was inhibited by TNF-alpha protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G2-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process.
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PMID:Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-alpha converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma. 1698 46

The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop that provides an oncogenic stimulus in the absence of proto-oncogene mutation. Targeting this protease, TNF-alpha-converting enzyme (TACE; also referred to as a disintegrin and metalloproteinase 17 [ADAM17]), with small molecular inhibitors or siRNAs reverted the malignant phenotype in a breast cancer cell line by preventing mobilization of 2 crucial growth factors, TGF-alpha and amphiregulin. We show that TACE-dependent ligand shedding was prevalent in a series of additional breast cancer cell lines and, in all cases examined, was amenable to inhibition. Using existing patient outcome data, we demonstrated a strong correlation between TACE and TGFA expression in human breast cancers that was predictive of poor prognosis. Tumors resulting from inappropriate activation of the EGFR were common in multiple tissues and were, for the most part, refractory to current targeted therapies. The data presented here delineate the molecular mechanism by which constitutive EGFR activity may be achieved in tumor progression without mutation of the EGFR itself or downstream pathway components and suggest that this important oncogenic pathway might usefully be targeted upstream of the receptor.
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PMID:Targeting TACE-dependent EGFR ligand shedding in breast cancer. 1721 88

The debilitating destruction of joint tissues seen in osteoarthritis (OA) is due, in large part, to the degradative activity of metalloproteinase (MP) enzymes that target extracellular matrix (ECM) components within articular cartilage. Although successful in suppressing the pain and inflammation associated with this disease, conventional OA therapeutics do not inhibit the underlying tissue catabolism, allowing the disease to progress into irreversible ECM loss and chronic disability. Therapeutic inhibition of metalloproteinase activity is not a new concept, however, its transfer into clinical use has been frustrating. Disappointing results from clinical trials with small molecule inhibitors of metalloproteinases have highlighted the critical importance of inhibitor specificity, and the need to identify the individual metalloproteinases responsible for joint destruction. We discuss strategies of inhibition using small molecule inhibitors and tissue inhibitors of metalloproteinases (TIMPs) engineered to increase inhibitory specificity, and present new data using of new reagents such as ribozymes and inhibitory RNAs that repress expression of specific enzymes. Recent data has implicated the disease stage-dependent involvement of matrix metalloproteinase-1, -2, -3, -9, -13, ADAM-17/TACE (tumor-necrosis factor-alpha converting enzyme), and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin 1 motifs) as major in vivo mediators of the ECM degradation seen in OA, and as such, they represent promising therapeutic targets. We conclude that the concept of molecular polypharmacy, in which the relevant enzymes are selectively targeted with multiple directed therapies, may offer a new therapeutic strategy that prevents joint destruction and minimizes toxicities.
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PMID:Molecular targets in osteoarthritis: metalloproteinases and their inhibitors. 1730 7

The membrane-anchored metalloproteinase tumor necrosis factor-alpha-converting enzyme (TACE/a disintegrin and metalloproteinase [ADAM] 17) is key in proteolytic ectodomain shedding of several membrane-bound growth factors, cytokines and receptors. The expression and activity of ADAM17 increases under some pathological conditions including stroke, and promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis. Hypoxia initiates cellular invasive processes that occur under both physiological and pathological conditions such as invasion and metastasis of some tumors. In the present study, we sought to elucidate whether ADAM17 contributes to brain tumor invasion. To this end, we examined the role of ADAM17 in the invasiveness of two different brain tumor cell lines, 9L rat gliosarcoma and U87 human glioma, under normoxic and hypoxic conditions. Additionally, we tested the effects of ADAM17 suppression on in vitro tumor cell invasion by means of ADAM17 proteolytic inhibitors and specific small interfering RNA. We found that tumor cells upregulated ADAM17 expression under hypoxia, and that ADAM17 activity correlated with increased tumor cell invasion. Conversely, suppression of ADAM17 proteolysis decreased invasiveness induced by hypoxia in 9L and U87 cells. Furthermore, the contribution of ADAM17 to tumor invasion was independent of matrix metalloproteinase (MMP)-2 and MMP-9 activity. ADAM17 was also found to activate the epidermal growth factor/phosphoinositide-3 kinase/serine/threonine kinase signal transduction pathway. Our data suggest that hypoxia-induced ADAM17 contributes to glioma cell invasiveness through activation of the EGFR signal pathway.
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PMID:Inhibition of ADAM17 reduces hypoxia-induced brain tumor cell invasiveness. 1735 61

With the current practice of surveillance programs in high-risk patients, early stage hepatocellular carcinoma HCC is commonly diagnosed. This poses great challenge to clinicians, in terms of prognostic estimation, patient stratification to various treatment modalities and patient management during long-term follow-up. This review focuses on the current trends in the management of HCC, with special attention to tumor staging, treatment algorithm, and outcome of various treatment modalities. According to the American Association for the Study of Liver Diseases AASLD practice guideline, Barcelona Clinic Liver Cancer BCLC staging system has fulfilled the criteria that HCC patients can be stratified into different prognostic subgroups, to which optimal treatments can be offered. Under this management scheme, curative treatments hepatic resection, liver transplantation, and percutaneous ablation would be reserved to the subgroup of patients with relatively good prognosis. For patients with advanced malignancy localized to the liver, local ablation or transarterial chemoembolization TACE may offer effective symptomatic palliation, and prolongation of patients' survival. For patients with distant metastases, no effective therapy can be offered, and symptomatic palliative care is the best option. Until now, favorable survival outcomes have been reported following hepatic resection, liver transplantation, and local ablation for HCC. Although the therapeutic effect of TACE is less pronounced than curative treatments, randomized controlled studies have proven its survival benefit for HCC patients. A comprehensive treatment algorithm involving these treatment modalities is mandatory to ensure optimal care of patients with HCC.
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PMID:Current treatment strategy for hepatocellular carcinoma. 1776 55

We constructed prokaryotic expression vectors for different domains of TACE gene and expressed the fusion proteins, so as to explore their effects on the proliferation, adhesion and invasion potential of tumor cells in vitro. The total RNA was isolated from THP1 cell. TACE cDNA was amplified by RT-PCR and subcloned into pMD18-T vector to construct pMD-18T-TACE vector. The different cDNA fragment of TACE were amplified from plasmid pMD-18T-TACE and then cloned into pET-28a( + ) to construct expression vector pET28a( + )- 300, pET28a( + )-T800, and pET28a( + )-T1300, which respectively transformed into E. coli BL21 (DE3). The expression of His-tagged fusion proteins were induced with IPTG and purified through BBST NTA resin. The proliferation ability was examined by MTT assay. The adhesive and invasive ability were examined by plated adhesion model and Transwell assay. The protein pET28a( + )-T300 and pET28a( + )-T1300 can reduce the proliferation, adhesion and invasion ability of human lung carcinoma cell A549 in vitro, but otherwise the protein pET28a( + )-T800 had not shown the inhibitive function. The fusion protein of disintegrin domain of TACE have the similar biological function to other disintegrins, which can be used for further research on function of TACE in inflammation and tumor.
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PMID:[Inhibition of proliferation, adhesion and invasion ability of human lung carcinoma cell A549 by tumor necrosis factor-alpha converting enzyme (TACE)]. 1782 26

TNF-alpha converting enzyme (TACE/ADAM17) is a transmembrane metalloprotease that plays a key role in the cleavage and mobilization of receptor ligands that are initially synthesized as membrane-tethered precursors. For many years, attention has focused on the role of TACE-dependent TNF-alpha cleavage in arthritis and, more recently, it has become apparent that TACE also plays an important role in regulating epidermal growth factor receptor activity in several tumor types. This review presents the background to these findings and a rationale for the continued development of TACE inhibitors for the treatment of epidermal growth factor receptor-dependent epithelial tumors.
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PMID:Tackling EGFR signaling with TACE antagonists: a rational target for metalloprotease inhibitors in cancer. 1790 59

The purpose of this study was to evaluate the size responses and vascular responses to three different sizes of Embosphere (EMBS) embolization particles used for chemo-embolization in patients with unresectable hepatocellular carcinoma (HCC). Forty-seven patients with biopsy proven HCC treated with TACE using EMBS (Biosphere Medical, Rockland, MA, USA) were included in this study. EMBS are non-resorbable tris-acryl gelatin defined-size microspheres. Sixteen patients were treated with 40-120 micron (40-microm), 13 patients with 100-300 (100-microm), and 18 patients with 300-500 (300-microm) EMBS particles. We measured the two-dimensional area and vascularity of the tumor index lesion on initial and subsequent CTs after treatment. Lesions were classified into four grades based on the degree of vascularity measured in 25% increments. Size of tumor after one treatment decreased by an average (avg) of 18% for 40-120-microm particles, 38% for 100-300-microm particles, and 17% for 300-500-microm particles. After three treatments, size decreased by an avg of 46% for 40-120-microm particles, 76% for 100-300-microm particles, and 46% for 300-500-microm particles. Vascularity decrease was also measured after the first and third treatments, and defined as a decrease of one or more grades in tumor vascularity. Results were as follows (% of patients with decrease). For 40-120-microm particles: 1 and 3 treatments, 53% and 88% of patients. For 100-300-microm particles: 1 and 3 treatments, 60% and 88% of patients. For 300-500-microm particles: 1 and 3 treatments, 50% and 57% of patients. It was concluded the 100-300-microm EMBS particles produce slightly higher responses.
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PMID:Chemo-embolization for unresectable hepatocellular carcinoma with different sizes of embolization particles. 1804 45


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