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)

Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. If detected early, it is easily treated by surgical excision. However, once melanoma metastasises it is notoriously resistant to existing therapies and for many patients the outlook is dismal. Thus a full description of melanoma etiology and a full understanding of the genetic lesions that underlie this disease is required to allow us to develop new and effective therapeutic strategies for its treatment. RAF proteins are a family of serine/threonine-specific protein kinases that form part of a signalling module that regulates cell proliferation, differentiation and survival. In mammals there are three isoforms, A-RAF, B-RAF and C-RAF, and recently it was shown that the B-RAF isoform is mutated in a high proportion of melanomas. In light of these exciting findings, we review what we have learned about B-RAF and its role in cutaneous melanoma.
Cancer Metastasis Rev 2005 Jan
PMID:The role of B-RAF in melanoma. 1578 79

Metastasis is one of the major causes of mortality in cancer. It is well known that the activities of cell surface serine proteases are especially enhanced in malignant tumors. Proteolytic degradation of the extracellular matrix and basal membrane is a crucial event for tumor cell invasion and metastasis formation. FOY-305 (Foypan), a remedy for tumor pancreatitis, is a broad spectrum synthetic serine protease inhibitor which inhibits enzymatic activities including trypsin, thrombin, kallikrein and plasmin. Using Lewis lung carcinoma cell, we found that FOY-305 inhibited both spontaneous and experimental pulmonary metastasis. Furthermore, the combined treatment of FOY-305 and a traditional anti-cancer drug, 5-FU or bleomycin, resulted in marked enhancement of anti-pulmonary metastatic activity.
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PMID:Antimetastatic activity of a synthetic serine protease inhibitor, FOY-305 (Foypan). 1579 65

Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DQ-collagen I (a bone matrix protein) and, for comparison, DQ-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, and this degradation was reduced by inhibitors of matrix metallo, serine, and cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells--cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, and LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.
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PMID:Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer. 1579 21

Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase C epsilon (PKC epsilon), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKC epsilon in breast cancer development and progression. High-density tissue microarray analysis showed that PKC epsilon protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKC epsilon staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKC epsilon was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKC epsilon in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKC epsilon levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKC epsilon MDA-MB231 clones was retarded by a striking 87% (P < 0.05) and incidence of lung metastases was inhibited by 83% (P < 0.02). PKC epsilon-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKC epsilon plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.
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PMID:Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. 1616 14

The ability of neoplastic cells to dissemination from a primary tumor to lymphatic nodes and to adjacent and distant tissues and organs is an inseparable feature of malignant tumors and the main cause of failure in their treatment. Metastasis formation is a multistage process which includes proteolysis, the motility and migration of cells, proliferation, and neoangiogenesis. In the first step, the cells released from the primary tumor have to penetrate to the blood or lymphatic vessels (intravasation), the road which dissemination follows. Circulating cells can then migrate through the walls of vessels to surrounding tissues (extravasation) where they settle, proliferate, and induce angiogenesis, creating metastases. Indispensable in the process of intra- and extravasation is the activation of proteolytic enzymes capable of degrading the extracellular matrix (ECM) surrounding the endothelium or creating the basement membrane of epithelial tissue in different organs. In this stage, the activation of proteolytic enzymes, such as proteinases of the plasmin system, serine proteinases, and matrix metalloproteinases (MMPs), is necessary. Simultaneously, changes occur in the expression of many superficial glycoproteins and factors responsible for cell adhesion (integrins) and intercellular communication (cadherins). Neoangiogenesis is connected with the expression of many markers of this process, among them vascular endothelial growth factor (VEGF), endoglin (CD105), a transmembranous glycoprotein which is a component of the receptor for transforming growth factor beta (TGFbeta), as well as neuropilin (NRP), the co-receptor for VEGF. Conventionally, the prognosis of neoplastic disease and its treatment are based mainly on exact clinical and histopathological staging. This prognosis could, however, be improved by measuring the molecular and cellular markers which play key roles in tumor progression. Understanding the cellular processes responsible for tumor dissemination can be useful not only in the diagnosis and prognosis of treatment results, but also in developing targeted drugs, selectively directed towards those factors responsible for tumor invasiveness, as well as in creating new therapeutic strategies permitting the use of such drugs. In the present review the authors concentrate mainly on one tumor type, colorectal carcinoma, in which distant metastases, predominantly to the liver, are the main cause of failure, in spite of surgical curing of the primary tumor.
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PMID:[Mechanisms of metastasis and molecular markers of malignant tumor progression. I. Colorectal cancer]. 1701 65

Over 70% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced stage III and IV disease. In spite of aggressive therapy, locoregional disease recurs in 60% and metastatic disease develops in 15% to 25% of patients causing a major decline in quality and length of life. Therefore, there is a need to identify and understand genes that are responsible for inducing an aggressive HNSCC phenotype. Evidence has shown that protein kinase C (PKC) epsilon is a transforming oncogene and may play a role in HNSCC progression. In this study, we determine the downstream signaling pathway mediated by PKC epsilon to promote an aggressive HNSCC phenotype. RNA interference knockdown of PKC epsilon in UMSCC11A and UMSCC36, two highly invasive and motile HNSCC cell lines with elevated endogenous PKC epsilon levels, resulted in cells that were significantly less invasive and motile than the small interfering RNA-scrambled control transfectants; 51 +/- 5% (P < 0.006) and 49 +/- 3% (P < 0.010) inhibition in invasion and 69 +/- 1% (P < 0.0005) and 66 +/- 3% (P < 0.0001) inhibition in motility, respectively. PKC epsilon-deficient UMSCC11A clones had reduced levels of active and serine-phosphorylated RhoA and RhoC. Moreover, constitutive active RhoA completely rescued the invasion and motility defect, whereas constitutive active RhoC completely rescued the invasion and partially rescued the motility defect of PKC epsilon-deficient UMSCC11A clones. These results indicate that RhoA and RhoC are downstream of PKC epsilon and critical for PKC epsilon-mediated cell invasion and motility. Our study shows, for the first time, that PKC epsilon is involved in a coordinated regulation of RhoA and RhoC activation, possibly through direct post-translational phosphorylation.
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PMID:Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. 1701 91

We have isolated a novel soluble factor(s), neutrophil activator of matrix metalloproteinases (NAM), secreted by unstimulated normal human peripheral blood neutrophils that causes the activation of cell secreted promatrix metalloproteinase-2 (proMMP-2). Partially purified preparations of NAM have been isolated from the conditioned media of neutrophils employing gelatin-Sepharose chromatography and differential membrane filter centrifugation. NAM activity, as assessed by exposing primary human umbilical vein endothelial cells (HUVEC) or HT1080 cells to NAM followed by gelatin zymography, was seen within one hour. Tissue inhibitor of metalloproteinase-2 (TIMP-2) and hydroxamic acid derived inhibitors of MMPs (CT1746 and BB94) abrogated the activation of proMMP-2 by NAM, while inhibitors of serine and cysteine proteases showed no effect. NAM also produced an increase in TIMP-2 binding to HUVEC and HT1080 cell surfaces that was inhibited by TIMP-2, CT1746, and BB94. Time-dependent increases in MT1-MMP protein and mRNA were seen following the addition of NAM to cells. These data support a role for NAM in cancer dissemination.
Clin Exp Metastasis 2006
PMID:Neutrophil activator of matrix metalloproteinase-2 (NAM). 1708 59

HtrA1 is a serine protease homologue to the bacterial serine-protease HtrA, also known as DegP, a heat shock-induced envelope-associated serine protease. It has been shown that over-expression of HtrA1 in human cancer cells inhibits cell growth and proliferation in vitro and in vivo, thus, suggesting a possible role as a tumor suppressor. The expression of HtrA1 was investigated in depth by means of immunohistochemistry in a large group of human lung cancer specimens and corresponding lymph node metastases. Univariate analysis showed, that the only statistically significant correlation was found between the HtrA1 expression level detected in the primary tumors and in the lymph node metastases. This result was also confirmed when the analysis was restricted only to the cases where both the primary tumor and the autologous lymph node metastasis were available. Our data suggest that HtrA1 may be involved in lung cancer progression by targeting several molecular pathways.
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PMID:Analysis of HtrA1 serine protease expression in human lung cancer. 1709 66

Influence of NSE on lipid composition of metastases and the neighbouring conditionally normal lung tissue in mice with Lewis carcinoma was investigated. The processes of peroxidation in investigated tissues were also studied. It was shown that under the influence of NSE the high level of antioxidant activity in the metastases was decreased, while in the neighbouring conditionally normal lung tissue the catalase activity was increased. The content of the thiobarbituric acid-reactive substances in comparison with animals which were not fed by NSE was decreased. The development of carcinoma was accompanied by significant decrease of cholesterol level and by the increase of unsaturated fatty acids esterified in membrane phospholipids in both the metastases and the neighbouring conditionally normal lung tissue. An analysis of the phospholipid spectra shows that under tumor growth in investigated tissues the high-level lysophosphatidylcholine (LPC) was observed. The content of phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), phosphatidyl serine (PS) was found to be significantly lower than in the lung of intact animals. It was found that administration of NSE to tumor-bearing mice contributed to the increase of cholesterol level, to the decrease of omega-6/omega-3 ratio polyunsaturated fatty acids of total phospholipids. NSE modulated the phospholipid membrane composition in both the metastases and the neighbouring conditionally normal lung tissue.
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PMID:[The effect of N-stearoylethanolamine on lipid composition of the metastases and conditionally normal lung tissue in mice with Lewis carcinoma]. 1710 Feb 91

Insulinomas represent the predominant syndromic subtype of endocrine pancreatic tumors (EPTs). Their metastatic potential cannot be predicted reliably using histopathological criteria. In the past few years, several attempts have been made to identify prognostic markers, among them TP53 mutations and immunostaining of p53 and recently cytokeratin 19 (CK19). In a previous study using conventional comparative genomic hybridization (CGH) we have shown that chromosomal instability (CIN) is associated with metastatic disease in insulinomas. It was our aim to evaluate these potential parameters in a single study. For the determination of CIN, we applied CGH to microarrays because it allows a high-resolution detection of DNA copy number changes in comparison with conventional CGH as well as the analysis of chromosomal regions close to the centromeres and telomeres, and at 1pter-->p32, 16p, 19 and 22. These regions are usually excluded from conventional CGH analysis, because they may show DNA gains in negative control hybridizations. Array CGH analysis of 30 insulinomas (15 tumors of benign, eight tumors of uncertain and seven tumors of malignant behavior) revealed that >or=20 chromosomal alterations and >or=6 telomeric losses were the best predictors of malignant progression. A subset of 22 insulinomas was further investigated for TP53 exon 5-8 gene mutations, and p53 and CK19 expression. Only one malignant tumor was shown to harbor an arginine 273 serine mutation and immunopositivity for p53. CK19 immunopositivity was detected in three malignant tumors and one tumor with uncertain behavior. In conclusion, our results indicate that CIN as well as telomeric loss are very powerful indicators for malignant progression in sporadic insulinomas. Our data do not support a critical role for p53 and CK19 as molecular parameters for this purpose.
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PMID:Molecular parameters associated with insulinoma progression: chromosomal instability versus p53 and CK19 status. 1712 12


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