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)

Cancer dissemination and metastasis is synonymous with invasive cell migration; a process in which the extracellular matrix (ECM) plays the dual role of the substratum on which the cells move as well as the physical obstacle that the cells have to surpass. To degrade the physical obstacle, which the ECM poses in the direction of migration, cells use proteolytic enzymes capable of degrading the ECM components. A major protease system responsible for ECM degradation is the plasminogen activation system, which generates the potent serine protease plasmin. The subject of this review, the urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays an impressive range of distinct, but overlapping functions in the process of cancer invasion and metastasis: Firstly, uPA/uPAR promotes extracellular proteolysis by regulating plasminogen activation. Secondly, uPA/uPAR regulates cell/ECM interactions as an adhesion receptor for vitronectin (Vn) and through its capacity to modulate integrin function. Thirdly, uPA/uPAR regulates cell migration as a signal transduction molecule and by its intrinsic chemotactic activity. This review is focused on recent insight into the cancer related biology of the uPA/uPAR system as well as its implications for clinical cancer diagnosis, prognosis and therapy.
Cancer Metastasis Rev
PMID:The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. 1278 97

Prothrombin, a protein involved in blood coagulation, is a plasma glycoprotein composed of the Gla domain, two adjacent kringle domains, and a serine protease domain. Kringles are triple-disulfide-loop folding domains, which are found in several other blood proteins. In this study, we showed that recombinant human prothrombin kringle-1, -2. and -1-2 (rk-1, -2, -1-2) all have potent anti-angiogenic activities, which inhibit Lewis lung carcinoma (LLC) tumor growth and metastases. Recombinant human prothrombin kringles were expressed by an E. coli expression system and purified to apparent homogeneity from crude E. coli extracts. Purified rk-1, -2, -1-2 migrated with a molecular mass of 14, 19, and 31 kDa, respectively, on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. rk-1, -2, -1-2 exhibited potent inhibitory effects on bFGF-stimulated bovine capillary endothelial cell growth with half-maximal concentrations (ED50) of approximately 41, 55, and 156 nM, respectively. All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane (CAM) of chick embryos at a dose of 20 microg. Systemic administration of rk-1, -2, -1-2 at a dose of 0.5 mg/kg/day suppressed the growth of primary LLC and at dose of 0.5 and 1.0 mg/kg/day inhibited LLC metastases in C57BL6/J mice lungs through their anti-angiogenic effects.
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PMID:Recombinant human prothrombin kringles have potent anti-angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases. 1283 Oct 60

Seprase is a cell surface serine protease that is expressed to high levels by infiltrating ductal carcinomas of the breast but its function in malignancy is unknown. MDA-MB-435 (WT435) and MDA-MB-436 (WT436) human breast cancer cells express high levels of seprase as do the carcinoma cells in tumors of human breast cancer patients. To investigate its role in the pathobiology of breast cancer, seprase was specifically reduced in WT436 and WT435 cells by expression of antisense seprase cDNA. Decreased expression of seprase was confirmed in the antisense transfectants by zymography, immunoblotting, and fluorescence-activated cell sorting of cells labeled with antibody to seprase. Control-transfectants continued to express high levels of seprase. Seprase-deficient cells growing on type I collagen gels reveal a markedly different morphology than the parental or control-transfected cells that express high levels of seprase. The seprase-deficient cells grow in islands and aggregates of tightly attached cells while cells with high seprase expression grow as groups of separate individual cells. Interestingly, the aggregated growth of the seprase-deficient cells was not correlated with increased expression of E-cadherin. Seprase-deficient breast cancer cells also exhibit altered growth properties. Seprase-deficient cells and those with high seprase levels proliferate in serum-containing media. However, in serum-free medium seprase-deficient cells proliferate much more slowly than their seprase-expressing counterparts. These findings indicate that seprase promotes the aberrant growth of breast cancer cells by reducing their dependence on exogenous growth factors. Seprase may contribute to the pathogenesis of breast cancer by promoting growth of the primary tumor and by facilitating the growth of breast cancer cells in metastases at other sites of the body.
Clin Exp Metastasis 2003
PMID:Seprase, a membrane-bound protease, alleviates the serum growth requirement of human breast cancer cells. 1452 36

The serine protease urokinase-type plasminogen activator (uPA) interacts with a specific receptor (uPAR) on the surface of various cell types, including tumor cells, and plays a crucial role in pericellular proteolysis. High levels of uPA and uPAR often correlate with poor prognosis of cancer patients. Therefore, the specific inhibition of uPA with small molecule active-site inhibitors is one strategy to decrease the invasive and metastatic activity of tumor cells. We have developed a series of highly potent and selective uPA inhibitors with a C-terminal 4-amidinobenzylamide residue. Optimization was directed toward reducing the fast elimination from circulation that was observed with initial analogues. The x-ray structures of three inhibitor/uPA complexes have been solved and were used to improve the inhibition efficacy. One of the most potent and selective derivatives, benzylsulfonyl-D-Ser-Ser-4-amidinobenzylamide (inhibitor 26), inhibits uPA with a Ki of 20 nm. This inhibitor was used in a fibrosarcoma model in nude mice using lacZ-tagged human HT1080 cells, to prevent experimental lung metastasis formation. Compared with control (100%), an inhibitor dose of 2 x 1.5 mg/kg/day reduced the number of experimental metastases to 4.6 +/- 1%. Under these conditions inhibitor 26 also significantly prolonged survival. All mice from the control group died within 43 days after tumor cell inoculation, whereas 50% of mice from the inhibitor-treated group survived more than 117 days. This study demonstrates that the specific inhibition of uPA by these inhibitors may be a useful strategy for the treatment of cancer to prevent metastasis.
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PMID:Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents. 1515 Feb 79

Raf kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding protein (PEBP) family. RKIP plays a pivotal modulatory role in several protein kinase signaling cascades. RKIP binds inhibits Raf-1-mediated phosphorylation of MEK through binding to Raf-1. Protein kinase C (PKC) phosphorylates RKIP, resulting in release of Raf-1 and activation of MEK and ERK. The phosphorylated RKIP binds to and inhibits G-protein-coupled receptor kinase, resulting in sustained G-protein signaling. The regulatory role that RKIP has in cell signaling is reflected in its role in physiology and pathophysiology. RKIP is involved in neural development, cardiac function and spermatogenesis and appears to have serine protease activity. In addition to its roles in physiology, dysregulated RKIP expression has the potential to contribute to pathophysiological processes including Alzheimer's disease and diabetic nephropathy. RKIP has been shown to fit the criteria of being a metastasis suppressor gene, including having decreased expression in prostate cancer metastases and restoring RKIP expression in a prostate cancer cell line diminishes metastasis in a murine model. Clearly, RKIP has multiple molecular and cellular functions. In this review, RKIP's molecular roles in intracellular signaling, its physiological functions and its role in disease are described.
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PMID:The role of Raf kinase inhibitor protein (RKIP) in health and disease. 1531

The plasminogen system is important in the proteolytic cascade that facilitates angiogenesis, a process that is essential for tumor growth and metastasis. The serine protease plasmin has a central role in the plasminogen system. This protease acts by degrading several components of the basement membrane and by activating other proteases. Therefore, inhibition of plasmin may be an effective method for blocking angiogenesis and, as a result, inhibiting the growth of primary tumors and secondary metastases. Three pairs of plasmin inhibitors were synthesized to compare the relative potency of inhibitors that are based upon a cyclohexanone or a tetrahydro-4H-thiopyran-4-one 1,1-dioxide nucleus. Compounds 1, 3, and 5 were cyclohexanone-based inhibitors, whereas compounds 2, 4, and 6 were tetrahydro-4H-thiopyran-4-one 1,1-dioxide-based inhibitors. Compounds 5 and 6 are reasonable inhibitors with IC50 values of 25 and 5.5 microM, respectively. Comparisons of the IC50 values of the three pairs show that the electron-withdrawing sulfone functional group is a beneficial element for the design of plasmin inhibitors. The presence of the sulfone increases inhibitor potency by a factor of 3-5 when compared to inhibitors that are based upon a simple cyclohexanone core.
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PMID:A comparison of cyclohexanone and tetrahydro-4H-thiopyran-4-one 1,1-dioxide as pharmacophores for the design of peptide-based inhibitors of the serine protease plasmin. 1620 72

Hepsin is a type II transmembrane serine protease that is expressed in normal liver, and at lower levels in kidney, pancreas, and testis. Several studies have shown that hepsin mRNA is significantly elevated in most prostate tumors, as well as a significant fraction of ovarian and renal cell carcinomas and hepatomas. Although the overexpression of mRNA in these tumors has been extensively documented, there has been conflicting literature on whether hepsin plays a role in tumor cell growth and progression. Early literature implied a role for hepsin in human tumor cell proliferation, whereas recent studies with a transgenic mouse model for prostate cancer support a role for hepsin in tumor progression and metastases. To evaluate this issue further, we have expressed an activatable form of hepsin, and have generated a set of monoclonal antibodies that neutralize enzyme activity. The neutralizing antibodies inhibit hepsin enzymatic activity in biochemical and cell-based assays. Selected neutralizing and nonneutralizing antibodies were used in cell-based assays with tumor cells to evaluate the effect of antibodies on tumor cell growth and invasion. Neutralizing antibodies failed to inhibit the growth of prostate, ovarian, and hepatoma cell lines in culture. However, potent inhibitory effects of the antibodies were seen on invasion of ovarian and prostate cells in transwell-based invasion assays. These results support a role for hepsin in tumor cell progression but not in primary tumor growth. Consistent with this, immunohistochemical experiments with a mouse monoclonal antibody reveal progressively increased staining of prostate tumors with advanced disease, and in particular, extensive staining of bone metastatic lesions.
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PMID:Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture. 1658 86

We used cDNA microarrays to study gene expression in fresh frozen papillary thyroid carcinoma (PTC) specimens. Seven clinically aggressive carcinomas were included, comprising poorly differentiated PTC and tumors with extensive local invasion or synchronous distant metastases. Ten differentiated (classic) papillary thyroid carcinomas (PTC) and non-neoplastic thyroid tissues were also investigated. TaqMan quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry verified the differential gene expression. The B-Raf gene was mutated with a T-->A transversion at nucleotide 1799 (V600E) in 8 of 10 differentiated PTC, and in 4 of 7 aggressive carcinomas. Among genes markedly and equally over-expressed in carcinomas of both the aggressive and classic PtC groups, compared to normal thyroid tissue, were CBP/p300 transactivator (CItED1), fibronectin, growth/differentiation factor 15, potassium inwardly rectifying channel KCNJ2, glutaminyl peptide cyclotransferase, WNT7A, and dipeptidyl peptidase IV. A marked upregulation in carcinomas of P-cadherin mRNA and protein concomitant with E-cadherin downregulation, indicates a possible P-E cadherin "switch" in PTC. The growth factor homologue Nel-like 2, dual specificity phosphatase 5, the serine protease kallikrein 10, and also the tight junction genes claudin 1 and claudin 16, were upregulated in classic PTC but not in aggressive tumors, which may be consistent with altered cell polarity in the dedifferentiated PtC. The aggressive, poorly differentiated PtC group was specifically characterized by marked upregulation of several genes related to cell proliferation such as cell division cycle 2 (CDC2), CDC7, kinesin-like 5, ubiquitin conjugating enzyme E2C, and topoisomerase IIalpha, and by upregulation of genes encoding extracellular matrix proteins such as seprase, extracellular matrix protein 1, and several collagens. These aggressive tumors were also characterized by overexpression of the integrin ligand periostin, and in some biopsies also of osteopontin and of the upstream Rac-regulator dedicator of cytokinesis 10 (DOCK10). These data are interpreted to be consistent with altered cell motility, extracellular matrix remodeling and increased cell proliferation, as important processes in PTC tumor progression.
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PMID:Gene expression in poorly differentiated papillary thyroid carcinomas. 1667 2

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

Prostate cancer cells, like normal prostate epithelial cells, produce high levels of the differentiation marker and serine protease prostate-specific antigen (PSA). PSA is used extensively as a biomarker to screen for prostate cancer, to detect recurrence following local therapies, and to follow response to systemic therapies for metastatic disease. While much is known about PSA's role as a biomarker, only a relatively few studies address the role played by PSA in the pathobiology of prostate cancer. Autopsy studies have documented that not only do prostate cancer cells maintain production of high amounts of PSA but they also maintain the enzymatic machinery required to process PSA to an enzymatically active form. A variety studies performed over the last 10 years have hinted at a role for PSA in growth, progression, and metastases of prostate cancer. A fuller understanding of PSA's functional role in prostate cancer biology, however, has been hampered by the lack of appropriate models and tools. Therefore, the purpose of this review is not to address issues related to PSA as a biomarker. Instead, by reviewing what is known about the genetics, biochemistry, and biology of PSA in normal and malignant prostate tissue, insights may be gained into the role PSA may be playing in the pathobiology of prostate cancer that can connect measurement of this biomarker to an understanding of the underlying etiology and progression of the disease.
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PMID:Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer? 1714 82


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