Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From its discovery in 1986 tetranectin (TN) has been suggested to participate in proteolytic processes through its binding to plasminogen, which enhances the activation of plasminogen to plasmin. Because extracellular proteolysis is an important factor in the ability of malignant cells to infiltrate normal tissues and metastasize, TN was considered to be a potential marker for this proteolysis. We have studied the variations in blood and tissue levels of TN in clinical conditions such as cancer and infection, where increased proteolysis can be expected. Five monoclonal antibodies (MAbs) were produced against human TN, and our study is the first report of stable hybridomas producing MAbs against human TN. All the MAbs reacted with epitopes located within aa-residues 50-181 of the primary sequence. In relative epitope mapping with enzyme immuno assay and isotachophoresis the five MAbs defined two independent epitope groups. Different combinations of MAbs were suitable for enzyme immuno assays and two MAbs could be used for immunohistochemical detection of TN in both fresh frozen and paraffin embedded tissues. The MAbs will facilitate future studies on structure, function, clinical significance and immunolocalization of TN. In primary ovarian cancer neither s/p-TN nor CA 125 were found valuable for diagnosis of localized cancer versus benign tumors. However, s/p-TN combined with CA 125, increased both sensitivity and specificity. S/p-TN should therefore be considered one of the screening markers in conjunction with CA 125, or other comparable markers, in future ovarian cancer screening research studies. Preoperative s-TN was significantly correlated to residual tumor and survival in ovarian cancer patients undergoing second or third look surgery. In conjunction with CA 125 and CASA the predictive value of TN for residual tumor was greatly improved, as the markers were found to supplement each other. If the second look operation had been restricted to patients who had a marker negative test, up to 37% would have avoided surgery. We therefore recommend that these tests are included as potential selection parameters in other studies evaluating second-look surgery. Low p-TN concentration and heavy extracellular staining of TN in the tumors was significantly correlated with a poor prognosis for patients with localized stage I or II or advanced primary ovarian cancer. The prognostic information can be especially valuable for patients with a localized ovarian cancer stage I or II, because about 20% of these patients, believed to be radically operated later present with relapse. We found the p-TN level to be especially useful for patients with localized cancer, indicating that adjuvant chemotherapy may be considered if the p-TN level is low. For patients with advanced primary ovarian cancer and low p-TN the survival was significantly reduced compared to patients with a higher p-TN. The p-TN level was significantly negatively correlated to the extracellular (stromal) staining of TN in the tumors. A heavy stromal TN staining was correlated with a shortened survival and was an independent prognostic factor in the Cox analyses. Patients with advanced primary cancer and a low p-TN, possibly in combination with a heavy stromal staining of TN in the tumors, should tentatively be offered palliative treatment or experimental chemotherapy. Furthermore, patients receiving chemotherapy may be monitored by s/p-TN measurements, as a decrease in TN concentration indicated recurrence 3.6 months prior to clinical diagnosis. A decrease in TN concentration during chemotherapy may therefore indicate change of treatment. Serum TN was a very strong independent prognostic factor of poor treatment response and a shortened survival in patients with metastatic breast cancer. A low pre-chemotherapy s-TN value together with clinical signs of poor treatment response may be an ominous combination, which may suggest change of treatment. For patients with Dukes' stage
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PMID:Human tetranectin: methodological and clinical studies. 986 84

Angiostatin, an internal fragment of plasminogen, has been shown to inhibit the process of angiogenesis or neovascularization. In this study, we have expressed the cDNA for murine angiostatin under the control of the human cytomegalovirus promoter from a human type-5 adenovirus and shown that this vector produces a protein which retains biological activity. Angiostatin expression was determined by Northern blot analysis and Western immunoblotting. Ad-angiostatin, but not a control vector Ad-dl70, significantly reduced the viability of infected human umbilical cord vein endothelial cells (HUVEC) in vitro. In an in vivo model of basic fibroblast growth factor-induced angiogenesis, Ad-angiostatin (1 x 10(9) pfu) could inhibit endothelial cell migration and the formation of capillaries within a Matrigel plug which had been implanted for one week subcutaneously into C57BL/6 mice. Endothelial cells in these plugs had an altered, rounded, phenotype with dark picnotic nuclei indicative of apoptosis, which was confirmed using transmission electron microscopy. In contrast, endothelial cells from bFGF alone or in combination with the control vector-treated plugs retained the long spindle shape characteristic of endothelial cells. Intranasal delivery of Ad-angiostatin into the lungs of FVB/n mice demonstrated comparable cellular infiltration in the recovered bronchoalveolar lavage fluid with no signs of abnormal pathology as compared to PBS or control vector-treated animals. In a pulmonary metastatic breast cancer model, the delivery of Ad-angiostatin (1 x 10(9) pfu) to the lung significantly delayed tumor growth as measured by the number of visible surface tumor nodules. This study has demonstrated that the specific targeting of tumors to inhibit angiogenesis using an adenovirus expressing angiostatin, may deliver localized concentrations of protein having a greater impact on inhibition of tumor growth.
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PMID:Adenoviral vector expressing murine angiostatin inhibits a model of breast cancer metastatic growth in the lungs of mice. 1154 7

The urokinase-dependent activation of plasminogen by breast cancer cells plays an important role in metastasis. We have previously shown that the metastatic breast cancer cell line MDA-MB-231 over-expresses urokinase and binds and efficiently activates plasminogen at the cell surface compared to non-metastatic cells. The aim of this study was to further characterise plasminogen binding and determine the topology of cell surface-bound plasminogen in terms of its potential for activation. The lysine-dependent binding of plasminogen at 4 degrees C to MDA-MB-231 cells was stable and resulted in an activation-susceptible conformation of plasminogen. Topologically, a fraction of bound plasminogen was co-localised with urokinase on the surfaces of MDA-MB-231 cells where it could be activated to plasmin. At 37 degrees C plasmin was rapidly lost from the cell surface. Apart from actin, other candidate plasminogen receptors were either not expressed or did not co-localise with plasminogen at the cell surface. Thus, based on co-localisation with urokinase, plasminogen binding is partitioned into two functional pools on the surface of MDA-MB-231 cells. In conclusion, these results shed further light on the functional organisation of the plasminogen activation cascade on the surface of a metastatic cancer cell.
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PMID:The topology of plasminogen binding and activation on the surface of human breast cancer cells. 1155 45

Breast cancer is the most common malignancy afflicting Western women today and is responsible for many deaths due to metastatic disease. Upregulation of the plasminogen-activation system (PAS) has been shown to correlate with poor prognosis in metastatic breast cancer and targeting this system represents an attractive strategy for the development of anti-metastasis prophylactic drugs. Two promising classes of PAS-targeting agents are inhibitors of the serine protease activity of urokinase plasminogen activator (uPA) and antagonists of the interaction of uPA with its cell surface receptor (uPAR). This review begins with a brief overview of the role of PAS in cancer metastasis before describing in detail a subset of the small molecules and peptides from the patent literature that target either uPA activity or uPA/uPAR interactions for use as anti-metastasis drugs.
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PMID:Peptides and small molecules targeting the plasminogen activation system: towards prophylactic anti-metastasis drugs for breast cancer. 1828 19

Angiogenin (ANG), a 14-kDa pro-angiogenic secreted protein, has been shown to play a role in cell migration and tumor invasion, which involve proteolytic cleavage of plasminogen to generate plasmin. However, the mechanism by which ANG regulates plasmin formation and cell migration was not known. Our studies here detected elevated levels of secreted and cell surface-bound ANG in highly invasive metastatic breast cancer cells. ANG was also detected at very high levels in the tumor cells in infiltrating ductal carcinomas. By immunofluorescence and immunoprecipitation analysis, ANG was detected at the leading edges of the cell surfaces where it colocalized and interacted with members of the plasminogen activation system (PAS) such as annexin A2 (A2), calpactin (S100-A10) and urokinase plasminogen activator receptor (uPAR). Analysis of lipid raft (LR) and non-lipid raft (NLR) regions of the cell membranes showed the predominance of ANG, A2 and S100-A10 in the LR regions. In contrast, uPAR was detected predominantly in the NLR fractions, suggesting that ANG interacts with uPAR at the junctions of LR and NLR regions. ANG knockdown in T47D and MDA-MB-231 breast cancer cell lines did not affect the cellular expression of A2, S100-A10 and uPAR but decreased cell migration and plasmin formation. Neutralization of ANG with monoclonal antibodies similarly decreased the migration of MDA-MB-231 cells. In the presence of ANG, uPAR was observed to interact with uPA, which is necessary for plasmin formation. Conversely, in the absence of ANG, uPAR did not interact with uPA and FAK and Src kinases were observed to be dephosphorylated. Exogenous addition of recombinant ANG to ANG knocked down MDA-MB-231 cells restored FAK phosphorylation, uPAR interactions with uPA, plasmin formation as well as migration of these cells. Taken together, our results identified a novel role for ANG as a member of the uPAR interactome that facilitates the interaction of uPAR with uPA, leading to plasmin formation and cell migration necessary for tumor invasion and metastasis of breast cancer cells.
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PMID:Angiogenin interacts with the plasminogen activation system at the cell surface of breast cancer cells to regulate plasmin formation and cell migration. 2445

Cell surface expression of alpha-enolase, a glycolytic enzyme displaying moonlighting activities, has been shown to contribute to the motility and invasiveness of cancer cells through the protein non-enzymatic function of binding plasminogen and enhancing plasmin formation. Although a few recent records indicate the involvement of protein partners in the localization of alpha-enolase to the plasma membrane, the cellular mechanisms underlying surface exposure remain largely elusive. Searching for novel interactors and signalling pathways, we used low-metastatic breast cancer cells, a doxorubicin-resistant counterpart and a non-tumourigenic mammary epithelial cell line. Here, we demonstrate by a combination of experimental approaches that epidermal growth factor (EGF) exposure, like lipopolysaccharide (LPS) exposure, promotes the surface expression of alpha-enolase. We also establish Heat shock protein 70 (Hsp70), a multifunctional chaperone distributed in intracellular, plasma membrane and extracellular compartments, as a novel alpha-enolase interactor and demonstrate a functional involvement of Hsp70 in the surface localization of alpha-enolase. Our results contribute to shedding light on the control of surface expression of alpha-enolase in non-tumourigenic and cancer cells and suggest novel targets to counteract the metastatic potential of tumours.
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PMID:Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha-enolase to the cell surface. 2863 Apr 80

The overexpression of the oncogene human epidermal growth factor receptor 2 (HER-2) has been associated with decreased disease-free survival and is a marker of poor prognosis of invasive breast cancer. Although the high efficacy of trastuzumab, a drug that targets the HER-2 oncogene, has been widely recognized, the efficiency of the treatment remains at ~30%. Therefore, novel effective treatments are required for patients with recurrent metastatic breast cancer. The present study aimed to investigate the effects of an engineered antibody-like molecule administered alone or in combination with trastuzumab on the tumor growth and metastasis of HER-2-positive breast cancer. Another aim was to investigate novel cancer therapies for HER-2-positive breast cancer. The engineered antibody-like molecule consists of the amino-terminal fragment (ATF) of human urokinase-type plasminogen (uPA) and is conjugated with the Fc fragment of human immunoglobulin G1 (ATF-Fc). The anti-cancer effect of ATF-Fc (alone and in combination with trastuzumab) on tumor cells and in a nude mouse tumor model was evaluated by detecting the expression of uPA, urokinase plasminogen activator receptor (uPAR) and HER-2. In vitro experiments demonstrated that specifically blocking the uPA-uPAR and HER-2 signaling pathways may effectively promote the apoptosis of breast cancer cells. Additionally, ATF-Fc-induced cell death in HER-2-positive breast cancer cells was observed in vivo. When ATF-Fc was administered in combination with trastuzumab, cell death was increased and breast cancer metastasis was reduced. The novel engineered antibody-like molecule ATF-Fc was able to inhibit HER-2-positive breast cancer cell growth and metastasis by interfering with uPA and its receptor (uPA-uPAR) system. Additionally, the antibody-like molecule exhibits a synergistic inhibitory effect when administered in combination with trastuzumab.
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PMID:Synergistic inhibitory effects of an engineered antibody-like molecule ATF-Fc and trastuzumab on tumor growth and invasion in a human breast cancer xenograft mouse model. 2911 54