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)

We performed coagulation profiles including a complete blood count (CBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), and quantitation of fibrinogen, antithrombin III (AT III), plasminogen, and fibrin/fibrinogen degradation products (FDP) on 73 cancer patients. All had solid tumors with clinically documented metastases. Eleven patients had strong clinical and laboratory evidence of disseminated intravascular coagulation (DIC). Fifty-five of the remaining 62 patients had no clinical evidence of serious hemorrhage or thrombosis at the time of testing. Thirty-one (50%) non-DIC patients had no abnormal clotting tests. Our data indicate that a majority of cancer patients, with or without hepatic involvement, are able to maintain normal or near normal hemostatic function in vitro until advanced stage of disease. Deviation from normal for PT, aPTT, or TT, depressed AT III activity, or increased FDP signal the presence of complicating pathophysiologic events such as DIC or cirrhosis. Diminution of fibrinogen level or AT III activity and elevation of FDP are more sensitive indicators of DIC than prolongation of PT, aPTT, or TT.
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PMID:Hemostatic function in cancer patients. 739 48

The phenomenon of inhibition of tumor growth by tumor mass has been repeatedly studied, but without elucidation of a satisfactory mechanism. In our animal model, a primary tumor inhibits its remote metastases. After tumor removal, metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kDa plasminogen fragment that we have sequenced and named angiostatin. A corresponding fragment of human plasminogen has similar activity. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by angiostatin.
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PMID:Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. 752 76

The prerequisite for a curative resection of metastases is their restriction to the key organs, the liver and lungs, in the sense of a limited dissemination. For long-term prognosis, the type of primary tumor as well as the radical resection of lung and liver metastases is essential. To improve the process of surgical indication and therapy of tumors, clear definitions for the terms "tumor recurrence" and "metastases" have been agreed upon. Research and clinical investigation have led to a better understanding of tumor-regulating factors, some of which are briefly described: Metastasis promoting factors include the lack of E-cadherin, which leads to a local penetration of basal membranes by tumor cells; CD44 seems to play an important role in cell-cell and cell-matrix interactions, apparently increasing the metastatic potential of tumors and reducing the long-term survival of patients. High levels of urokinase in primary tumors are also associated with a poorer prognosis, as well as plasminogen inactivator inhibitor PAI II, which plays a crucial role in tumor growth. Positive findings in bone marrow aspirates of patients with different malignancies, stained for cytokeratin 18, either are associated with higher recurrence rates in colon and breast cancer or can be correlated to the prognosis of patients with gastric cancer. Technical aspects of surgery for hepatic, pulmonary and skeletal metastases are presented and discussed with respect to curative and palliative indications.
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PMID:Surgical treatment of tumor metastases: general considerations and results. 753 64

Secretion of plasminogen activators (PA) has been shown to be an important method by which cells can initiate degradation of the extracellular matrix (ECM). In this study we have examined the PA production of two murine cell lines, KHT-LP1, a fibrosarcoma and SCC-VII, a squamous cell carcinoma, and have found a high degree of clonal heterogeneity. Our method for assaying PA activity measures the PA activity of small colonies of cells derived from single cells, using an in vitro fibrin/agarose PA assay in which colonies with PA activity form discernable 'halos' in the fibrin/agarose semisolid growth medium. When these small colonies of cells were disassociated and the component cells were reassayed for PA activity it was again found to be heterogeneous, suggesting that this property can be generated during the growth of the colonies. KHT-LP1 cells derived from single cell clones were assayed for PA activity to determine the rate at which this phenotype was produced. It was found that the rate of formation of the PA activity phenotype was 6.5 x 10(-6) events per cell generation. The component cells of colonies which initially demonstrated high PA activity produced more PA activity than the component cells of the colonies that had low PA activity. This suggests that some aspects of the phenotype may be more stable than others. To examine whether the addition of lethally irradiated cells could stabilize the phenotype we determined whether fibrin/agarose PA assays supplemented with lethally irradiated cells would reduce the heterogeneity of PA activity. The results indicated that the heterogeneity was not reduced, and there was an increase in the average amount of PA activity.
Clin Exp Metastasis 1995 Nov
PMID:Clonal heterogeneity in plasminogen activator activity produced by two murine tumor cell lines. 758 2

Proteolytic activity is important for tumor growth and metastasis. Plasminogen and urokinase-type plasminogen activator (u-PA) constitute one of the most extensively studied proteolytic systems believed to participate in these processes. u-PA cleaves plasminogen to plasmin, which in turn degrades surrounding extracellular matrix and allows tumor cells to migrate to other areas. The specific receptor for u-PA (u-PAR) has also been implicated as an essential modulator in this pathway. Eleven paired samples of colorectal cancers and normal mucosal tissues from the same patients were removed at surgery. The tissues were homogenized and the supernatants assayed for u-PAR immunoreactivity, u-PAR antigen concentration, u-PAR binding activity and u-PA activity. Immunoblot analysis showed that a major u-PAR species of approximately 55 kDa was present in all tissues. In addition, a protein band of approximately 41 kDa, which crossreacted with anti-u-PAR antibodies, was also found in the tumors. This protein band was either absent, or present in relatively small amounts in the normal colorectal tissues. Cross-linking experiments showed that the approximately 55 kDa band only, and not the approximately 41 kDa band, was able to bind either single chain urokinase-type plasminogen activator (scu-PA) or the amino terminal fragment of urokinase (ATF). The tumor samples also exhibited highly elevated u-PA activity and u-PAR antigen relative to the corresponding normal tissues. Elevated u-PA activity appeared to correlate with elevated u-PAR antigen in colorectal cancers, but not in the normal tissues. These increases were also associated with increase of the u-PAR-related, low-molecular-weight protein in the tumor samples. The measurement of u-PAR and the u-PAR-related protein, in addition to u-PA activity, could have diagnostic or prognostic value in this type of cancer.
Clin Exp Metastasis 1995 Nov
PMID:Increase of a urokinase receptor-related low-molecular-weight molecule in colorectal adenocarcinomas. 758 7

Invasive tumor growth or severe inflammation is accompanied by the extravasation of fibrinogen from leaky or damaged blood vessels and the formation of a fibrin clot. The clot provides a matrix for the inward migration ('invasion,' 'infiltration') of tumor cells as well as inflammatory cells. The factors that govern the cell/fibrin interaction are not known. We have explored in vitro the possible role of the cell-surface-associated pathway of plasminogen activation in the adhesion of keratinocytes to fibrin and in the invasion of melanoma cells into fibrin gels. Our experiments provided evidence that generation of plasmin at the cell surface destabilizes the adhesive interaction between keratinocytes and fibrin, most likely by cleaving fibrin into fibrinopeptides and destroying its adhesive capacity. Moreover, we found that plasmin generated at the melanoma cell surface promotes the inward migration of these cells into three-dimensional fibrin matrices. In conclusion, the generation of plasmin at the cellular surface may be an important factor in pericellular proteolysis and the dynamic interaction between cells and fibrin-containing pericellular matrix under conditions of tumor invasion and inflammation.
Invasion Metastasis
PMID:Plasmin in pericellular proteolysis and cellular invasion. 765 14

Many enzymes capable of proteolytic degradation of extracellular matrix and basement membranes have been implicated in tumor progression, including the matrix metalloproteinases, cathepsins, plasminogen activators, and heparanase. Matrix metalloproteinases, a family of zinc-dependent proteases, participate in several steps in tumor progression, including invasion, metastasis, and angiogenesis. In this review, we will give a brief overview of this protease family, and we will review in vitro and in vivo evidence implicating a particular metalloproteinase, the 92-kD type IV collagenase/gelatinase (MMP-9 or gelatinase B), as well as other metalloproteinases, in cancer progression. Finally, using recent studies from our laboratory, we will demonstrate the importance of both tumor cell and host stromal cell production of MMP-9 in tumor progression.
Invasion Metastasis
PMID:Metalloproteinases in tumor progression: the contribution of MMP-9. 765 17

The human colon carcinoma cell lines Co112 and Co115 are both invasive in nude mice following intraperitoneal implantation. Co115 cells only exhibit metastasis capacity under this condition. Characterization of the plasminogen activation system demonstrates that Co112 cells express the urinary-type plasminogen activator (uPA) and Co115 cells the tissue-type (tPA), exclusively. Immunocytochemical analyses revealed that the in vitro plasminogen-dependent lysis of exogenous basement membrane laminin induced by Co112 cells displayed a gradient-like pattern, whereas, in the case of Co115 cells, it was sharply confined to the pericellular area. Double-labeling experiments showed that uPA on Co112 and tPA on Co115 cells are cell-surface-associated constituents. The cellular distribution of laminin expressed by tumor cells themselves appears to be distributed homogeneously in the cytoplasm of both cell types. We suggest that the extracellular matrix degradation induced by tumor cell surface-associated plasmin implies two different mechanisms which are specifically related to uPA or to tPA, both contributing to matrix degradation and malignant invasion.
Invasion Metastasis
PMID:Laminin degradation by human colon carcinoma cells: a role for urinary and tissue plasminogen activators. 765 15

Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's). It has been contemplated that these inhibitors counteracted the proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications. 766 68

Human carcinomas of the oesophagus, stomach, colorectum, and their liver metastases were previously shown to have increased levels of the urokinase-type plasminogen activator (u-PA). The proteolytic activity of u-PA on the surface of tumour cells is thought to play a key role in invasion and metastasis of malignancies. Therefore, in this study we quantitatively determined the presence of specific u-PA receptors in human gastrointestinal carcinomas, premalignant colonic adenomas, liver metastases, and adjacent normal tissues. All carcinomas showed a 2- to 13-fold higher level of u-PA receptor than their corresponding normal tissues at both the antigen level (ELISA) and the mRNA level (Northern blotting). Colonic adenomas also showed enhanced levels of the u-PA receptor protein. The state of occupancy of the u-PA receptors was determined using a specific ligand-binding assay in which free u-PA receptors were cross-linked with 125I-u-PA and visualized by autoradiography. Colonic carcinomas and liver metastases contained higher levels of free u-PA receptor compared to their corresponding normal tissues. Acid treatment of the receptors prior to cross-linking did not enhance the u-PA/u-PA receptor complex formation. The free u-PA receptor levels in colonic adenomas and in oesophageal and stomach carcinomas showed less difference compared with their normal reference tissues. The increased presence of specific receptors for u-PA in gastrointestinal carcinomas, particularly primary colonic carcinomas and their metastatic lesions in the liver, emphasizes the involvement of the urokinase pathway of plasminogen activation in gastrointestinal carcinogenesis and renders it a putative target for clinical intervention.
Invasion Metastasis 1993
PMID:Increased urokinase receptor levels in human gastrointestinal neoplasia and related liver metastases. 786 Feb 21


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