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)

The increased expression of proteolytic systems is one of the characteristics of transformed and malignant cells and their evaluations in whole tumor homogenates were considered as possible diagnostic and/or prognostic factors. Abnormal intracellular distribution, increased activities and secretion of cysteine proteinases (CPs) cathepsin B (Cat B) and L (Cat L), were associated with tumor progression. In the present study of matched pairs of breast carcinoma and normal breast tissue, the activities of Cat B and Cat L in breast carcinoma homogenates were found to be 20 and 50 fold higher, respectively, than in normal tissues. In contrast, a decrease in total inhibitory activity of cysteine proteinase inhibitors (CPIs) was observed but an average ratio between tumor and normal tissues was only 0.75. One of the CPIs, stefin A, was also determined immunochemically. The activities of CPs and CPIs were compared to the increased levels of cathepsin D (Cat D) activities in individual patients, but no statistically significant correlations were found. We correlated CPs and CPIs with morphological and receptor data as well as the axillary lymph node metastases. There was no statistical correlation of CP and CPIs with the number of lymph node metastases. However, highly elevated levels of Cat B and Cat L and lowered CPI activities in tumor cytosols were often associated with poorly differentiated carcinomas and those with negative ER and PR values. We conclude that cysteine-dependent proteolysis may play an important role in breast tumors.
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PMID:Cystatins and cathepsins in breast carcinoma. 151 89

We have evaluated in a homologous system the mechanisms of platelet activation by cells isolated from fresh human tumor tissues and the role of thromboxane B2 (TxB2) generation in this process. Thirty-eight of the 46 tumor tissues considered showed a high platelet-aggregating activity, with no particular distribution in any specific tumor type. Apyrase caused a nonsignificant reduction in the aggregation response, hirudin did not change it, while iodoacetic acid or p-hydroxymercuriphenylsulfonate, specific cysteine proteinase inhibitors, significantly reduced the platelet-aggregating capacity of these tumor cells. In 9 colon carcinomas and in 8 breast carcinomas the levels of TxB2 produced by platelets after addition of tumor cells were measured: tumor cell-induced platelet aggregation was accompanied by a significant production of the metabolite; indobufen, a cyclooxygenase inhibitor, significantly reduced aggregation and particularly TxB2 production, while the drug had no effect on both parameters if preincubated with tumor cells only. These data suggest that cells isolated from different human tumor tissues activate platelets through the activity of tumor-associated cysteine proteinase(s); platelet aggregation by tumor cells is largely dependent on arachidonic acid metabolism in platelets, while such metabolism in tumor cells does not play a significant role.
Invasion Metastasis 1991
PMID:Thromboxane production by platelets during tumor cell-induced platelet activation. 191 83

Several lysosomal proteinases including the cysteine proteinase cathepsin B have been implicated in malignant progression of tumors. Many investigators have demonstrated correlations between increased activity of cathepsin B and increased metastatic capability of animal tumors or malignancy of human tumors. Such increases in cathepsin B activity in malignant tumors may reflect alterations in synthesis, in activation and processing, and/or in intracellular trafficking and delivery as well as in the endogenous inhibitors of cathepsin B. Increases in mRNA transcripts for cathepsin B have been observed in both murine and human tumors and multiple transcripts for cathepsin B have been identified, but an association of multiple transcripts with malignancy has not been confirmed. Cathepsin B precursors found in human malignant ascites fluid do not possess mannose-rich carbohydrates suggesting that a defect in the post translational processing of carbohydrate moieties on tumor cathepsin B may be responsible for the release of cathepsin B observed in many tumor systems. However, the intracellular trafficking of cathepsin B responsible for its association with plasma membrane/endosomal systems and for its release will require further study as both latent, precursor forms of cathepsin B and native forms of cathepsin B are involved. We speculate that malignant tumor cells adherent to basement membrane are capable of forming a digestive microenvironment in which lysosomal proteinases such as cathepsin B function optimally, a microenvironment similar to that formed between adherent osteoclasts and bone. One of the endogenous cysteine proteinase inhibitors, stefin A, also is affected by malignancy. Reduced expression (mRNA and protein) of stefin A is found as well as a reduction in its inhibitory capacity against cysteine proteinases. The data to date at both the molecular and protein levels supporting a functional role(s) for cathepsin B and its endogenous inhibitors in cancer progression are only correlative. Experimental approaches utilizing well-defined model systems in conjunction with genetic manipulation of cathepsin B and its endogenous inhibitors are needed to provide convincing evidence that cathepsin B has an important role in cancer.
Cancer Metastasis Rev 1990 Dec
PMID:Cathepsin B and its endogenous inhibitors: the role in tumor malignancy. 209 84

The samples of breast cancer and cell lines MCF-7 and ZR-75-1 were tested for the occurrence of cysteine proteinase inhibitors ACPI and NCPI. Further, the influence of estradiol on the expression of these inhibitors was examined. Both the tested inhibitors were found in tumor cells and in cell lines. Moreover, the positivity was found also in the connective tissue, especially in the vicinity of dysplastic changes and normal lobules. The expression of both the inhibitors can be regulated by estrogens. The data indicate a possible connection of NCPI expression with the regulation of cell proliferation and ACPI with cellular differentiation. The role of these inhibitors in invasive processes and metastases is not clear so far.
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PMID:Demonstration of cysteine proteinase inhibitors ACPI and NCPI in breast cancer and in cell lines MCF-7 and ZR-75-1. 253 Aug 10

The cysteine proteinase cathepsin B (EC 3.4.22.1) is believed to take part in biochemical processes underlying tumor metastasis. In the present study, the cellular localization, intracellular levels and extracellular release of cathepsin B activity were examined in vitro in cells of two rat sarcoma variants, LW13K2 and RPS, differing in their capacity to metastasize spontaneously to the lung of syngeneic LEW/CUB rats. The LW13K2 sarcoma metastasizes rarely, whereas the LW13K2-derived RPS variant produces a metastasis incidence of above 50%. Using fluorescent cytochemical staining, microgranular reaction centers of cathepsin B were observed in the cell cytoplasm, in some cellular processes, with apical localization in some of them, as well as at the extreme cell periphery in cells of both sarcoma variants. The appearance of this distribution of cathepsin B activity was delayed in the RPS variant. Biochemically, the intracellular level of cathepsin B activity was significantly higher in homogenates of LW13K2 cells than RPS cells. In contrast to the intracellular enzyme activity, RPS cells cultured in serum-free medium at pH 6.5 released a substantially higher amount of cathepsin B activity than LW13K2 cells into the extracellular environment; at pH 7.4 the initially higher release of cathepsin B activity from RPS cells later equalized with that from LW13K2 cells. Taken together, the results indicate that changes of pericellular pH can modulate the extracellular release of cathepsin B in both sarcoma cell variants and suggest that the rate of cathepsin B release under conditions of mildly acid pericellular pH could be related to the incidence of metastases observed in these rat sarcoma variants. Total intracellular cathepsin B activity did not exhibit positive correlation with the metastatic potential of the studied rat sarcoma variants.
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PMID:Cathepsin B in cells of two rat sarcomas with different rates of spontaneous metastasis. 281 49

It has repeatedly been proposed that fibrin plays a role in tumor growth and metastasis. Among tumor cell products or activities which may promote clot formation, cancer procoagulant (CP), a direct activator of coagulation factor X, has been suggested to be selectively associated with the malignant phenotype. We report here the enzymatic and immunological identification of this cysteine proteinase procoagulant in extracts and cells from human melanoma. CP activity was independent of both the intrinsic and extrinsic pathways of blood coagulation, using factor IX and factor VII deficient plasmas, and was inhibited by the cysteine proteinase inhibitors iodoacetamide and HgCl2. CP activity was detectable in extracts and cell suspensions from all 32 patients studied and was higher in extracts from metastases (14.8 +/- 3.9 units/mg protein) than from the primary tumors (3.7 +/- 1.0 units/mg protein). CP activity was not affected by an anti-apoprotein III antibody or by concanavalin A, a known inhibitor of thromboplastin. In contrast, no CP activity or antigen was detected in extracts from six benign melanocytic lesions. The procoagulant activity was dependent on factor VII and was inhibited by anti-apoprotein III antibody and by concanavalin A, properties that suggest that the procoagulant was tissue thromboplastin. These data indicate that CP can be expressed by human tumor cells and that, among melanotic lesions, its presence is associated with the malignant phenotype and its activity is particularly high in metastatic cells.
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PMID:Cancer procoagulant in human tumor cells: evidence from melanoma patients. 353 81

In a previous work we found a correlation between in vivo metastatic potential of cancer cells and their platelet aggregating activity in sublines of the mFS6 murine fibrosarcoma. In the present study the effects of different proteinase inhibitors on platelet aggregation induced by these cells were investigated. When the platelets were incubated with the inhibitors, only those effective against cysteine proteinases strongly reduced platelet aggregation by cancer cells; serine protease inhibitors, including hirudin, had no effect on platelet response. Incubation of neoplastic cells with the same inhibitors gave similar, though less evident results. Addition of neoplastic cells to platelet-rich plasma also caused significant production of fibrinopeptide A, more by the less malignant cells. Thus, in this experimental model a cysteine proteinase of the neoplastic cells appears to play an important role in the platelet aggregation induced by them, and this property was detected in the M4 cells with high metastatic in vivo activity.
Invasion Metastasis 1986
PMID:Role of tumor proteinases in tumor cell-induced platelet aggregation. 353 93

The tissue levels of two proteolytic enzymes, plasminogen activator and cathepsin B - like cysteine proteinase, which were found to be increased in malignant tumors and to be proportional to tumor metastatic potential in some instances, have been determined in a panel of solid metastasizing tumors in mice. The examination of B16 melanoma, MCa mammary carcinoma and of two lines of Lewis lung carcinoma with widely different potential to spontaneously metastasize, showed no correlation between metastatic potential and the tissue content of the proteinases considered. The treatment of the animals with cytotoxic antitumor drugs (CCNU, GANU, cisplatin, and cyclophosphamide) or with antimetastatic drugs acting with a mechanism unrelated with cytotoxicity (ICRF 159 and DM-COOK) caused only marginal inhibition in some instances, whereas no meaningful pattern of inhibition either based in terms of metastatic potential of the tumor or on drug mechanism of action was recognizable. A direct involvement of the two proteinases examined in the process of metastasis in the tumor panel used is thus not apparent, although a more complex interaction with other latent proteinases and inhibitors might be operative.
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PMID:Proteinases and proteinase inhibition by cytotoxic and antimetastatic drugs in transplantable solid metastasizing tumors in mice. 389 94

Cysteine proteinases are a subclass of endopeptidases which require activation by thiol reagents. A tumor cysteine proteinase which appears to be related to lysosomal cathepsin B has been implicated in the ability of tumor cells to invade the extracellular matrix and to metastasize to secondary sites. Lysosomal cathepsin B can degrade such components of the extracellular matrix as collagen, fibronectin and proteoglycans. Activity of this cathepsin B-like cysteine proteinase (CB) has been correlated with tumor malignancy in a number of tumor lines yet not in all tumor lines studied. CB activity in tumors seems to be associated with the viable tumor cells, probably with the plasma membrane of these tumor cells. CB activity has been measured in the sera, urine, ascites fluid and pancreatic fluid of tumor-bearing patients. CB is released from tumor explants and tumor cells in vitro as well as from normal subcutaneous tissue exposed to tumor-conditioned medium. Cathepsin B from normal tissues is rapidly inactivated above pH 7.0. Therefore, CB in tumor cell membranes or released from tumor cells (or from host cells in response to tumor cells) may not possess proteolytic activity at neutral pH and thus may not facilitate tumor cell invasion. However, CB exhibits enhanced stability at neutral or slightly alkaline pH's. There is not yet definitive proof that CB plays a role in tumor invasion and metastasis. There is, however, an increasing body of correlative evidence relating CB activity and tumor malignancy. This correlative evidence plus preliminary evidence that tumor CB can degrade components of the extracellular matrix in vitro suggests that CB may be one proteinase active in a proteolytic cascade resulting in tumor invasion and metastasis.
Cancer Metastasis Rev 1984
PMID:Cysteine proteinases and metastasis. 609 95

Specimens of the rabbit V2 carcinoma were maintained in organ culture to study the secretion of proteinases. Elastase-like, chymotrypsin-like, plasminogen activator-like, cathepsin B-like and collagenase activities were assayed with sensitive fluorimetric techniques. Of these enzymes, the only activities that were secreted in considerable amounts in primary cultures of tumor tissue were collagenase and a cysteine proteinase resembling cathepsin B. Co-cultures of intraperitoneally grown tumor and normal subcutaneous tissue of the rabbit resulted in significantly higher production of the cysteine proteinase and collagenase compared to the sum of the activities of the separate tissues. Explants of subcutaneous tissue of tumor-bearing rabbits secreted significantly more cysteine proteinase and collagenase than explants from normal animals. Explants from normal subcutaneous tissue stimulated with tumor-conditioned culture medium secreted both enzymes in higher amounts compared to the controls. The cysteine proteinase was similar in some properties to rabbit liver cathepsin B, but the enzyme from the tumor-host system showed a remarkable stability to a moderately alkaline pH. We suggest that a diffusible factor, derived from the tumor or immigrated cells, promotes an increased synthesis and secretion of collagenase and cysteine proteinase in the host, and that both enzymes may play cooperative roles during invasion of the surrounding tissues by the V2 carcinoma.
Invasion Metastasis 1984
PMID:Extracellular cysteine proteinase and collagenase activities as a consequence of tumor-host interaction in the rabbit V2 carcinoma. 632 87


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