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)

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

Cathepsin B activity, including that of a plasma membrane-associated cathepsin B, has been linked to tumor malignancy. As cathepsin B at the tumor cell surface has been hypothesized to play a role in the focal degradation of basement membrane during the metastatic cascade, we have examined the ability of human tumor cathepsin B to degrade laminin, an adhesive glycoprotein found exclusively in the basement membrane. We report that at pH 6.5 and 7.0 tumor cathepsin B degraded by specific, limited proteolysis both subunits of native laminin. The disappearance of both subunits and the appearance of lower Mr protein bands could be observed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Accumulation of degradation products was also observed using gel filtration chromatography and a fluorescamine assay. The proteolysis of laminin by tumor cathepsin B could be inhibited by an active site titrant for cysteine proteinases or stefin B, an endogenous low-Mr cysteine proteinase inhibitor.
Clin Exp Metastasis
PMID:Degradation of laminin by human tumor cathepsin B. 278 14

Organ cultures of explanted V2 carcinoma specimens as well as cultured V2 carcinoma cells produced a cytokine which stimulated rabbit skin fibroblasts to synthesize increased amounts of cathepsin B. The cytokine was released by the tumor cells as a heterogeneous family of polypeptides: two inactive forms (Mr = 55,000 and 68,000) which could be activated by limited proteolysis with trypsin and three active forms with Mr values of 12,000, 16,000 and 18,000. The treatment of inactive cytokine-containing tumor-conditioned media with trypsin, followed by chromatographic separation of the products, suggested that the high-Mr inactive components may represent precursors of the active forms. Cathepsin B was immunolocalized in the tumor-host interzone in co-cultures of tumor and host tissues. Some other possible activities of the tumor cytokine which emerged from previous studies, such as the induction of host cells to produce increased levels of collagenase and extracellular matrix, as well as the stimulation of host cell proliferation, are discussed in the light of the new findings and are proposed as an important mechanism in tumor invasion.
Invasion Metastasis 1988
PMID:Tumor-host interactions in the rabbit V2 carcinoma: stimulation of cathepsin B in host fibroblasts by a tumor-derived cytokine. 328 70

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

Cathepsin B and cathepsin L--cysteine proteinases--may play an important role in cancer invasion and metastasis. The authors determined tissue antigen concentrations of cathepsins, using the ELISA method, in 25 patients with gastric cancer (17 males, 8 females, mean age 62, range 31-84). They evaluated the possible relationship that these proteinases may have with the presence of metastases, differentiation and histotype. Significantly higher cathepsin B and cathepsin L antigen levels were found: 1. in gastric cancer tissues vs. normal tissues distant from tumors (CATB: p < 0.05, CATL: p < 0.005); 2. in diffuse vs. intestinal type cancers (p < 0.05); 3. in patients with poorly vs. well-differentiated cancers (p < 0.05); in gastric cancers with vs. without metastasis (p < 0.05). Their results confirm that cathepsin B and L play an important role in gastric cancer invasion and metastasis. Considering the significantly higher cathepsins detected in cancers with metastasis, a poor differentiation and of diffuse histotype, these proteinases could be useful for identification gastric cancer patients with a poor prognosis.
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PMID:[Role and behavior of cathepsin B and cathepsin L in gastric cancer]. 759 89

Hydrolysis of extracellular matrix is a necessary step for malignant cells to invade, and metastasize. Three groups of proteinases, mainly serine, thiol and metalloproteinases, have been found to be secreted by cancer cells and responsible for the proteolytic cascade triggered during invasion. Previous studies from our group and others have shown that the thiol proteinase cathepsin B1 is a constant indicator of tumor invasion in carcinoma of the cervix, although others point to plasminogen activators and collagenases. So far, there are no systematic studies to correlate cathepsin B and plasminogen activator activity with advancing malignant disease and thus estimate its capability as a marker of progression. The purpose of this study was to determine the activity of cathepsin B like proteinase and plasminogen activators in invasive carcinoma of the breast at various clinical stages and with different estrogen receptor status. One hundred patients with carcinoma of the breast at different clinical stages were studied. Cathepsin B and plasminogen activators activity was assessed in tumor cytosols using different synthetic oligopeptides as substrates following the method of Smith. Estrogen receptor concentration was determined with monoclonal antibodies. A statistical analysis and correlation with different clinical stages was performed. Cathepsin B-like activity had a consistent and progressive elevation in direct correlation with clinical stage (stage I, 1.97 SE +/- 0.46; stage II, 6.67 SE +/- 1.12; stage III, 28.19 SE +/- 3.48; nmol/mg/30 min), while plasminogen activators, although constantly elevated, had no correlation with tumor progression. No relation could be found with estrogen receptor status. It is concluded that cathepsin B, but not plasminogen activator, is a good indicator of tumor progression in invasive carcinoma of the breast.
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PMID:Proteinase activity in invasive cancer of the breast. Correlation with tumor progression. 884 43

The value of cathepsin B activity determination for evaluation of the extent of disease was investigated in 98 patients with the cervix uteri carcinoma and 25 women with cervix uteri dysplasia. The measurements were performed before treatment. Cathepsin B activity was estimated in serum using Z-Phe-Arg-NMec, and in tumor tissue using Z-Arg-Arg-pNA . HCl as substrates. The mean activity of the enzyme increased both in serum and tumor tissue with progression of neoplastic disease and was dependent on the clinical stage of cervical carcinoma. It should be stressed, however, that among the patients with the clinically observed early stage of the disease, higher cathepsin B activity was observed in those in whom metastases to pelvic lymph nodes were detected than in those in whom the disease was limited to cervix uteri.
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PMID:A possible application of cathepsin B activity determination for estimating the spread of the cervix uteri carcinoma. 892 36

Some proteolytic enzymes, trypsin, cathepsin B, cathepsin D, collagenase, elastase and their inhibitors, API and AMG, in serum of patients with colorectal carcinoma have been evaluated. Twenty patients belonged to stage B of colorectal carcinoma, twenty two patients to stage D (Astler and Coller classification) and a control group of thirty healthy volunteers were evaluated. Except in cathepsin D, patients exhibit higher enzymatic activities than healthy subjects, and both groups have all the proteolytic activities assayed in serum. Patients with disseminated disease have increased cathepsin B and collagenase levels, with a decrease of trypsin activity, showing an increment in API and AMG in sera. However, only the API values were significantly higher in patients with metastases. The coexistence of proteolytic activities in human sera together with their inhibitors is considered as well as the origin of these, tumoral and/or reactive, increments. Cathepsin B levels are raised in colorectal neoplasms and contribute to the destruction of the extracellular matrix and the proliferation of tumoral cells. There is evidence that a relation between collagenase like activity and tumor invasiveness exists. Cathepsin B and collagenase increases agree with the tumoral mass. On the other hand, trypsin decrease in metastatic carcinoma is probably related to the increment of their inhibitors, API and AMG, acute phase reactant proteins.
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PMID:Serum proteolytic activities and antiproteases in human colorectal carcinoma. 973 3

The expression of Cathepsin B (CB) and matrix metalloproteinase-9 (MMP-9) in extirpated tissues of adenocarcinomas in non-small cell lung cancer from 90 cases was investigated immunohistologically, and the correlations between the extent of the expression and the clinicopathological features were assessed for investigating the process of tumor metastasis. It is important to reveal the mechanisms of destruction of the basal membrane and infiltration of tumor cells at the primary lesion. Sections were obtained from 10%-formalin-fixed and paraffin-embedded tissues. They were reacted with an anti-human CB polyclonal antibody or an anti-human MMP-9 polyclonal antibody. Of 90 patients, 58 (64.4%) and 39 (48.3) cases were found to be positive for CB and MMP-9 expression, respectively. A significantly higher extent of the CB expression was observed in the tissues of patients who showed postoperative recurrence of the tumor (P = 0.013). Especially, a similar observation was obtained among early cases of T1N0 (P = 0.023). In contrast, no such tendency was demonstrated in the expression profile of MMP-9. Furthermore, the enzyme expressions were compared among different types of metastases. Patients with higher extents of CB expression tended to show significantly higher rates of hematogenous and intrapulmonary metastases (P = 0.023 and P = 0.010, respectively). However, there was no significant correlation between MMP-9 expression and the prognostic factor of the patients. Therefore, we suggested that evaluation of CB expression in the tumor tissue might be useful as a postoperative prognostic factor of pulmonary adenocarcinoma. Especially, early cancer of T1N0 cases showing higher expression of CB may need postoperative adjuvant chemotherapy.
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PMID:Prognostic impact of cathepsin B and matrix metalloproteinase-9 in pulmonary adenocarcinomas by immunohistochemical study. 1067 80

Cathepsin B is a lysosomal cysteine protease in normal cells and tissues. In malignant tumors and premalignant lesions, the expression of cathepsin B is highly upregulated and the enzyme is secreted and becomes associated with the cell surface. Increases in expression are mediated at many levels ranging from gene amplification to increased stability of mRNA and protein. Cathepsin B is synthesized as a preproenzyme and the primary pathways for its normal trafficking to the lysosome utilize mannose 6-phosphate receptors (MPRs). Inactive procathepsin B is processed to active single and double chain forms of cathepsin B in the late endosomes and lysosomes, respectively. Tumor cells secrete procathepsin B and both active forms of cathepsin B. Secretion of procathepsin B occurs principally as a result of increased expression, whereas secretion of active cathepsin B seems to involve active processes that can be induced by a variety of mechanisms. Once secreted procathepsin B binds to the tumor cell surface via p11, the light chain of the annexin II heterotetramer. This binding seems to facilitate conversion of procathepsin B to its active forms. Cathepsin B and the annexin II heterotetramer colocalize in caveolae (lipid raft) fractions isolated from tumor cells. Serine proteases and matrix metalloproteinases also have been found to associate with caveolae and some with the annexin II heterotetramer. Our working hypothesis is that pericellular cathepsin B through its proximity to other proteases in caveolae participates in, perhaps even initiates, a proteolytic cascade on the tumor cell surface.
Cancer Metastasis Rev
PMID:Pericellular cathepsin B and malignant progression. 1278 1


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