Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 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.
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PMID:Cathepsin B and its endogenous inhibitors: the role in tumor malignancy. 209 84

Cathepsin B is a lysosomal cysteine proteinase that has the ability to degrade several extracellular matrix components at both neutral and acidic pH and has been implicated in the progression of several human and rodent tumors. We have studied the expression of cathepsin B in human colorectal tissues using a monospecific polyclonal rabbit antibody raised against human liver cathepsin B. In immunoblots of normal and neoplastic colorectal tissues this antibody specifically recognized only cathepsin B. We studied 101 cases of formalin-fixed, paraffin-embedded tissue (15 normal mucosa, 17 adenomas, and 69 carcinomas). Epithelial cells of normal mucosa and adenomas were either negative or showed a weak granular reactivity located in the paranuclear and apical cytoplasm of superficial cells. Small clusters of histiocytes were also positive in the region of the superficial area of the lamina propria. In carcinomas, increased expression of cathepsin B correlated with advanced stage of the disease. Increased immunoreactivity of cathepsin B in malignant cells was associated with either a diffuse cytoplasmic staining or was polarized to the basal pole of the cells. This is in contrast to the punctate paranuclear staining pattern observed in normal colonic mucosal cells. In tumor stromal cells, increased expression of the enzyme correlated with neoplastic progression. Expression of high levels of cathepsin B in the tumor epithelial cells was associated with a significantly shorter survival of the patients. In conclusion, our results indicate that cathepsin B expression is up-regulated in human colorectal carcinomas compared with normal mucosa and adenomas and correlates with tumor progression.
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PMID:Cathepsin B expression in colorectal carcinomas correlates with tumor progression and shortened patient survival. 805 86

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

Cathepsin B has been linked to tumor progression through observations that its activity, secretion or membrane association are increased. The most malignant tumors, and specifically the cells at the invasive edge of those tumors, express the highest activity. Cathepsin B may facilitate invasion directly by dissolving extracellular matrix barriers like the basement membrane, or indirectly by activating other proteases capable of digesting the extracellular matrix. Cathepsin B also might play a role in tumor growth and angiogenesis. Cathepsin B activity is the result of several levels of regulation: transcription, post-transcription processing, translation and glycosylation, maturation and trafficking, and inhibition. The majority of reports on cathepsin B expression in tumors have focused on measurements of activity or protein staining. In some tumors, e.g. gliomas, a correlation between the amounts of cathepsin B mRNA, protein and activity and tumor progression has been established. Regulation of cathepsin B at the transcriptional and post-transcriptional levels is still poorly understood. Although the putative promoter regions have characteristics of housekeeping-type promoters, cathepsin B mRNA expression varies depending on the cell type and state of differentiation. We have evidence that more than one promoter could direct expression of human cathepsin B. Multiple transcript species have been detected, resulting from alternative splicing in the 5'- or 3'-untranslated regions, and possibly the use of alternative promoter regions. The existence of transcript variants indicates a potential for post-transcriptional control of expression. In support of this, ras-transformation of MCF-10A human breast epithelial cells results in an increase in protein levels without a concomitant increase in mRNA levels. Cathepsin B mRNA species with distinct 5'- or 3'-untranslated regions may differ in their stability and translatability. Variations in the coding region may also alter cathepsin B properties. We and Frankfater's group have observed transcript species that would encode a truncated protein, lacking the prepeptide and about half of the propeptide. This truncated protein, if synthesized in cells, would be expected to be cytosolic; therefore its function is unclear. Once the several mechanisms of regulation of cathepsin B expression and activity are better understood, they could provide us with new strategies to specifically reduce cathepsin B activity in tumors.
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PMID:Cathepsin B expression in human tumors. 886 Oct 22

Cathepsin B, a thiol protease, has been reported to be involved in cancer progression and metastasis. The suppressive effects of two kinds of protease inhibitors, leupeptin and dietary camostate (FOY-305), on tumorigenesis and progression in 1, 2-dimethylhydrazine (DMH)-induced rat colon neoplasm were examined in relation to tissue cathepsin B activity. Male Donryu rats were treated with leupeptin or FOY-305 during or after the administration of DMH. There were no significant differences in average tumor numbers among all DMH-treated groups. However, the percentage of small tumors was significantly higher in the group in which leupeptin was supplied during DMH administration. This trend was not recognized in the FOY-305-treated groups. The ratio of cathepsin B activity in the tumors to that in the tumor-bearing tissue (T/Tb) was significantly increased with increasing tumor size (P = 0.009). The cathepsin B activity levels in the tumor-bearing mucosa in the groups which received leupeptin or FOY-305 following DMH treatment were both significantly lower than that in the group which received neither protease inhibitor (P = 0.046 and P = 0.0067, respectively). The results obtained indicate that leupeptin may have suppressed tumor growth by lowering the tissue cathepsin B activity.
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PMID:Cathepsin B in the growth of colorectal cancer: suppressive effect of leupeptin on the growth of DMH-induced rat colon neoplasm. 898 66

Cathepsin B, a thiol protease, is involved in cancer metastasis. To clarify the role of cathepsin B in tumor progression in human colorectal cancer, the relationship between its activity, immunohistochemical staining, and clinical tumor progression was investigated. Cathepsin B activity in adenocarcinomas was significantly elevated compared with that in the tumor-bearing tissue. Furthermore, the tumor/tumor-bearing tissue (T/Tb) ratio of the activity was significantly higher than that of colorectal adenoma. Immunohistochemical studies demonstrated intense staining in the cancerous tissue. With respect to the clinical stage of tumors, the activity tended to be higher in tumors that had invaded the serosa or subserosa than in those that invaded the proper muscle. The results suggest that cathepsin B participates in the progression of human colorectal cancer, and its increased expression is a sensitive marker of the differentiation between colorectal adenoma and adenocarcinoma.
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PMID:Cathepsin B in the growth of colorectal cancer: increased activity of cathepsin B in human colorectal cancer. 898 67

Cathepsin B has been implicated in progression of various human tumors. Overexpression of cathepsin B mRNA, increased cathepsin B staining and elevated cathepsin B activity have been found in different human cancers. These occur especially at the invasive edges of cancers, suggesting a role for cathepsin B in tumor invasion. In some tumors, mRNA expression and protein staining for cathepsin B correlate with clinical progression. Cathepsin B can facilitate tumor progression directly through degradation of components of the basement membrane and extracellular matrix. In vitro studies show that cathepsin B may exert its degradative effects intracellularly or extracellularly, depending on the cell type and location of cathepsin B. Cathepsin B can also facilitate tumor progression indirectly through activation of other latent proteases and/or degradation of protein inhibitors of other proteases. Thus cathepsin B may be an integral component of the proteolytic cascade linked to malignant progression of human tumors.
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PMID:Cathepsin B and human tumor progression. 952 62

Cathepsin B is a lysosomal cysteine proteinase associated with degradation of laminin. It is increased in colorectal carcinoma (CA). Laminin is a major component of basement membrane involved in cell-matrix interactions and tumor progression. The aim of this study was to correlate cathepsin B and tumor-associated laminin in colorectal adenomas (ADs) with increasing grades of dysplasia and in invasive CAs. Forty-five ADs (8 tubular, 16 tubulovillous, 21 villous), 13 adenomas with high-grade dysplasia/carcinoma in situ (AHDs), and 17 invasive CAs were immunostained with polyclonal antibodies to cathepsin B and laminin. Statistical analysis was performed using exact linear by linear association test and Spearman rank correlation coefficient. Cathepsin B-positive tumor cells were seen in 30 (67%) ADs, 13 (100%) AHDs, and 17 (100%) CAs. The grade of cathepsin B staining was significantly increased in AHDs and CAs, compared with ADs (P < .0001). Laminin was continuous in all of the ADs and discontinuous or fragmented in the AHDs and CAs (P < .0001). The degree of cathepsin B staining in tumor cells also correlated with breakdown of laminin. Increased cathepsin B expression and decrease in tumor-associated laminin might suggest a mechanism for progression of ADs to CAs.
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PMID:Cathepsin B and tumor-associated laminin expression in the progression of colorectal adenoma to carcinoma. 972 Apr 96

Cathepsin B (CB) is involved in degradation of extracellular matrix proteins during tumor progression in human solid organ tumors (such as colorectal, bladder, and breast cancers), including human prostate cancer. Its activities are regulated by endogenous inhibitors (such as stefins or cystatins). Increased expression of cathepsin B message, protein, and membrane association have been linked to malignancy, but there are very few studies of their mRNA expression in prostate cancer using in situ hybridization techniques. Our objective was to determine the relationship of CB and stefin A (cystatin A) mRNA localization to the Gleason grading system for histologic scores in the hope of distinguishing aggressive and less aggressive variants of prostate cancer. We used a 25-base biotinylated oligonucleotide CB cDNA antisense probe to localize CB message and a 27-base biotinylated oligonucleotide stefin A cDNA antisense probe to localize stefin A message. Prostate samples from 41 prostatectomy patients were collected along with their pre-surgery serum PSA levels and clinical stage of the disease. Sections prepared from frozen prostate tissue samples were hybridized with the CB and stefin A and control pBR 322 probes using techniques reported by Sinha et al. [1] and their distribution quantitated by an image analysis system. Prostate sections treated with RNAse before hybridization or incubated with the pBR 322 control probe showed little or no reaction products, confirming that localization of CB and stefin A probes was specific. In prostate cancer, the reaction products were found in neoplastic and invasive cells and occasionally in stromal cells. The ratios of CB to stefin A were similar in normal prostate and benign prostatic hyperplasia (BPH) whereas they varied consistently within and between Gleason histologic scores for prostate cancer. These variations showed three localization patterns; namely, prostate cancers with higher levels of CB than stefin A, lower levels of CB than stefin A, and similar levels of CB and stefin A. All three patterns and ratios for CB and stefin A were found in prostate samples (22/41) represented by the Gleason histologic score 6 tumors. In these tumors, serum PSA levels ranged from 1 to 78 ng/ml and prostate cancers showed B, C, and D clinical stages. There was no correlation of CB/stefin A ratio and serum PSA values or clinical stage in a limited number of prostate cancer cases. Our data showed that there were prostate cancer cases within Gleason histologic scores which expressed high, similar, and low levels of CB when compared to stefin A. We postulate that prostate cancer cases showing higher levels of CB compared to stefin A probably represent an aggressive variant of this cancer within any one Gleason histologic score. If this is the case, aggressive variants of prostate cancer would occur within Gleason scores 3 to 10 even though higher scores are usually considered more aggressive forms of prostate cancers. Since our study is based upon a very limited number of frozen prostate samples, we emphasize that a larger series of archival prostate cancer samples along with their survival data should be analyzed to establish any relationship of CB/stefin A ratio and aggressive variants of this cancer. Therefore, our conclusion is tentative. Our study provides a partial explanation for differences in the clinical course of prostate cancer in patients. This is the first study to show that determination of CB and stefin A mRNA ratios may lead to identification of aggressive and less aggressive variants of prostate cancer within a Gleason histologic score.
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PMID:The relationship of cathepsin B and stefin A mRNA localization identifies a potentially aggressive variant of human prostate cancer within a Gleason histologic score. 1065 60

Cathepsin B is a lysosomal cysteine proteinase that may participate in cancer progression. We compared localization of its protein and activity during progression of human colorectal cancer. In adenomas and carcinomas, protein expression and, particularly, activity were elevated compared with those in normal colorectal mucosa. In normal mucosa, cathepsin B protein expression was moderate in stroma and variable in epithelium, whereas activity was mainly present in distinct areas of stroma directly underneath the surface of the colon and in epithelium at the surface of the colon. Stroma in adenomas and carcinomas contained moderate to high protein levels but little activity except for areas of angiogenesis, inflammation, and necrosis, in which activity was high. In adenomas and the majority of well-differentiated carcinomas and moderately differentiated carcinomas, cathepsin B protein and activity were found in granular form in the epithelium, close to the basement membrane. Protein and activity levels were low and diffusely distributed in cancer cells in the remainder of the well-differentiated and moderately differentiated carcinomas and in all poorly differentiated carcinomas. Invasive fronts in most cancers contained moderate protein levels but high activity. We conclude that (a) activity localization is essential to understand the role of cathepsin B in cancer progression, and (b) cathepsin B activity in human colon is associated with invasion of cancer cells, endothelial cells, and inflammatory cells, and in cell death, both apoptotic and necrotic.
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PMID:Comparative localization of cathepsin B protein and activity in colorectal cancer. 1099 Apr 95


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