Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 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.
 ...
PMID:Cystatins and cathepsins in breast carcinoma. 151 89

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.
 ...
PMID:Cathepsin B and its endogenous inhibitors: the role in tumor malignancy. 209 84

Cystatin A (acid cysteine proteinase inhibitor; ACPI) is a natural inhibitor of cysteine proteinases. It has been suggested that an inverse correlation exists between cystatin A and malignant progression. We wanted to assess the biological and clinical significance of cystatin A in infiltrative breast carcinoma by immunohistochemical staining. Formalin-fixed paraffin-embedded material from 440 cases treated during the years 1988-1991 was used in the study. After exclusion of patients with disseminated disease at diagnosis, previous contralateral breast carcinoma, and absence of follow-up data, 384 patients could be included in the survival analysis. For immunohistochemical analysis of cystatin A, we used monoclonal cystatin A antibody WR-23/2/3/3, the binding of which was detected by the avidin-biotin-peroxidase method. Immunohistochemical analysis of Bcl-2 and p53 was also done, and mitotic activity was evaluated. Positive staining for cystatin A was found in 52 of 440 cases. The staining was irregular but showed irrefutably positive areas within neoplastic tissue. Most of the positive tumors were of the ductal infiltrative type, but two were mucinous carcinomas, one medullary and one squamous cell carcinoma. No lobular carcinomas showed positive staining. Focal cystatin A positivity was seen in myoepithelial cells of benign ducts. Occasional apoptotic bodies within the neoplasm showed strong positivity for cystatin A. Tumors positive for cystatin A were of larger size and had higher mitotic activity than cystatin A-negative tumors. Cystatin A was associated with negative Bcl-2 staining, but there was no statistically significant association between axillary lymph node status or p53 immunostaining. The risk for breast cancer-related death was significantly higher in patients with cystatin A-positive tumors than in those with cystatin A-negative ones. The risk increase was significant also in lymph node-negative patients. After adjusting for the effect of tumor size, histological grade, and lymph node status, cystatin A-positive patients still had a higher risk of death. Patients with cystatin A and p53 coexpression had a higher risk of death than the other patients. The findings reveal a new variant of aggressive breast cancer. This type of carcinoma may develop during tumor progression through genetic instability that allows cystatin A expression and gives growth advantage to a clone of tumor cells.
 ...
PMID:Cysteine proteinase inhibitor cystatin A in breast cancer. 945 85

The cysteine endopeptidase, cathepsin (Cat) B, and its endogenous inhibitor, stefin A, were found relevant for cancer progression of many neoplasms, including human brain tumors. Histological sections of 100 primary brain tumors, 27 benign and 73 malignant, were stained immunohistochemically for Cat B and stefin A. The immunohistochemical staining of Cat B in tumor cells, endothelial cells, and macrophages was scored separately from 0-12. The score in tumor and endothelial cells was significantly higher in malignant tumors compared with benign tumors (P<0.000). A significant correlation between immunostaining of Cat B (scored together for tumor and endothelial cells) and clinical parameters, such as duration of symptoms, Karnofsky score, psycho-organic symptoms, and histological score was demonstrated. Univariate survival analysis indicated that total Cat B score above 8 was a significant predictor for shorter overall survival (P = 0.003). In glioblastoma multiforme, intense Cat B staining of endothelial cells was a significant predictor for shorter survival (P = 0.003). Stefin A immunostaining was weak and detected only in a few benign and some malignant tumors, suggesting that this inhibitor alone is not sufficient in balancing proteolytic activity of Cat B. We conclude that specific immunostaining of Cat B in tumor and endothelial cells can be used to predict the risk of death in patients with primary tumors of the central nervous system.
 ...
PMID:Cathepsin B immunohistochemical staining in tumor and endothelial cells is a new prognostic factor for survival in patients with brain tumors. 1010 Jul 7

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.
 ...
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

Cysteine protease cathepsin B (CatB) and its endogenous inhibitor stefin A (StA) play an important role in tumor progression. Increase of CatB expression and lower levels of its inhibitors were associated with tumor malignancy in brain tumors. In this study of 100 patients, CatB was localized by immunostaining to both, tumor and endothelial cells of primary brain tissue. Significant correlation with poor prognosis was found by univariate Cox's regression model. Intense overall immunostaining and immunostaining in endothelial cells alone were prognostic for survival (p=0.003 in both). When comparing CatB expression at mRNA level, we found considerable differences between center and periphery of a tumor as well as between different tumor samples. StA mRNA was only detected in benign, but not in malignant tissues. We suggest that screening of cysteine-protease genes expression can be applied in clinical prognosis of brain tumors.
 ...
PMID:Cathepsin B and its inhibitor stefin A in brain tumors. 1065 64

Proteolytic enzymes have been proposed as new biological prognostic indicators to facilitate decisions about treatment of breast cancer patients following surgery. We reported earlier that the activities of cysteine proteinases (CP), cathepsin (Cat) B and cathepsin (Cat) L and the expression of stefin A might be associated with breast tumor progression and prognosis. Here, the protein concentrations of Cats D, B and L and stefin A have been measured in a series of 60 matched pairs of breast tumours and control adjacent tissues, using ELISAs developed in our laboratory. Median tumor concentrations of Cat D (47 pm/mg), Cat B (222 ng/mg) and Cat L (88 ng/mg) were significantly (p<0.0005) increased by 7 fold, 27 fold and 6 fold, respectively. Much greater increases in the activities of Cat B (63 fold) and of Cat L (274 fold) were found, indicating activation of proCat B and proCat L and/or to a decrease in specific endogenous cystatins. However, the 1.6-fold decreased (p<0.0001) levels of inhibition by cystatins could not be entirely responsible for more than 100-fold increased ratio of CP:cystatins activity. Moreover, stefin A was either increased or decreased in tumor samples, resulting in a 1.4-fold median increase in tumors. Comparing the biological parameters with the established histo-pathological prognosticators, we found that the increased protein concentration of Cat B was associated with lymph node involvement (p<0.009) and higher stage (p<0.003), and both Cat B and Cat L activities were more increased in high grade tumours (p<0.05). Survival analysis revealed that stefin A was the most significant prognostic factor for disease-free (p<0.008) and overall survival (p<0.02), followed by increased Cat B activity and protein concentration. Cat L was of borderline significance while Cat D was not significant for prognosis. We conclude that enhanced activation of CP, due partially to an imbalance between cysteine proteinases and inhibitors is linked to the progression of breast cancer. Larger sample size is needed to confirm the prognostic significance of stefin A, Cat B and Cat L.
 ...
PMID:The Expression of Lysosomal Proteinases and Their Inhibitors in Breast Cancer: Possible Relationship to Prognosis of the Disease. 1117 33

Cystatins function as cysteine protease inhibitors, are expressed in numerous cell types, and regulate a number of physiological processes. Four cystatins have been extensively studied: cystatin A, cystatin B, cystatin C, and cystatin M. Aberrant regulation of cystatins occurs in a number of diseases, including cancer and certain neurodegenerative disorders. Recent advances in the understanding of cystatin function suggest that these proteins may regulate promotion or suppression of tumor growth, invasion, and metastasis. Cancer is a disease of abnormal gene expression and cancer cells exhibit aberrant epigenetic events (such as DNA methylation), leading to gene silencing. Cystatins are epigenetically silenced through DNA methylation-dependent mechanisms in several forms of cancer, including breast, pancreatic, brain, and lung. These findings suggest that DNA methylation-dependent epigenetic mechanisms may play an important role in the loss of cystatin gene expression and protein function during neoplastic transformation and/or tumor progression. This review summarizes the biological processes in which cystatins function, focuses on the neoplastic events that involve aberrant regulation of cystatins, and discusses the possible epigenetic regulation of cystatins in cancer.
 ...
PMID:Epigenetic regulation of cystatins in cancer. 1927 77

Here we directly compared gene expression profiles in human esophageal squamous cell carcinomas and in human fetal esophagus development. We used the suppression subtractive hybridization technique to subtract cDNAs prepared from tumor and normal human esophageal samples. cDNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analysis of RNAs from human tumor and the normal esophagus revealed 10 differentially transcribed genes: CSTA, CRNN, CEACAM1, MAL, EMP1, ECRG2, and SPRR downregulated, and PLAUR, SFRP4, and secreted protein that is acidic and rich in cysteine upregulated in tumor tissue as compared with surrounding normal tissue. In turn, genes up- and downregulated in tumor tissue were down- and upregulated, respectively, during development from the fetal to adult esophagus. Thus, we demonstrated that, as reported for other tumors, gene transcriptional activation and/or suppression events in esophageal tumor progression were opposite to those observed during development from the fetal to adult esophagus. This tumor 'embryonization' supports the idea that stem or progenitor cells are implicated in esophageal cancer emergence.
 ...
PMID:Identification of some human genes oppositely regulated during esophageal squamous cell carcinoma formation and human embryonic esophagus development. 1973 25

Cysteine protease cathepsin B (CatB) and its endogenous inhibitor stefin A (StA) play an important role in tumor progression. Increase of CatB expression and lower levels of its inhibitors were associated with tumor malignancy in brain tumors. In this study of 100 patients, CatB was localized by immunostaining to both, tumor and endothelial cells of primary brain tissue. Significant correlation with poor prognosis was found by univariate Cox's regression model. Intense overall immunostaining and immunostaining in endothelial cells alone were prognostic for survival (p=0.003 in both). When comparing CatB expression at mRNA level, we found considerable differences between center and periphery of a tumor as well as between different tumor samples. StA mRNA was only detected in benign, but not in malignant tissues. We suggest that screening of cysteine-protease genes expression can be applied in clinical prognosis of brain tumors.
 ...
PMID:Cathepsin B and its inhibitor stefin A in brain tumors. 2817 95


1 2 Next >>