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)

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

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

Oxidative stress has been suggested to play an integral role in the cancer process. It may be particularly significant during tumor progression, where there is likely to be a large amount of free radicals generated by infiltrating inflammatory cells and dying tumor cells. In order to test this hypothesis, a variety of free radical scavengers and antioxidants were assessed for their ability to inhibit tumor progression. The murine skin multistage carcinogenesis model was used to generate papillomas, which are a population of putative precancerous lesions. Various test agents were applied topically to papillomas in order to determine if they would decrease the incidence of the malignant lesion, squamous cell carcinoma. The agents tested included: reduced glutathione (GSH), butylated hydroxyanisole, vitamin E, copper(II) (3,5-diisopropylsalicylate)2, sodium benzoate, N-acetyl cysteine and disulfiram. Under the conditions of our experiments, only GSH and disulfiram inhibited tumor progression to a significant degree. Additional studies indicated that GSH prevented cancer development in a dose-dependent manner. Another experiment demonstrated that when papillomas received repeated topical applications of diethylmaleate, a GSH-depleting agent, tumor progression was enhanced. Collectively these data suggest that sufficient glutathione levels may be important in preventing cancer formation.
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PMID:Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model. 313 44

SPARC (Secreted Protein, Acidic and Rich in Cysteine)/osteonectin is a secreted glycoprotein that exhibits restricted expression in murine adult and embryonic tissues and is associated with cell migration, matrix mineralization, steroid hormone production, cell cycle regulation, and angiogenesis. We produced a monoclonal antibody, MAb SSP2, against a Ca(2+)-binding region of SPARC and evaluated the immunoreactivity of normal and malignant tissue from 118 human samples. In normal tissue we found restricted and moderate reactivity with SSP2 in steroidogenic cells, chondrocytes, placental trophoblasts, vascular smooth muscle cells, and endothelial cells. Strong reactivity was found in fibrocytes and endothelial cells involved in tissue repair and in invasive malignant tumors, including those of the gastrointestinal tract, breast, lung, kidney, adrenal cortex, ovary, and brain. We conclude that SSP2 is a useful reagent for detection of SPARC in human tissue. Given the broad reactivity of malignant tissues, we propose that SPARC expression might contribute to some aspects of tumor progression.
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PMID:Distribution of SPARC in normal and neoplastic human tissue. 762 42

IL-2 therapy can induce marked oxidative stress via reactive oxygen and nitrogen intermediates. Glutathione, the major intracellular reductant, may become rate limiting to cytotoxic lymphocyte activation and proliferation under these circumstances. N-Acetyl cysteine (NAc-cys) was used to increase intracellular glutathione levels during lymphokine-activated killer (LAK) cell activation by IL-2. Incubation of splenocytes with NAc-cys (0.6 to 1.0 mM) resulted in significant changes in intracellular reduced and total glutathione (92% and 58% increase, respectively) at 96 h. These levels correlated with markedly enhanced cell proliferation (threefold) and cytolytic effector cell generation (> fivefold increase in LU/10(6) cells) induced by the combination of NAc-cys with IL-2. IL-2 exposure by itself unexpectedly increased intracellular reduced glutathione by 43%. IL-2 and NAc-cys were synergistic in increasing glutathione levels (reduced glutathione: 292% increase; total: 251% increase). Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAc-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity. This experiment established that the effects of NAc-cys required de novo glutathione synthesis. In conjunction with IL-2/LAK treatment, oral NAc-cys administration (260 to 900 mg/kg/day for 7 days) significantly decreased tumor progression in a refractory s.c. tumor model. A small fraction of mice (11 to 17%) had complete tumor regressions. NAc-cys may be useful as an adjunct to increase the antitumor activity of IL-2/LAK therapy.
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PMID:Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2. 820 9

The human genome contains large regions that are highly structured. Sequence-related members of multigene families are often found in a clustered organization. Here we describe a previously unrecognized gene cluster composed of genes coding for calcium-binding proteins of the S100 family. The linkage of six S100 genes was established by pulsed-field gel electrophoresis, and a contiguous DNA sequence of 15 kilobases containing the full coding region of four different S100 genes was characterized. This is the tightest mammalian gene cluster discovered so far to our knowledge. Two additional S100 genes are located within the cluster, both of which exhibit unique structural features when compared with other S100 genes. The product of S100E is cysteine-rich, whereas that of S100D contains a long hydrophobic N-terminal tail. The gene cluster was assigned to chromosome 1q21, one of the bands showing rearrangements in neoplasms at high frequency. The deregulated expression of some S100 genes in the cluster during tumor progression suggests that chromosomal abnormalities may influence the expression of S100 genes in late stages of cancer, particularly in association with the formation of metastases.
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PMID:Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for the two previously unreported calcium-binding proteins S100D and S100E. 834 67

Tissue damage and repair processes are important factors in renal tumor progression. To determine whether protein kinase C (PKC) is involved in these processes, we characterized PKC isozymes during rat kidney regeneration using 3 models: (a) diffuse cortical hyperplasia and hypertrophy induced by folic acid; (b) focal necrosis of the S3 segments induced by S-(1,2-dichlorovinyl)-L-cysteine; and (c) compensatory renal hypertrophy. Immunoblot analyses demonstrated that 5 PKC isozymes, alpha, beta, delta, epsilon, and zeta, were expressed in rat kidney. Six h after folic acid treatment, phorbol ester receptors were down-modulated. Down-modulation preceded an increase in DNA synthesis which was maximal at 24 h. The reduction in phorbol ester receptors was due largely to a decrease in alpha-PKC. zeta-PKC, which is not a phorbol ester receptor, was also decreased. delta- and epsilon-PKCs were not changed. However, alpha-PKC was not down-modulated during compensatory hypertrophy induced by unilateral nephrectomy. Thus, the observed decrease of alpha-PKC after folic acid treatment is most likely associated with the hyperplastic and not the hypertrophic effects of this renal toxin. These results demonstrate that activation-associated down-modulation of PKC, in particular alpha-PKC, occurs during chemical-induced renal regeneration and suggests a general role for PKC activation in non-phorbol ester tumor promotion.
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PMID:Regulation of protein kinase C isozymes in kidney regeneration. 840 25

Transfected ras oncogenes have been shown to induce metastatic properties in some cells. Clarification of the mechanisms by which ras is able to increase the metastatic ability in model systems will improve our understanding of tumor progression to metastasis, even in those cells in which ras activation has not been implicated. Many of the consequences of ras expression also have been detected in cells that have become metastatic in the apparent absence of an altered ras gene, suggesting that there is a set of common changes that can lead to metastasis with multiple signals capable of eliciting these changes. These changes, which have been documented for some ras-transformed cells, include increased expression or activity of various degradative enzymes, including metalloproteinases (type IV collagenases) and cysteine proteinases (cathepsins L and B), as well as decreased expression or activity of their inhibitors (TIMPs and cystatins, respectively). In addition, some metastatic ras-transformed cells have an increased expression of calcyclin, a cytoplasmic calcium-binding protein, and osteopontin, a secreted calcium-binding protein with possible adhesive function. Not all cells, however, respond in the same fashion to a ras oncogene signal. Some cells are resistant to ras-mediated tumor progression to metastasis. Understanding the mechanism by which these cells fail to respond to a specific oncogene signal may provide clues with broader applicability and potential therapeutic relevance. In this review, we summarize some of the studies in which ras has been used as a tool to learn about the molecular requirements for metastasis. We discuss ras-mediated changes in gene expression and how these may contribute to metastatic ability, as well as some possible mechanisms by which ras expression may result in altered expression of other genes. We also consider some cell lines which appear to be resistant to an oncogenic ras signal and possible mechanisms for this nonresponsiveness. These studies are providing insights into the molecular mechanisms of tumor metastasis and the responses of cells to oncogenic signals.
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PMID:Ras-responsive genes and tumor metastasis. 842 May 73

The lack of HLA class I antigen expression by the melanoma cell line SK-MEL-33 is caused by a unique lesion in beta 2-microglobulin (beta 2-mu). Sequencing of beta 2-mu mRNA detected a guanosine deletion at position 323 in codon 76 that causes a frameshift with a subsequent introduction of a stop codon at a position 54 base upstream of the normal position of the stop codon in the message. The loss of 18 amino acids and the change of 6 amino acids, including a cysteine at position 80 in the carboxy terminus of beta 2-mu, are likely to cause marked changes in the structure of the polypeptide. The latter may account for the inability of beta 2-mu to associate with HLA class I heavy chains and for its lack of reactivity with the anti-beta 2-mu mAb tested. HLA class I antigen expression on SK-MEL-33 cells was reconstituted after transfection with a wild-type B2m gene, therefore indicating that the abnormality of endogenous B2m gene is the only mechanism underlying lack of HLA class I antigen expression by SK-MEL-33 cells. The guanosine deletion in B2m gene was detected also in the melanoma tissue from which SK-MEL-33 cells had originated. Therefore, the molecular lesion identified in the SK-MEL-33 melanoma cell line is not caused by a mutation acquired during growth in vitro but is likely to reflect a somatic mutation during tumor progression.
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PMID:Lack of HLA class I antigen expression by melanoma cells SK-MEL-33 caused by a reading frameshift in beta 2-microglobulin messenger RNA. 843 69

O(6)-methylguanine-DNA methyltransferase (MGMT) removes and repairs chloroethylnitrosourea (CENU)-induced O(6)-methylguanine-DNA by accepting the alkyl group at a cysteine moiety. MGMT activity is, therefore, predictive of resistance or sensitivity to CENU chemotherapy. We measured the levels of MGMT mRNA expression in human brain tumors using a reverse transcription-polymerase chain reaction (RT-PCR) method, and studied the significance of MGMT mRNA levels in CENU chemotherapy. The level of MGMT mRNA was represented as a percentage relative to the MGMT mRNA in U138MG brain tumor cells. Forty-three patients with brain tumors were entered into the study. High-grade gliomas had significantly lower levels of MGMT mRNA than did low-grade gliomas and non-glial tumors (p < 0.05 determined by analysis of covariance). Out of 14 high-grade gliomas, 4 had a level of MGMT mRNA below 10%, indicating chemosensitivity to CENU. Out of 11 patients who received CENU chemotherapy, 3 had a partial response. All 3 responders had a low level of MGMT mRNA. The time to tumor progression (TTP) for 6 patients with a level lower than the median was short, but significantly longer than the TTP for 5 patients with a higher level (p < 0.05 determined by Gehan's Wilcoxon test). These results indicate that a fraction of brain tumors have a low expression of MGMT mRNA, and that the level of MGMT mRNA is a useful indicator of effectiveness in selective CENU chemotherapy.
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PMID:Human brain tumor O(6)-methylguanine-DNA methyltransferase mRNA and its significance as an indicator of selective chloroethylnitrosourea chemotherapy. 890 Mar 78


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