Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of tumor cells that have little if any metastatic potential with certain drugs that have little or no mutagenic activity has been found to result in marked phenotypic alterations of the cells, including development of a metastatic potential. We found that polar compounds and butyric acid, which are known to alter the expressions of normally silent genes, enhanced the lung-colonizing ability of cloned low-metastatic Lewis lung carcinoma cells. This change was accompanied by increases in the activities of degradative enzymes such as glycosidases, cathepsin B, and plasminogen activator; adhesion of the cells to culture dishes, monolayers of endothelial cells, and a subendothelial matrix; and homotypic aggregation. The effects of these drugs in enhancing the lung-colonizing ability of the cells was found to be reversible, suggesting that it was due to epigenetic alterations. Other investigators have shown that treatment of nonmetastatic tumor cells with 5-azacytidine, which causes hypomethylation of DNA and activates normally silent genes, results in the emergence of a small number of clones with a heritable but unstable metastatic phenotype. These findings suggest that epigenetic mechanisms are involved in rapid cellular phenotypic diversification and tumor progression.
 ...
PMID:Modification of the metastatic potential of tumor cells by drugs. 243 28

The topics reviewed in this article include transcriptional regulation of plasminogen activators, their relevance to differentiation, tumor progression, and to the metastatic spread of cancer. Recent information on the nature of cellular plasminogen activator receptors is also discussed. Particular attention is paid to the increasing number of observations indicating that several of the inducers of plasminogen activator synthesis utilize distinct regulatory pathways.
 ...
PMID:The relevance of plasminogen activators to neoplastic growth. A review of recent literature. 304 65

Vimentin-positive, desmin-negative cells were established in culture from the nodule and from apparently normal palmar aponeurosis of a patient with Dupuytren's disease and compared with normal human embryonic and adult fibroblasts or sarcomatous cells. Cells from the nodule display in vitro biological properties that are intermediate between those expressed by normal fibroblasts and sarcoma cells or cells from the nodule transformed with SV40 virus. Thus, they represent an interesting in vitro model of partially transformed human cells. This behavior is not evolutive and justifies the classification of Dupuytren's disease among the benign mesenchymal tumors. The production of high level of plasminogen activator probably explains the local reactive pathology, and could act as a mitogenic stimulus for the proliferation of the nodule itself. Cultures derived from the apparently normal palmar aponeurosis show some but not all the abnormal growth properties of cells from nodules; this may help to explain the onset of local recurrences. Our results suggest that Dupuytren's disease is not strictly local and limited to the nodules, but affects, at least partially, the whole aponeurosis. Dupuytren's nodules could be considered as a model of tumor progression in a benign situation.
 ...
PMID:Abnormal behavior of cultured fibroblasts from nodule and nonaffected aponeurosis of Dupuytren's disease. 619 20

The effects of two agents, 12-O-tetradecanoylphorbol-13-acetate (TPA) and deoxycholic acid (DOC), which act as tumor promoters in the gastrointestinal epithelium of experimental animals, were compared using primary cultures of human premalignant colonic epithelial cells at different stages in tumor progression. Both DOC and TPA enhanced the size of the proliferative fraction in colonies of early-stage premalignant cells, with DOC providing more stimulation. TPA-treated intermediate- and late-stage premalignant cells elongated and then disrupted the monolayer by forming rills several cells in thickness and then multicellular clusters. This multilayering was reminiscent of the areas of carcinoma found within adenomas. DOC had no such effects on morphology. Cell clustering was concomitant with secretion of a protease with characteristics of a plasminogen activator. Premalignant cells secreted severalfold higher levels of protease in response to TPA than did either TPA-treated primary cultures of colonic adenocarcinomas or established colon carcinoma cell lines. These results suggest that (a) DOC and TPA act sequentially during tumor promotion and (b) cell clustering and protease release may be associated with the transition of premalignant epithelial cells to colonic carcinoma.
 ...
PMID:Differential response of premalignant epithelial cell classes to phorbol ester tumor promoters and to deoxycholic acid. 703 Apr 77

The ability of p53 to activate or repress transcription suggests that its biological function as tumor suppressor is in part accomplished by regulating a number of genes including such required for inhibition of cell growth. We here give evidence that p53 also may regulate genes responsible for the proteolytic degradation of the extracellular matrix, which is considered a crucial feature for local invasion and metastasis of neoplastic cells. An important and highly regulated cascade of such proteolytic events involves the plasminogen activator system. We show that wild-type p53 represses transcription from the enhancer and promoter of the human urokinase-type (u-PA) and the tissue-type plasminogen activator (t-PA) gene through a non-DNA binding mechanism. Oncogenic mutants lost the repressing activity. In contrast, wild-type but not mutant p53 specifically binds to and activates the promoter of the plasminogen activator inhibitor type-1 (PAI-1) gene. Interestingly, one of the p53 mutants (273his) inhibited PAI-1 promoter activity. Our results suggest that altered function of oncogenic forms of p53 may lead to altered expression of the plasminogen activators and their inhibitor(s) and thus to altered activation of the plasminogen/plasmin system during tumor progression.
 ...
PMID:Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53. 747 1

Proteolytic enzymes are required to mediate tumor cell invasion of adjacent tissues and spread of primary tumors to distant sites. Our objective was to examine the activities and molecular forms of plasminogen activator (PA) and matrix metalloproteases (MP) in primary and secondary growths of SC tumors of three human prostatic cell lines (Du-145, PC-3, and 1-LN-PC-3-1A [1-LN], a subline of PC-3) grown in nude mice. The plasminogen activator activities were 1.7 +/- 1.3 (+/- SD), 6.2 +/- 2.8, and 11.5 +/- 4.2 for Du-145, PC-3, and 1-LN in primary SC tumors, respectively. Urokinase was the predominant molecular form of PA found in each tumor as determined from its molecular size (predominantly 54 kDa with a minor activity of 33 kDa) and sensitivity to amiloride. Prominent MP activities of approximately 68, 76, and 96 kDa as well as lesser activities of about 56, 59, 63, 84, 165, and 180 kDa were found in 1-LN tumors, whereas only less active MP of 59, 68, and 96 kDa were detected in the parental PC-3 cells. Du-145 tumors expressed MP activities of 59 and 96 kDa. Treatment of 1-LN tumor extracts with p-aminophenylmercuric acetate (APMA) significantly reduced the MP activities of 76 and 165 kDa while increasing activities of 56, 59, 65, 68, and 84 kDa. The 76 and 165 kDa MP activities thus appear to be prominent proenzyme forms of MP expressed in the 1-LN tumor. Secondary growths of tumor were subsequently found near the site of initial injection of PC-3 and 1-LN cells following removal of the primary tumor. There was a 42% increase in PA activity in the PC-3 secondary tumors, but only an 8% increase in 1-LN secondary tumors. However, there was no difference in the activities or number of molecular forms of MP in extracts of PC-3 or 1-LN primary or secondary tumors. The substantial expression of MP activities in the more aggressive 1-LN subline of the human prostatic PC-3 cell line indicates that induction of certain MP may be an important regulatory event in prostate tumor progression.
 ...
PMID:Plasminogen activator and metalloprotease activities of Du-145, PC-3, and 1-LN-PC-3-1A human prostate tumors grown in nude mice: correlation with tumor invasive behavior. 795 14

The high prevalence of prostatic carcinoma (PRCA) and the limited therapeutic possibilities provide a strong stimulus for exploring new approaches in experimental research that ultimately may lead to improved therapy. Indeed, methods for assessing carcinoma prognosis, such as clinical staging (clinical examination, ultrasound, and plasmatic levels of prostatic acid phosphatase and prostate specific antigen) and histopathological grading according to the Gleason score, usually fail to provide consistent predictive information regarding the clinical outcome of single tumors. Increased plasminogen activator (PA) activities have been associated with high-grade malignancies and with the potential for invasion/metastasis in many tumors. Urokinase-type plasminogen activator (uPA) is present in prostatic secretion, and an increased uPA activity has been noted in human prostatic cell lines with metastatic behavior. Unfortunately, any study of uPA production or gene regulation in primary tumors is complicated by the inherent mixture of host stromal cells, infiltrating macrophages, and subpopulations of tumor cells that may have variable metastatic capacity and ability to synthesize uPA. In short-term tissue culture of prostatic samples, it is possible to grow in vitro cancer prostatic epithelial cells and thus exclude the presence of contaminant cells. We have shown elsewhere that the levels of a type IV collagenase, 92-kDa matrix metalloproteinase, a protease involved in tumor progression and invasion, are increased in PRCA primary cell cultures if compared with benign prostatic hyperplasia (BPH) cell cultures (C. Festuccia et al., manuscript in preparation). Activation of matrix metalloproteinases also can be correlated with uPA expression; therefore we studied the expression of uPA in serum-free culture media of primary cultures of PRCA or BPH tissue samples.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Plasminogen activator activities in short-term tissue cultures of benign prostatic hyperplasia and prostatic carcinoma. 855 46

Thrombospondin (TSP-1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP-1, the following observations suggest that TSP-1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP-1 and inhibited by anti-TSP-1 antibodies. (2) TSP-1 promotes tumor cell adhesion, migration and invasion. (3) TSP-1 promotes angiogenesis in the rat aorta model. (4) TSP-1 up-regulates the plasminogen activator system through a mechanism involving the activation of TGF-beta 1. (5) Human tumors express increased levels of the CSVTCG-specific TSP-1 receptor. (6) Tumor stroma is enriched in TSP-1. (7) Cancer patients have high blood levels of TSP-1. (8) Poor patient survival correlates with a higher expression of the CSVTCG-specific TSP-1 receptor on tumor cells. In this paper we discuss the evidence that TSP-1 promotes tumor progression and present a hypothetical scheme for its mechanism of action.
 ...
PMID:The role of thrombospondin-1 in tumor progression and angiogenesis. 859 67

Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.
 ...
PMID:Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions. 868 34

A large body of evidence suggests a role for the proteolytic plasminogen activation system in invasion and metastatic spread of tumor cells including melanoma cells. Plasminogen activation by human melanoma cell lines and B16 mouse melanoma cell lines has been extensively studied. Apart from expression of urokinase-type plasminogen activator, melanoma cells differ from cells derived from other tumors in the abundant expression of tissue-type plasminogen activator. The possible role of both types of plasminogen activator in metastatic spread of melanoma cells is discussed. In recent years the localization of mRNAs and proteins of the plasminogen activation system and of related proteins in cutaneous melanocytic tumor progression has been well documented. A possible mechanism for migration of melanoma cells in vivo is suggested.
 ...
PMID:The plasminogen activation system in melanoma cell lines and in melanocytic lesions. 879 Dec 64


1 2 3 4 5 6 Next >>