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

In an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis, metastatic human breast cancer cell lines (MCF7, ZR75-1) were found to secrete a 52,000 dalton (52K) protein under estrogen stimulation. Following its purification to homogeneity, the 52K protein was identified as a secreted procathepsin-D-like aspartyl protease bearing mannose-6-phosphate signals. This precursor displays an in vitro autocrine mitogenic activity on estrogen-deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its autoactivation. The total protease (52K + 48K and 34K) was detected and assayed by monoclonal antibodies and was found to be highly concentrated in proliferative and cystic mastopathies. In breast cancer, its cytosolic concentration appears to be correlated more to tumor invasiveness than to hormone responsiveness. The mRNA of the 52K protease accumulates rapidly following estradiol treatment, as was shown by Northern blot analysis with cloned cDNA. The 52K cathepsin-D-like protease is the first example of a lysosomal protease induced by estrogens in cancer cells. Results obtained using different approaches suggest that two cysteinyl cathepsins are also related to cell transformation and invasiveness. It has been proposed that cathepsin-B is involved in breast cancer and metastatic melanoma, and its regulation by estrogen has been shown in the rat uterus. Cathepsin-L corresponds to the major excreted protein (MEP) whose synthesis and secretion are markedly increased by transformation of NIH 3T3 cells with Ki ras and are regulated by several growth factors. In addition to secreted autocrine growth factors and to other proteases (plasminogen activator, collagenase), lysosomal cathepsins may therefore play an important role in the process of tumor growth and invasion as long as their precursor is secreted abundantly.
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PMID:Estrogen-induced lysosomal proteases secreted by breast cancer cells: a role in carcinogenesis? 331 45

Sheep pituitary glands contain a protein that stimulates plasminogen activator (PA) activity 3- to 20-fold in serum-free cultures of T47D, MTW9/PL, and SC115 breast tumor cells. This protein was found to be similar to basic fibroblast growth factor (bFGF) in size, cationic nature, and affinity for heparin. Purified human placental bFGF, a homologue of human and bovine pituitary bFGF, was effective in stimulating mammary tumor cell PA at a concentration of 1 ng/ml. Antibodies to placental bFGF blocked the PA stimulatory activity of sheep pituitary extracts. Because of these properties, the active protein in sheep pituitary glands was identified as bFGF. This represents another function of bFGF, indicating that its spectrum of target cells is wider than previously thought. Because of previously established correlations between PA production in vitro and tumor growth in vivo, we suggest that bFGF may contribute to the growth of breast carcinomas in vivo. Other types of carcinomas may also be affected by bFGF.
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PMID:Identification of a pituitary factor responsible for enhancement of plasminogen activator activity in breast tumor cells. 346 98

The present study was carried out to evaluate a drug delivery system with regard to the sustained drug-release properties and antitumor effects of a unique preparation composed of 5-fluorouracil (5-FU) and biodegradable polymer, poly L-lactic acid. The composite (F-PLA) was formed into plastic needles designed for the topical application in tumor tissue. Donryu rats implanted subcutaneously with ascites hepatomas AH 109A and AH 130 were used for the experiments. Release of the drug from the F-PLA needles containing 50% w/w 5-FU was maintained for one month or more in rat subcutaneous tissue and for about two weeks in the liver or AH 109A subcutaneous tumor. When the needles were implanted in the liver or AH 109A tumor, 5-FU concentrations in the treated tissues were sustained at high levels, whereas levels in the peripheral blood were very low. Histologically, coagulation necrosis of AH 130 tumor tissues was observed widely around the F-PLA needle implant areas. Meanwhile, in experiments on the antitumor effects of F-PLA preparation in AH 130- or AH 109A-bearing rats, it was demonstrated that tumor growth in the groups treated with F-PLA needles was significantly suppressed as compared with that in the controls. The results obtained in this study show that the F-PLA needle can be useful as a drug delivery system in cancer chemotherapy.
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PMID:[Experimental study of an anticancer drug delivery system using polylactic acid]. 358 19

Hypofibrinogenemia and disseminated intravascular coagulation are common events in patients with metastatic prostate carcinoma. This study tests the hypothesis that prostate tumor growth and metastasis is associated with sustained activation of fibrinolysis secondary to increased release of plasminogen activator. We implanted an androgen-insensitive prostate tumor into an inbred strain of rats and serially measured plasminogen, plasminogen activator, plasmin and fibrinogen. Control groups included animals without tumor and a group implanted with transitional cell bladder carcinoma, a locally infiltrating tumor not usually associated with hemostatic complications. Our results showed a significant and steady rise in plasma plasminogen activator, plasmin and fibrinogen levels in animals implanted with prostate cancer. This, however, is not specific for prostate tumor. Similar, perhaps more profound changes were noted in animals implanted with the transitional cell carcinoma.
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PMID:The fibrinolytic system in experimental prostate tumor. 381 May 52

The expression of plasminogen activator activity (PA) by L1210 leukemic ascitic cells, obtained from the peritoneum of BDF1 mice, increases in the terminal stages of the disease. Treatment of mice carrying advance leukemia (day 6 following inoculation with 10(6) cells i.p.) with 6-azauridine (AzUR) results in prolonged survival (2-3 days) and also in increased expression of PA activity by the ascitic cell population. Similar treatment with pyrazofurin (PF), another inhibitor of orotidylate decarboxylase and of de novo pyrimidine synthesis, fails to produce either of these effects. Neither AzUR or PF, given at the early stage of tumor growth (day 3), extend the life span nor do they cause increase of the PA activity. Thus, the elevation in PA activity following treatment with AzUR is associated with the asymptotic stage of the disease and this phenomenon correlates positively with the life-prolonging effects of this drug. An analysis of the PA activity elicited by intact cells, secretions, and cellular digests suggests that most of the activity originates on the surface of the cells. The results indicate that the described in vivo effect of AzUR, but not that of PF, on late-stage leukemia, is mediated by the changes in the fibrinolytic potential of the tumor or host cells rather than through the inhibition of the de novo pyrimidine synthesis.
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PMID:Effect of 6-azauridine and pyrazofurin on fibrinolysis by L1210 leukemic cells. 617 11

The human carcinoma HEp3 grows on the chorioallantoic membrane and metastasizes to the chicken embryo with kinetics that are quantitatively predictable. We have used this experimental system to test whether plasminogen activator produced by the tumor is required for metastasis. Rabbit antibodies were raised against human urinary urokinase; these cross-reacted with and blocked the catalytic activity of HEp3-PA but did not inhibit chicken PA. When administered intravenously to embryos that had received an inoculum of HEp3 cells, the anti-urokinase antibodies did not inhibit tumor growth at the site of primary inoculation on the chorioallantoic membrane, but they either prevented or strongly inhibited metastasis to the embryo lung. Antibody treatment delayed the onset of pulmonary metastasis, indicating that plasminogen activator is required during early stages of the process.
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PMID:Antibodies to plasminogen activator inhibit human tumor metastasis. 641 88

The aberrant expression of a plasminogen activator (PA) by Moloney virus (MuLV)-transformed mouse lymphocytes and its relation to cell phenotype and tumor growth have been studied. Nine cultured cell lines were established from neoplastic splenic and thymic tissues obtained from B10 congeneic mice inoculated with MuLV and killed when overtly leukemic. Cell surface markers were assayed by microcytotoxicity tests, the concentration of MuLV p30 and group-specific MuLV gp 70 was determined by radioimmunoassays and the expression of PA activity was assessed in a fibrin-agar plate method. PA activity of 24 h serum-free culture supernatant, intact cells or cell lysates (2 X 10(5) cells/ml) was expressed in International Units by reference to a urokinase standard curve. Tumor extension and cell morphology were investigated by histologic and cytomorphologic analysis. In all cases the cell lines were derived from T cells. PA activity is not expressed by normal lymphocytes, but variations in PA expression were observed in the transformed cells. Five out of nine transformed cell lines showed PA activity with a range of 1.3 to 9.9 IU/ml. No PA activity could be detected in the other cell lines. No correlation was found between PA expression and the cell-surface-expressed phenotype, neither was there any correlation between the PA content, the cytopathological features and the degree and type of organ infiltration. This lack of correlation indicates that there is no relation between PA activity and the expression of the transformed phenotype, and that the presence of PA activity seems to be irrelevant to the tumorigenic capacities of the transformed cell lines.
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PMID:Heterogeneity of plasminogen activator expression in various Moloney virus-induced tumor cell lines. Lack of correlation with tumor growth and cell phenotype. 653 48

The production of plasminogen activator by the human breast cancer cell line MCF-7 was stimulated by physiological concentrations of estradiol under conditions where the growth of the cells was neither dependent on nor stimulated by estradiol. Stimulation was measurable within 8 hr after the addition of estradiol and was evident in both the level of plasminogen activator released into the culture medium and the level within the cells. The level of production varied with cell density, but production was stimulated by estradiol at all densities tested. The antiestrogen tamoxifen inhibited estrogen stimulation, and this inhibition could be overcome by increased concentrations of estradiol. Production was also stimulated by progesterone and could be stimulated by lower levels of progesterone in cells pretreated with estradiol or tamoxifen, both of which have been reported to increase the level of progesterone receptor in these cells. It has been reported that estrogen is essential and that progesterone is stimulatory for the formation of tumors by MCF-7 cells in athymic mice. The ability of these same two hormones to stimulate the production of plasminogen activator by these cells, under conditions where they have no effect on cell growth, raises the possibility that estrogen may not play a mitogenic role in the growth of these tumors. Rather, it may support tumor growth by inducing the cells to produce products, such as plasminogen activator, and possibly take on other characteristics essential to the malignant state.
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PMID:Steroid stimulation of plasminogen activator production in a human breast cancer cell line (MCF-7). 668 6

The production of plasminogen activator (PA) and its regulation by hormones and other effectors were studied in organ cultures of primary rat and mouse mammary tumors. PA was quantitated using the radioiodinated fibrin plate method. The level of PA in tumor tissue was 10- to 100-fold higher than that in normal rat or mouse mammary glands; the rates of PA secretion were 10- to 1000-fold higher in the tumor cultures. PA production was stimulated by prolactin and pituitary extracts in N-nitrosomethylurea- and 7,12-dimethylbenz(a)anthracene-induced rat tumors but not in mammary tumor virus-induced mouse tumors; hydrocortisone inhibited PA production in all three tumor categories. Sex hormones and agents such as cholera toxin and retinoic acid effectively modulated enzyme production by some tumors. Three major points of interest emerge from our findings: (a) the pattern of tumor PA response to hormones differs qualitatively and quantitatively from that previously determined for the normal mammary; (b) the profile of responses of tumor PA and tumor growth to hormones shows numerous correlations suggesting that these two parameters may be coordinately regulated; (c) pituitary extracts contain an apparently novel factor that stimulates rat mammary tumor PA synthesis.
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PMID:Modulation of plasminogen activator in rodent mammary tumors by hormones and other effectors. 668 1

The quantitative expression of five properties of chemical carcinogen-induced, neoplastically transformed NIH strain 2 guinea pig fibroblasts was compared in cells possessing thousandfold differences in tumorigenicity. Plasminogen activator synthesis, sensitivity to lymphotoxin inhibition of cell proliferation, and the ability to induce a natural delayed tuberculin-type skin reaction in nonimmune syngeneic guinea pigs correlated directly with the number of cells required to produce a tumor. The most tumorigenic cells (10(2)-cell threshold dose) produced the most plasminogen activator, were most sensitive to lymphotoxin, and produced the greatest skin reactivity. Cells with a threshold tumor dose of 10(5)-10(7) cells exhibited the lowest expression of these properties. Fibronectin incorporation into an extracellular matrix was diminished in tumorigenic cells, as was anchorage-dependent growth; but neither diminished fibronectin incorporation nor the decreased anchorage requirement correlated quantitatively with the number of cells required to produce a tumor. The present investigation indicates that plasminogen activator synthesis, sensitivity to lymphotoxin, and the capacity of tumorigenic cells to induce natural delayed-type skin reactivity are among the factors that influence initial tumor growth. Plasminogen activator, an extracellular protease, may aid in the growth and spread of tumor cells in vivo by interfering with host fibrin deposition and by inactivating other host proteins such as lymphotoxin.
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PMID:Plasminogen activator, fibronectin, lymphotoxin sensitivity, and natural skin reactivity relationships to guinea pig cell tumorigenicity. 697 71


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